Genetic Polymorphisms of DNA Repair Genes and DNA Repair Capacity Related to Aflatoxin B1 (AFB1)-Induced DNA

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(B) genotype decreased AFB1-related DNA repair capacity.

Genetic Polymorphisms of DNA Repair Genes and DNA Repair Capacity Related to Aflatoxin B1 (AFB1)-Induced DNA Damages http://dx.doi.org/10.5772/53967 391

**Figure 2.** The meta-analysis of the relationship between genetic polymorphism at codon 399 (Arg/Gln) XRCC1 and AFB1-related HCC risk, a biomarker for DNA repair capacity correlated with AFB1-induced DNA damage, based on overall studies size. Compared with Arg/Arg genotype, Arg/Gln (A) genotype decreased AFB1-related DNA repair ca‐

pacity. This effect was not observed in Gln/Gln genotype (B).

390 New Research Directions in DNA Repair

**Figure 3.** The meta-analysis of the relationship between genetic polymorphism at codon 399 (Arg/Gln) XRCC1 and AFB1-related HCC risk, a biomarker for DNA repair capacity correlated with AFB1-induced DNA damage, based on overall studies size excluded possible repeated studies. Compared with Arg/Arg genotype, Arg/Gln (A) and Gln/Gln (B) genotype decreased AFB1-related DNA repair capacity.

**9. Genetic polymorphisms of DNA repair genes involved in DSBR**

DSBR pathway involves a series of DNA repair genes. In published molecular epidemiologi‐ cal studies, only XRCC3 gene codon Thr241Met polymorphism and XRCC7 rs#7003908

Genetic Polymorphisms of DNA Repair Genes and DNA Repair Capacity Related to Aflatoxin B1 (AFB1)-Induced DNA

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The product of the XRCC3 gene is one of identified paralogs of the strand-exchange protein RAD51 in human beings [188-192]. This protein correlates directly with DNA breaks and fa‐ cilitates of the formation of the RAD51 nucleoprotein filament, which is crucial both for ho‐ mologous recombination and HRR [188-192]. Previous studies have shown that a common polymorphism at codon 241 of XRCC3 gene (Thr to Met) modifies the function of this gene [193-205]. Two reports from high AFB1-exposure areas all of world supported above-men‐

In the first frequent case-control study in Guangxiese [90], we observed that the genotypes with XRCC3 codon 241 Met alleles (namely Thr/Met and Met/Met) was significantly differ‐ ent between controls (33.01%) and HCC cases (61.48%, *P* < 0.001). Met alleles increases about 2- to 10-fold risk of HCC and this running-up risk is modulated by the number of Met alleles (adjusted OR 2.48 and 10.06 for one and two this alleles). Considering small sample size in this study, we recruited, in another independent frequent case-control study [15], a relative‐ ly larger sample size to compare the results. Subjects included in this study, 491 HCC cases and 862 age-, sex, race, hepatitis virus infection information-matching controls, were perma‐ nent residents of Guangxi areas. Similar to the results of the first report, the distribution of XRCC3 codon 241 Met allele frequencies was found to be significantly different between cas‐ es (59.7%) and controls (32.1%). Individuals having the Thr/Met or Met/Met were at a 2.22 fold or 7.19 fold increased risk of developing HCC cancer. Above two studies showed this allele multiplicatively interacted with AFB1 exposure in the process of hepato-tumorigene‐ sis. These results exhibits that the polymorphism at codon 241 of XRCC3 gene is a genetic

DNA repair gene XRCC7, called DNA-dependent protein kinase catalytic subunit (DNA-PKcs), DNAPK, DNPK1, HYRC, HYRC1, or p350) (Genbank ID. 5591), spans about 197 kb on chromosome 8q11 and contains 85 exons and 86 introns (Gene dBase in PubMed). This gene encodes DNA-PKcs that constitutes the large catalytic subunit of the DNA-PK complex. When DNA-PKcs is recruited to the site of DSBs by the Ku70/Ku80 heterodim‐ er, DNA-PK complex changes into its active form and subsequently initiates the non-ho‐ mologous end joining (NHEJ) repair, an important DSBR pathway [206-213]. Murine mutants defective in the XRCC7 have non-detectable DNA-PK activity, suggesting that XRCC7 is required for NHEJ pathway protein. More than 20 polymorphisms have been

**pathway for AFB1-related DNA damage repair**

**9.1. XRCC3**

**9.2. XRCC7**

tioned conclusions [15, 90].

polymorphism affect AFB1-related DNA repair capacity [8, 15, 78].

determinant in AFB1-related DNA repair ability for DSBR pathway.

**Figure 4.** The meta-analysis of the relationship between genetic polymorphism at codon 399 (Arg/Gln) XRCC1 and AFB1-related HCC risk, a biomarker for DNA repair capacity correlated with AFB1-induced DNA damage, based on overall studies size excluded possible repeated studies and studies from low AFB1 exposure areas. Compared with Arg/Arg genotype, Arg/Gln (A) and Gln/Gln (B) genotype decreased AFB1-related DNA repair capacity.

These data support XRCC1 codon 399 Gln alleles decrease AFB1-related DNA repair capaci‐ ty. Additionally, several studies have shown that the other two genetic polymorphisms (at codon 194 and codon 280) of XRCC1 also decrease DNA repair capacity related AFB1-in‐ duced DNA damage, with adjusted value 2.25-2.27 for codon 194 polymorphism and 4.95-6.27 for codon 280 polymorphism (*P* < 0.05) [175]. Furthermore, this decreasing DNA repair ability might more noticeable under the haplotypes with both codon 194 Arg alleles and codon codon 280 His alleles conditions [183].

## **9. Genetic polymorphisms of DNA repair genes involved in DSBR pathway for AFB1-related DNA damage repair**

DSBR pathway involves a series of DNA repair genes. In published molecular epidemiologi‐ cal studies, only XRCC3 gene codon Thr241Met polymorphism and XRCC7 rs#7003908 polymorphism affect AFB1-related DNA repair capacity [8, 15, 78].

#### **9.1. XRCC3**

The product of the XRCC3 gene is one of identified paralogs of the strand-exchange protein RAD51 in human beings [188-192]. This protein correlates directly with DNA breaks and fa‐ cilitates of the formation of the RAD51 nucleoprotein filament, which is crucial both for ho‐ mologous recombination and HRR [188-192]. Previous studies have shown that a common polymorphism at codon 241 of XRCC3 gene (Thr to Met) modifies the function of this gene [193-205]. Two reports from high AFB1-exposure areas all of world supported above-men‐ tioned conclusions [15, 90].

In the first frequent case-control study in Guangxiese [90], we observed that the genotypes with XRCC3 codon 241 Met alleles (namely Thr/Met and Met/Met) was significantly differ‐ ent between controls (33.01%) and HCC cases (61.48%, *P* < 0.001). Met alleles increases about 2- to 10-fold risk of HCC and this running-up risk is modulated by the number of Met alleles (adjusted OR 2.48 and 10.06 for one and two this alleles). Considering small sample size in this study, we recruited, in another independent frequent case-control study [15], a relative‐ ly larger sample size to compare the results. Subjects included in this study, 491 HCC cases and 862 age-, sex, race, hepatitis virus infection information-matching controls, were perma‐ nent residents of Guangxi areas. Similar to the results of the first report, the distribution of XRCC3 codon 241 Met allele frequencies was found to be significantly different between cas‐ es (59.7%) and controls (32.1%). Individuals having the Thr/Met or Met/Met were at a 2.22 fold or 7.19 fold increased risk of developing HCC cancer. Above two studies showed this allele multiplicatively interacted with AFB1 exposure in the process of hepato-tumorigene‐ sis. These results exhibits that the polymorphism at codon 241 of XRCC3 gene is a genetic determinant in AFB1-related DNA repair ability for DSBR pathway.

#### **9.2. XRCC7**

**Figure 4.** The meta-analysis of the relationship between genetic polymorphism at codon 399 (Arg/Gln) XRCC1 and AFB1-related HCC risk, a biomarker for DNA repair capacity correlated with AFB1-induced DNA damage, based on overall studies size excluded possible repeated studies and studies from low AFB1 exposure areas. Compared with

These data support XRCC1 codon 399 Gln alleles decrease AFB1-related DNA repair capaci‐ ty. Additionally, several studies have shown that the other two genetic polymorphisms (at codon 194 and codon 280) of XRCC1 also decrease DNA repair capacity related AFB1-in‐ duced DNA damage, with adjusted value 2.25-2.27 for codon 194 polymorphism and 4.95-6.27 for codon 280 polymorphism (*P* < 0.05) [175]. Furthermore, this decreasing DNA repair ability might more noticeable under the haplotypes with both codon 194 Arg alleles

Arg/Arg genotype, Arg/Gln (A) and Gln/Gln (B) genotype decreased AFB1-related DNA repair capacity.

and codon codon 280 His alleles conditions [183].

392 New Research Directions in DNA Repair

DNA repair gene XRCC7, called DNA-dependent protein kinase catalytic subunit (DNA-PKcs), DNAPK, DNPK1, HYRC, HYRC1, or p350) (Genbank ID. 5591), spans about 197 kb on chromosome 8q11 and contains 85 exons and 86 introns (Gene dBase in PubMed). This gene encodes DNA-PKcs that constitutes the large catalytic subunit of the DNA-PK complex. When DNA-PKcs is recruited to the site of DSBs by the Ku70/Ku80 heterodim‐ er, DNA-PK complex changes into its active form and subsequently initiates the non-ho‐ mologous end joining (NHEJ) repair, an important DSBR pathway [206-213]. Murine mutants defective in the XRCC7 have non-detectable DNA-PK activity, suggesting that XRCC7 is required for NHEJ pathway protein. More than 20 polymorphisms have been reported in the XRCC7 gene, some of which are correlated with malignant tumors such as bladder cancer (dbSNP in NCBI Database). Of these genetic polymorphisms in XRCC7 gene, only two loci (rs7003908 and rs10109984) are investigated their modifying effects on AFB1-related DNA repair capacity [8].

DNA repair proteins encoded by the relative genes and decrease the AFB1-correlated DNA repair capacity. Based on this knowledge, DNA repair capacity related to AFB1-in‐ duced DNA damage can be elucidated via the following three methods: testing the lev‐ els of AFB1-DNA adducts (mainly AFB1-FAPy adduct), analyzing the frequency of

Genetic Polymorphisms of DNA Repair Genes and DNA Repair Capacity Related to Aflatoxin B1 (AFB1)-Induced DNA

Numerous studies reviewed in this paper have demonstrated that the hereditary variations in DNA repair genes are associated with DNA repair capacity of DNA damage induced by AFB1. These molecular epidemiological studies have significantly contributed to our knowl‐ edge of the importance of genetic polymorphisms in DNA repair genes in the individual's susceptibility to AFB1 exposure. It would be expected that genetic susceptibility factors in‐ volved in DNA repair genes for AFB1-induced DNA damage repair could serve as useful biomarkers for identifying at-low-DNA-repair-capacity individuals by AFB1 exposure and,

However, there are several issues to be noted. The conclusions should first be drawn care‐ fully, because of conflicting data existing in the same ethnic population in view of between some genotypes of DNA repair genes and the AFB1-related DNA damage repair capacity. Second, because of the fact that AFB1-related DNA repair is polygenic, no single genetic marker may sufficiently predict DNA repair capacity. Therefore, a panel of susceptive bio‐ markers is warranted to define individuals at low DNA repair capacity. Last, the corre‐ sponding molecular mechanisms of risk types modifying DNA repair capacity correlated

We are grateful to Yuan-Feng Zhou for the collection and management of data. This study is partly supported by the National Nature & Science Foundation of China (NO. 81160255), the Science Foundation of Youjiang Medical College for Nationalities (NO. 2005 and 2008), and

guanyl)-9-hydroxy–AFB1; AFB1-FAPy, ring-opened formamidopyridine AFB1; AFF, afla‐ toxins family; APE1, AP endonuclease-1; BER, base excision repair; CI, confidence interval; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; DSB, double-strand break; DSBR, double-strand break repair; HBV, hepatitis virus B; HCV, hepatitis virus C; HCC, hepatocellular carcinoma; hOGG1, Human oxoguanine glycosylase 1; NER, nucleotide exci‐ sion repair; OR, odds ratio; 8-oxodG, 8-oxodeoxyguanosine; PARP, poly (ADP-ribose) poly‐ merase; PLC, Primary liver cancer; PNK, polynucleotide kinase; Pol β, DNA polymerase β; ROS, reactive oxygen species; SSB, single-strand break; SSBR, single-strand break repair;

Damages

395

http://dx.doi.org/10.5772/53967

TP53M, and evaluating the risk of HCC by AFB1 exposure.

therefore, targeting prevention of this toxicity-related malignant tumor.

with AFB1-induced DNA damages should be paid close attention.

Guangxi Key Construction Project of Laboratory Room (NO. 2009).

AFB1, Aflatoxin B1; AFB1-epoxide, AFB1-8,9-epoxide; AFB1-N7

**Acknowledgments**

**Abbreviations**

In this hospital-based case-control study conducted by Long, *et al*. [8], they found that these individuals with XRCC7 rs7003908 G alleles increased HCC risk compared the homozygote of XRCC7 rs7003908 T alleles (XRCC7-TT), with OR value 3.45 (2.40–4.94) for XRCC7-TG and 5.04 (3.28–7.76) for XRCC7-GG, respectively. Additionally, they also found this genetic polymorphism was correlated with higher the levels of AFB1-DNA adducts (*r* = 0.142, *P* < 0.001). However, another polymorphism rs10109984 did not modify AFB1-related HCC risk (*P* > 0.05). As a result, these data explore that genetic polymorphism of XRCC7 rs7003908 but not rs10109984 might decrease AFB1-related DSBR capacity, inquiring more studies to support this conclusion.

## **10. Future directions**

Recently, great progress has been made in understanding the molecular mechanisms of the genetic susceptibility to DNA repair capacity related to AFB1-induced DNA damages. How‐ ever, we are still far from a comprehensive view of the issue. The molecular mechanism about genetic polymorphisms in the DNA repair genes modifying DNA repair capacity re‐ lated AFB1-induced DNA damages remains largely unknown. Although several reports have shown the spot mutation resulting from genetic polymorphisms may decrease DNA repair capacity via changing the structure of DNA repair proteins, downregulating expres‐ sion of DNA repair genes or decreasing the function of DNA repair genes, more direct evi‐ dence is lost. Disclosing the roles of different genetic types of DNA repair genes in the different toxicity of AFB1 will greatly benefit our understanding of pathological mecha‐ nisms of the genetic polymorphisms in the DNA repair genes affecting DNA repair capacity related to AFB1-induced DNA damage, and will shed important light on the clinical therapy for these patients with risk types.

#### **11. Summary**

AFB1 is an important environment variation of DNA damage. This toxic variation is characterized by: (1) the attraction of specific organs, especially liver; (2) genotoxicity, mainly inducing the formation of AFB1-DNA adducts and the hot-spot mutation of p53 gene; and (3) carcinogenicity, primarily causing HCC. Among these chronic DNA dam‐ age characteristics, AFB1-DNA adducts play a central role because of their genotoxicity and interactions with genetic susceptive factors. In human, there are several repair path‐ ways, including NER, BER, SSBR, and DSBR, is able to repair this type damage. Genetic polymorphisms in DNA repair genes might modify the expression and the functions of DNA repair proteins encoded by the relative genes and decrease the AFB1-correlated DNA repair capacity. Based on this knowledge, DNA repair capacity related to AFB1-in‐ duced DNA damage can be elucidated via the following three methods: testing the lev‐ els of AFB1-DNA adducts (mainly AFB1-FAPy adduct), analyzing the frequency of TP53M, and evaluating the risk of HCC by AFB1 exposure.

Numerous studies reviewed in this paper have demonstrated that the hereditary variations in DNA repair genes are associated with DNA repair capacity of DNA damage induced by AFB1. These molecular epidemiological studies have significantly contributed to our knowl‐ edge of the importance of genetic polymorphisms in DNA repair genes in the individual's susceptibility to AFB1 exposure. It would be expected that genetic susceptibility factors in‐ volved in DNA repair genes for AFB1-induced DNA damage repair could serve as useful biomarkers for identifying at-low-DNA-repair-capacity individuals by AFB1 exposure and, therefore, targeting prevention of this toxicity-related malignant tumor.

However, there are several issues to be noted. The conclusions should first be drawn care‐ fully, because of conflicting data existing in the same ethnic population in view of between some genotypes of DNA repair genes and the AFB1-related DNA damage repair capacity. Second, because of the fact that AFB1-related DNA repair is polygenic, no single genetic marker may sufficiently predict DNA repair capacity. Therefore, a panel of susceptive bio‐ markers is warranted to define individuals at low DNA repair capacity. Last, the corre‐ sponding molecular mechanisms of risk types modifying DNA repair capacity correlated with AFB1-induced DNA damages should be paid close attention.

## **Acknowledgments**

reported in the XRCC7 gene, some of which are correlated with malignant tumors such as bladder cancer (dbSNP in NCBI Database). Of these genetic polymorphisms in XRCC7 gene, only two loci (rs7003908 and rs10109984) are investigated their modifying effects

In this hospital-based case-control study conducted by Long, *et al*. [8], they found that these individuals with XRCC7 rs7003908 G alleles increased HCC risk compared the homozygote of XRCC7 rs7003908 T alleles (XRCC7-TT), with OR value 3.45 (2.40–4.94) for XRCC7-TG and 5.04 (3.28–7.76) for XRCC7-GG, respectively. Additionally, they also found this genetic polymorphism was correlated with higher the levels of AFB1-DNA adducts (*r* = 0.142, *P* < 0.001). However, another polymorphism rs10109984 did not modify AFB1-related HCC risk (*P* > 0.05). As a result, these data explore that genetic polymorphism of XRCC7 rs7003908 but not rs10109984 might decrease AFB1-related DSBR capacity, inquiring more studies to

Recently, great progress has been made in understanding the molecular mechanisms of the genetic susceptibility to DNA repair capacity related to AFB1-induced DNA damages. How‐ ever, we are still far from a comprehensive view of the issue. The molecular mechanism about genetic polymorphisms in the DNA repair genes modifying DNA repair capacity re‐ lated AFB1-induced DNA damages remains largely unknown. Although several reports have shown the spot mutation resulting from genetic polymorphisms may decrease DNA repair capacity via changing the structure of DNA repair proteins, downregulating expres‐ sion of DNA repair genes or decreasing the function of DNA repair genes, more direct evi‐ dence is lost. Disclosing the roles of different genetic types of DNA repair genes in the different toxicity of AFB1 will greatly benefit our understanding of pathological mecha‐ nisms of the genetic polymorphisms in the DNA repair genes affecting DNA repair capacity related to AFB1-induced DNA damage, and will shed important light on the clinical therapy

AFB1 is an important environment variation of DNA damage. This toxic variation is characterized by: (1) the attraction of specific organs, especially liver; (2) genotoxicity, mainly inducing the formation of AFB1-DNA adducts and the hot-spot mutation of p53 gene; and (3) carcinogenicity, primarily causing HCC. Among these chronic DNA dam‐ age characteristics, AFB1-DNA adducts play a central role because of their genotoxicity and interactions with genetic susceptive factors. In human, there are several repair path‐ ways, including NER, BER, SSBR, and DSBR, is able to repair this type damage. Genetic polymorphisms in DNA repair genes might modify the expression and the functions of

on AFB1-related DNA repair capacity [8].

support this conclusion.

394 New Research Directions in DNA Repair

**10. Future directions**

for these patients with risk types.

**11. Summary**

We are grateful to Yuan-Feng Zhou for the collection and management of data. This study is partly supported by the National Nature & Science Foundation of China (NO. 81160255), the Science Foundation of Youjiang Medical College for Nationalities (NO. 2005 and 2008), and Guangxi Key Construction Project of Laboratory Room (NO. 2009).

[7] Yeh FS, Mo CC, Yen RC. Risk factors for hepatocellular carcinoma in Guangxi, Peo‐

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## **Author details**

Qiang Xia1\*, Xiao-Ying Huang2 , Feng Xue1 , Jian-Jun Zhang1 , Bo Zhai1 , De-Chun Kong3 , Chao Wang2 , Zhao-Quan Huang2 and Xi-Dai Long1\*

\*Address all correspondence to<EMAIL_ADDRESS>
\*Address all correspondence to<EMAIL_ADDRESS>
1 Department of Liver Surgery, the Affiliated Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China

2 Department of Pathology, the Affiliated Hospital, Youjiang Medical College for Nationali‐ ties, Baise, P.R. China

3 Department of Physiology, the Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China

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XPA, xeroderma pigmentosum A; XPC, xeroderma pigmentosum C; XPD, xeroderma pig‐ mentosum D; XRCC1, x-ray repair cross complementary 1; XRCC3, x-ray repair cross com‐ plementary 3; XRCC4, x-ray repair cross complementary 4; XRCC7, x-ray repair cross

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3 Department of Physiology, the Basic Medicine, Shanghai Jiao Tong University School of

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**Chapter 16**

**DNA Damage, DNA Repair and Cancer**

DNA damage appears to be a fundamental problem for life. In this chapter we review evi‐ dence indicating that DNA damages are a major primary cause of cancer. DNA damages give rise to mutations and epimutations that, by a process of natural selection, can cause progression to cancer. First, we describe the distinguishing characteristics of DNA damage,

DNA damage is a change in the basic structure of DNA that is not itself replicated when the DNA is replicated. A DNA damage can be a chemical addition or disruption to a base of DNA (creating an abnormal nucleotide or nucleotide fragment) or a break in one or both chains of the DNA strands. When DNA carrying a damaged base is replicated, an incorrect base can often be inserted opposite the site of the damaged base in the complementary strand, and this can become a mutation in the next round of replication. Also DNA doublestrand breaks may be repaired by an inaccurate repair process leading to mutations. In addi‐ tion, a double strand break can cause rearrangements of the chromosome structure (possibly disrupting a gene, or causing a gene to come under abnormal regulatory control), and, if such a change can be passed to successive cell generations, it is also a form of mutation. Mu‐ tations, however, can be avoided if accurate DNA repair systems recognize DNA damages as abnormal structures, and repair the damages prior to replication. As illustrated in Figure 1, when DNA damages occur, DNA repair is a crucial protective process blocking entry of

We note that DNA damages occur in both replicating, proliferative cells (e.g. those forming the internal lining of the colon or blood forming "hematopoietic" cells), and in differentiat‐ ed, non-dividing cells (e.g. neurons in the brain or myocytes in muscle). Cancers occur pri‐ marily in proliferative tissues. If DNA damages in proliferating cells are not repaired due to

and reproduction in any medium, provided the original work is properly cited.

© 2013 Bernstein et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

Carol Bernstein, Anil R. Prasad,

http://dx.doi.org/10.5772/53919

**1. Introduction**

mutation and epimutation.

cells into carcinogenesis.

Valentine Nfonsam and Harris Bernstein

Additional information is available at the end of the chapter

## **DNA Damage, DNA Repair and Cancer**

Carol Bernstein, Anil R. Prasad, Valentine Nfonsam and Harris Bernstein

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53919

**1. Introduction**

[210] Smider V, Chu G. The end-joining reaction in V(D)J recombination. Semin Immunol,

[211] Jolly CJ, Cook AJ, Manis JP. Fixing DNA breaks during class switch recombination.

[212] Sipley JD, Menninger JC, Hartley KO, et al. Gene for the catalytic subunit of the hu‐ man DNA-activated protein kinase maps to the site of the XRCC7 gene on chromo‐

[213] Johnston PJ, MacPhail SH, Stamato TD, et al. Higher-order chromatin structure-de‐ pendent repair of DNA double-strand breaks: involvement of the V(D)J recombina‐

tion double-strand break repair pathway. Radiat Res, 1998; 149(5): 455-462.

The Journal of experimental medicine, 2008; 205(3): 509-513.

some 8. Proc Natl Acad Sci U S A, 1995; 92(16): 7515-7519.

1997; 9(3): 189-197.

412 New Research Directions in DNA Repair

DNA damage appears to be a fundamental problem for life. In this chapter we review evi‐ dence indicating that DNA damages are a major primary cause of cancer. DNA damages give rise to mutations and epimutations that, by a process of natural selection, can cause progression to cancer. First, we describe the distinguishing characteristics of DNA damage, mutation and epimutation.

DNA damage is a change in the basic structure of DNA that is not itself replicated when the DNA is replicated. A DNA damage can be a chemical addition or disruption to a base of DNA (creating an abnormal nucleotide or nucleotide fragment) or a break in one or both chains of the DNA strands. When DNA carrying a damaged base is replicated, an incorrect base can often be inserted opposite the site of the damaged base in the complementary strand, and this can become a mutation in the next round of replication. Also DNA doublestrand breaks may be repaired by an inaccurate repair process leading to mutations. In addi‐ tion, a double strand break can cause rearrangements of the chromosome structure (possibly disrupting a gene, or causing a gene to come under abnormal regulatory control), and, if such a change can be passed to successive cell generations, it is also a form of mutation. Mu‐ tations, however, can be avoided if accurate DNA repair systems recognize DNA damages as abnormal structures, and repair the damages prior to replication. As illustrated in Figure 1, when DNA damages occur, DNA repair is a crucial protective process blocking entry of cells into carcinogenesis.

We note that DNA damages occur in both replicating, proliferative cells (e.g. those forming the internal lining of the colon or blood forming "hematopoietic" cells), and in differentiat‐ ed, non-dividing cells (e.g. neurons in the brain or myocytes in muscle). Cancers occur pri‐ marily in proliferative tissues. If DNA damages in proliferating cells are not repaired due to

© 2013 Bernstein et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

inadequate expression of a DNA repair gene, this increases the risk of cancer. In contrast, when DNA damages occur in non-proliferating cells and are not repaired due to inadequate expression of a DNA repair gene, the damages can accumulate and cause premature aging. As examples, deficiencies in DNA repair genes *ERCC1* or *XPF* [1] or in *WRN* [2, 3] cause both increased risk of cancer as well as premature aging. In Figure 1, DNA repair is indicat‐ ed as a crucial process impeding both cancer and premature aging.

A mutation is a change in the DNA sequence in which normal base pairs are substituted, added, deleted or rearranged. The DNA containing a mutation still consists of a sequence of standard base pairs, and the altered DNA sequence can be copied when the DNA is replicat‐ ed. A mutation can prevent a gene from carrying out its function, or it can cause a gene to be translated into a protein that functions abnormally. Mutations can activate oncogenes, inac‐ tivate tumor suppressor genes or cause genomic instability in replicating cells, and an as‐ semblage of such mutations, together in the same cell, can lead to cancer. Cancers usually arise from an assemblage of mutations conferring a selective advantage that leads to clonal expansion (Figure 1). Colon cancers, for example, have an average of 15 "driver" mutations (mutations occurring repeatedly in different colon cancers) and about 75 "passenger" muta‐ tions (mutations occurring infrequently in colon cancers) [4, 5]. Colon cancers also were found to have an average of 9 duplications or deletions of chromosome segments [6] or, more recently, 17 focal amplifications, 28 recurrent deletions and up to 10 translocations [5]. Since mutations have normal DNA structure, they cannot be recognized or removed by DNA repair processes in living cells. Removal of a mutation only occurs if it is sufficiently

DNA Damage, DNA Repair and Cancer http://dx.doi.org/10.5772/53919 415

Another type of inheritable alteration, similar in some ways to a mutation, is an epige‐ netic change. An epigenetic change refers to a functionally relevant modification of the DNA, or of the histone proteins controlling the relaxation or tightened winding of the DNA within their nucleosome structures. Some epigenetic changes involve specific altera‐ tions of the DNA nucleotides. Examples of such changes include methylation of the DNA at particular sites (CpG islands) where the DNA starts to be transcribed into RNA. These changes may inhibit transcription. Other epigenetic changes involve modification of histones associated with particular regions of the DNA. These may inhibit or promote the ability of these regions to be transcribed into mRNA. Methylation of CpG islands or modification of histones can directly alter transcription of gene-encoded mRNAs but they can also occur in parts of the genome that code for microRNAs (miRNAs). MiRNAs are endogenous short non-protein coding RNAs (~22 nucleotides long) that post-tran‐ scriptionally regulate mRNA expression in a sequence specific manner. miRNAs either cause degradation of mRNAs or block their translation. Epigenetic modifications can play a role similar to mutation in carcinogenesis, and about 280 cancer prone epigenetic alterations are listed by Schnekenburger and Diederich [7]. Epigenetic alterations are usu‐ ally copied onto the daughter chromosomes when the parental chromosome replicates.

Although epigenetic changes can be passed down from one cell generation to the next, they are not regarded as true mutations. Most epigenetic changes appear to be part of the differentiation program of the cell and are necessary to allow different types of cells to carry out different functions. In most cells of a human body, only about 5% of genes are active at any one time, often due to epigenetic modifications. However, abnormal un‐ programmed epigenetic changes may also occur that alter the functioning of a cell and these changes are referred to as "epimutations." Programmed epigenetic changes can be reversed. During development, as daughter cells of a stem cell differentiate, some epige‐

deleterious to cause the death of the cell.

**Figure 1.** The roles of DNA damage and DNA repair in cancer and aging.

A mutation is a change in the DNA sequence in which normal base pairs are substituted, added, deleted or rearranged. The DNA containing a mutation still consists of a sequence of standard base pairs, and the altered DNA sequence can be copied when the DNA is replicat‐ ed. A mutation can prevent a gene from carrying out its function, or it can cause a gene to be translated into a protein that functions abnormally. Mutations can activate oncogenes, inac‐ tivate tumor suppressor genes or cause genomic instability in replicating cells, and an as‐ semblage of such mutations, together in the same cell, can lead to cancer. Cancers usually arise from an assemblage of mutations conferring a selective advantage that leads to clonal expansion (Figure 1). Colon cancers, for example, have an average of 15 "driver" mutations (mutations occurring repeatedly in different colon cancers) and about 75 "passenger" muta‐ tions (mutations occurring infrequently in colon cancers) [4, 5]. Colon cancers also were found to have an average of 9 duplications or deletions of chromosome segments [6] or, more recently, 17 focal amplifications, 28 recurrent deletions and up to 10 translocations [5]. Since mutations have normal DNA structure, they cannot be recognized or removed by DNA repair processes in living cells. Removal of a mutation only occurs if it is sufficiently deleterious to cause the death of the cell.

inadequate expression of a DNA repair gene, this increases the risk of cancer. In contrast, when DNA damages occur in non-proliferating cells and are not repaired due to inadequate expression of a DNA repair gene, the damages can accumulate and cause premature aging. As examples, deficiencies in DNA repair genes *ERCC1* or *XPF* [1] or in *WRN* [2, 3] cause both increased risk of cancer as well as premature aging. In Figure 1, DNA repair is indicat‐

ed as a crucial process impeding both cancer and premature aging.

414 New Research Directions in DNA Repair

**Figure 1.** The roles of DNA damage and DNA repair in cancer and aging.

Another type of inheritable alteration, similar in some ways to a mutation, is an epige‐ netic change. An epigenetic change refers to a functionally relevant modification of the DNA, or of the histone proteins controlling the relaxation or tightened winding of the DNA within their nucleosome structures. Some epigenetic changes involve specific altera‐ tions of the DNA nucleotides. Examples of such changes include methylation of the DNA at particular sites (CpG islands) where the DNA starts to be transcribed into RNA. These changes may inhibit transcription. Other epigenetic changes involve modification of histones associated with particular regions of the DNA. These may inhibit or promote the ability of these regions to be transcribed into mRNA. Methylation of CpG islands or modification of histones can directly alter transcription of gene-encoded mRNAs but they can also occur in parts of the genome that code for microRNAs (miRNAs). MiRNAs are endogenous short non-protein coding RNAs (~22 nucleotides long) that post-tran‐ scriptionally regulate mRNA expression in a sequence specific manner. miRNAs either cause degradation of mRNAs or block their translation. Epigenetic modifications can play a role similar to mutation in carcinogenesis, and about 280 cancer prone epigenetic alterations are listed by Schnekenburger and Diederich [7]. Epigenetic alterations are usu‐ ally copied onto the daughter chromosomes when the parental chromosome replicates.

Although epigenetic changes can be passed down from one cell generation to the next, they are not regarded as true mutations. Most epigenetic changes appear to be part of the differentiation program of the cell and are necessary to allow different types of cells to carry out different functions. In most cells of a human body, only about 5% of genes are active at any one time, often due to epigenetic modifications. However, abnormal un‐ programmed epigenetic changes may also occur that alter the functioning of a cell and these changes are referred to as "epimutations." Programmed epigenetic changes can be reversed. During development, as daughter cells of a stem cell differentiate, some epige‐ netic changes are programmed for reversal. However, a double strand break in DNA (a type of DNA damage) can initiate unprogrammed epigenetic gene silencing both by causing methylation of a CpG island as well as by promoting silencing types of histone modifications [8]. Another form of epigenetic silencing may occur during DNA repair. The enzyme Parp1 (poly(ADP)-ribose polymerase) and its product poly(ADP)-ribose (PAR) accumulate at sites of DNA damage as part of a repair process [9]. This, in turn, directs recruitment and activation of the chromatin remodeling protein ALC1 that may cause nucleosome remodeling [10]. Nucleosome remodeling has been found to cause, for instance, epigenetic silencing of DNA repair gene *MLH1* [11]. Chemicals previously iden‐ tified as DNA damaging agents, including benzene, hydroquinone, styrene, carbon tetra‐ chloride and trichloroethylene, were shown to cause considerable hypomethylation of DNA, some through the activation of oxidative stress pathways [12]. Dietary agents also have been shown to affect DNA methylation or histone modification by numerous path‐ ways [13]. Recent evidence indicates that epimutations occur in DNA repair genes that reduce their function. Epimutations in DNA repair genes allow DNA damages to accu‐ mulate, and are a cause of progression to cancer [14].

**DNA damages Reported rate of occurrence Ref.**

10,000 per cell per day in humans 100,000 per cell per day in rats

11,500 per cell per day for humans 74,000 per cell per day for rats

2,800 per cell per day in humans 34,800 per cell per day in mice

86,000 per cell per day in rats [18]

10,000 per cell during 20-hour generation period [21]

13,920 per cell per day (580/cell/hr) [22]

2,000 to 10,000 per cell per day [23,24]

9,000 per cell per day [25]

696 per cell per day (29/cell/hr) [22]

~10 per cell cycle in humans [26]

~50 per cell cycle in humans [27]

500 pyrimidines per cell during 20-hour generation

period

Single-strand breaks 55,200 per cell per day (2,300/cell/hr) [22]

O6-methylguanine 3,120 per cell per day (130/cell/hr) [22]

Cytosine deamination 192 per cell per day (8/cell/hr) [22]

**Table 1.** DNA damages due to natural endogenous causes in mammalian cells

[19]

417

DNA Damage, DNA Repair and Cancer http://dx.doi.org/10.5772/53919

[16]

[20]

[21]

Oxidative

Specific oxidative damage products 8-

(hydroxymethyl) uracil

Depurinations

Depyrimidinations

Double-strand breaks

hydroxyguanine, 8-hydroxydeoxyguanosine, 5-

## **2. DNA damages are frequent, and DNA repair processes can be overwhelmed**

Tens of thousands of DNA damages occur per day per cell, on average, in humans, due to reactive molecules produced by metabolism or by hydrolytic reactions in the warm aqueous cellular media. Some types of such endogenous damages, and their rates of occurrence, are shown in Table 1.

A considerable number of other types of endogenous DNA damages have been identified, many of which are mutagenic. These include propano-, etheno- and malondialdehyde-de‐ rived DNA adducts, base propenals, estrogen-DNA adducts, alkylated bases, deamination of each of cytosine, adenine and guanine (to form uracil, hypoxanthine and xanthine, re‐ spectively) and adducts formed with DNA by reactive carbonyl species [15].

While there are repair pathways that act on these DNA damages, the repair processes are not 100% efficient, and further damages occur even as current DNA damages are being re‐ paired. Thus there is a steady state level of many DNA damages, reflecting the efficiencies of repair and the frequencies of occurrence. For instance, Helbock et al. [16] estimated the steady state level of oxidative adducts in rat liver as 24, 000 adducts per cell in young rats and 66, 000 adducts per cell in old rats. Nakamura and Swenberg [17] determined the num‐ ber of AP sites (apurinc and apyrimidinic sites) in normal tissues of the rat (i.e. in lung, kid‐ ney, liver, testis, heart, colon and brain). The data indicated that the number of AP sites ranged from about 50, 000 per cell in liver, kidney and lung to about 200, 000 per cell in the brain. These steady state numbers of AP sites in genomic DNA were considered to represent the balance between formation and repair of AP sites.

**Table 1.** DNA damages due to natural endogenous causes in mammalian cells

netic changes are programmed for reversal. However, a double strand break in DNA (a type of DNA damage) can initiate unprogrammed epigenetic gene silencing both by causing methylation of a CpG island as well as by promoting silencing types of histone modifications [8]. Another form of epigenetic silencing may occur during DNA repair. The enzyme Parp1 (poly(ADP)-ribose polymerase) and its product poly(ADP)-ribose (PAR) accumulate at sites of DNA damage as part of a repair process [9]. This, in turn, directs recruitment and activation of the chromatin remodeling protein ALC1 that may cause nucleosome remodeling [10]. Nucleosome remodeling has been found to cause, for instance, epigenetic silencing of DNA repair gene *MLH1* [11]. Chemicals previously iden‐ tified as DNA damaging agents, including benzene, hydroquinone, styrene, carbon tetra‐ chloride and trichloroethylene, were shown to cause considerable hypomethylation of DNA, some through the activation of oxidative stress pathways [12]. Dietary agents also have been shown to affect DNA methylation or histone modification by numerous path‐ ways [13]. Recent evidence indicates that epimutations occur in DNA repair genes that reduce their function. Epimutations in DNA repair genes allow DNA damages to accu‐

mulate, and are a cause of progression to cancer [14].

the balance between formation and repair of AP sites.

**overwhelmed**

416 New Research Directions in DNA Repair

shown in Table 1.

**2. DNA damages are frequent, and DNA repair processes can be**

spectively) and adducts formed with DNA by reactive carbonyl species [15].

Tens of thousands of DNA damages occur per day per cell, on average, in humans, due to reactive molecules produced by metabolism or by hydrolytic reactions in the warm aqueous cellular media. Some types of such endogenous damages, and their rates of occurrence, are

A considerable number of other types of endogenous DNA damages have been identified, many of which are mutagenic. These include propano-, etheno- and malondialdehyde-de‐ rived DNA adducts, base propenals, estrogen-DNA adducts, alkylated bases, deamination of each of cytosine, adenine and guanine (to form uracil, hypoxanthine and xanthine, re‐

While there are repair pathways that act on these DNA damages, the repair processes are not 100% efficient, and further damages occur even as current DNA damages are being re‐ paired. Thus there is a steady state level of many DNA damages, reflecting the efficiencies of repair and the frequencies of occurrence. For instance, Helbock et al. [16] estimated the steady state level of oxidative adducts in rat liver as 24, 000 adducts per cell in young rats and 66, 000 adducts per cell in old rats. Nakamura and Swenberg [17] determined the num‐ ber of AP sites (apurinc and apyrimidinic sites) in normal tissues of the rat (i.e. in lung, kid‐ ney, liver, testis, heart, colon and brain). The data indicated that the number of AP sites ranged from about 50, 000 per cell in liver, kidney and lung to about 200, 000 per cell in the brain. These steady state numbers of AP sites in genomic DNA were considered to represent DNA repair pathways are usually able to keep up with the endogenous damages in rep‐ licating cells, in part by halting DNA replication at the site of damage until repair can occur [28, 29]. In contrast, non-replicating cells have a build-up of DNA damages, caus‐ ing aging [30, 31].

**More developed areas Less developed areas**

DNA Damage, DNA Repair and Cancer http://dx.doi.org/10.5772/53919 419

*Incidence Mortality Incidence Mortality*

7.0 2.2 2.8 1.9

**Table 2.** Incidence and mortality rates for the most common cancers in age standardized rates per 100, 000 (excluding

Carcinogenic exogenous factors have been identified as a major cause of many common can‐ cers, including cancers of the lung, colorectum, esophagus, stomach, liver, cervix/uterus and melanoma. Often such exogenous factors have been shown to cause DNA damage, as de‐

Melanoma (men) 9.5 1.8 0.7 0.3 Melanoma (women) 8.6 1.1 0.6 0.3 Ovarian (women) 9.4 5.1 5.0 3.1

**4. Exogenous DNA damaging agents in carcinogenesis**

non-melanoma skin cancer) (Adapted from Jemal et al. [35]).

Breast (women) 66.4 15.3 27.3 10.8 Prostate (men) 62.0 10.6 12.0 5.6 Lung (men) 47.4 39.4 27.8 24.6 Lung (women) 18.6 13.6 11.1 9.7 Colorectum (men) 37.6 15.1 12.1 6.9 Colorectum (women) 24.2 9.7 9.4 5.4 Esophagus (men) 6.5 5.3 11.8 10.1 Esophagus (women) 1.2 1.0 5.7 4.7 Stomach (men) 16.7 10.4 21.1 16.0 Stomach (women) 7.3 4.7 10.0 8.1 Liver (men) 8.1 7.2 18.9 17.4 Liver (women) 2.7 2.5 7.6 7.2 Bladder (men) 16.6 4.6 5.4 2.6 Bladder (women) 3.6 1.0 1.4 0.7 Cervix/Uterine (women) 12.9 2.4 5.9 1.7 Kidney (men) 11.8 4.1 2.5 1.3 Kidney (women) 5.8 1.7 1.4 0.8 Non-Hodgkin lymphoma (men) 10.3 3.6 4.2 3.0

Non-Hodgkin lymphoma

scribed below.

(women)

However, some exogenous DNA damaging agents, such as those in tobacco smoke, dis‐ cussed below, may overload the repair pathways, either with higher levels of the same type of DNA damages as those occurring endogenously or with novel types of damage that are repaired more slowly. In addition, if DNA repair pathways are deficient, due to inherited mutations or sporadic somatic epimutations in DNA repair genes in replicating somatic cells, unrepaired endogenous and exogenous damages will increase due to insufficient re‐ pair. Increased DNA damages would likely give rise to increased errors of replication past the damages (by trans-lesion synthesis) or increased error prone repair (e.g. by non-homolo‐ gous end-joining), causing mutations. Increased mutations that activate oncogenes, inacti‐ vate tumor suppressor genes, cause genomic instability or give rise to other driver mutations in replicating cells would increase the risk of cancer.

#### **3. Cancers are often caused by exogenous DNA damaging agents**

Cancer incidence, in different areas of the world, varies considerably. Thus, the incidence of colon cancer among Black Native-Africans is less than 1 person out of 100, 000, while among male Black African-Americans it is 72.9 per 100, 000, and this difference is likely due to dif‐ ferences in diet [32, 33]. Rates of colon cancer incidence among populations migrating from lower-incidence to higher-incidence countries change rapidly, and within one generation can reach the rate in the higher-incidence country. This is observed, for instance, in migrants from Japan to Hawaii [34].

The most common cancers for men and women and their rates of incidence per 100, 000, averaged over the more developed areas and less developed areas of the world, are shown in Table 2 (from [35]). Overall, worldwide, cancer incidence in all organs combined is 300.1 per 100, 000 per year in more developed areas and 160.3 per 100, 000 per year in less devel‐ oped areas [35]. The differences in cancer incidence between more developed areas of the world and less developed areas are likely due, in large part, to differences in exposure to exogenous carcinogenic factors. The lowest rates of cancers in a given organ (Table 2) may be due, at least in part, to endogenous DNA damages (as described in the previous section) that cause errors of replication (trans-lesion synthesis) or error prone repair (e.g. non-homol‐ ogous end-joining), leading to carcinogenic mutations. The higher rates (Table 2) are likely largely attributable to exogenous factors, such as higher rates of tobacco use or diets higher in saturated fats that directly, or indirectly, increase the incidence of DNA damage.

It is interesting to note in Table 2 that, in cases where cancers occur in the same organs of men and women, men consistently have a higher rate of cancer than women. The basis for this is currently unknown.

DNA repair pathways are usually able to keep up with the endogenous damages in rep‐ licating cells, in part by halting DNA replication at the site of damage until repair can occur [28, 29]. In contrast, non-replicating cells have a build-up of DNA damages, caus‐

However, some exogenous DNA damaging agents, such as those in tobacco smoke, dis‐ cussed below, may overload the repair pathways, either with higher levels of the same type of DNA damages as those occurring endogenously or with novel types of damage that are repaired more slowly. In addition, if DNA repair pathways are deficient, due to inherited mutations or sporadic somatic epimutations in DNA repair genes in replicating somatic cells, unrepaired endogenous and exogenous damages will increase due to insufficient re‐ pair. Increased DNA damages would likely give rise to increased errors of replication past the damages (by trans-lesion synthesis) or increased error prone repair (e.g. by non-homolo‐ gous end-joining), causing mutations. Increased mutations that activate oncogenes, inacti‐ vate tumor suppressor genes, cause genomic instability or give rise to other driver

mutations in replicating cells would increase the risk of cancer.

**3. Cancers are often caused by exogenous DNA damaging agents**

Cancer incidence, in different areas of the world, varies considerably. Thus, the incidence of colon cancer among Black Native-Africans is less than 1 person out of 100, 000, while among male Black African-Americans it is 72.9 per 100, 000, and this difference is likely due to dif‐ ferences in diet [32, 33]. Rates of colon cancer incidence among populations migrating from lower-incidence to higher-incidence countries change rapidly, and within one generation can reach the rate in the higher-incidence country. This is observed, for instance, in migrants

The most common cancers for men and women and their rates of incidence per 100, 000, averaged over the more developed areas and less developed areas of the world, are shown in Table 2 (from [35]). Overall, worldwide, cancer incidence in all organs combined is 300.1 per 100, 000 per year in more developed areas and 160.3 per 100, 000 per year in less devel‐ oped areas [35]. The differences in cancer incidence between more developed areas of the world and less developed areas are likely due, in large part, to differences in exposure to exogenous carcinogenic factors. The lowest rates of cancers in a given organ (Table 2) may be due, at least in part, to endogenous DNA damages (as described in the previous section) that cause errors of replication (trans-lesion synthesis) or error prone repair (e.g. non-homol‐ ogous end-joining), leading to carcinogenic mutations. The higher rates (Table 2) are likely largely attributable to exogenous factors, such as higher rates of tobacco use or diets higher

in saturated fats that directly, or indirectly, increase the incidence of DNA damage.

It is interesting to note in Table 2 that, in cases where cancers occur in the same organs of men and women, men consistently have a higher rate of cancer than women. The basis for

ing aging [30, 31].

418 New Research Directions in DNA Repair

from Japan to Hawaii [34].

this is currently unknown.

**Table 2.** Incidence and mortality rates for the most common cancers in age standardized rates per 100, 000 (excluding non-melanoma skin cancer) (Adapted from Jemal et al. [35]).

## **4. Exogenous DNA damaging agents in carcinogenesis**

Carcinogenic exogenous factors have been identified as a major cause of many common can‐ cers, including cancers of the lung, colorectum, esophagus, stomach, liver, cervix/uterus and melanoma. Often such exogenous factors have been shown to cause DNA damage, as de‐ scribed below.

## **5. Exogenous DNA damaging agents in lung cancer**

In both developed and undeveloped countries, lung cancer is the most frequent cause of cancer mortality (Table 2, data for men and women combined). Lung cancer is large‐ ly caused by tobacco smoke, since risk estimates for lung cancer indicate that, in the United States, tobacco smoke is responsible for 90% of lung cancers. Also implicated in lung cancer (and somewhat overlapping with smoking) are occupational exposure to carcinogens (approximately 9 to 15%), radon (10%) and outdoor air pollution (perhaps 1 to 2%) [36].

al. [39], benzo[a]pyrene damages DNA by forming DNA adducts at the N2 position of gua‐ nine (similar to where acrolein forms adducts). However, by the "Margin of Exposure" ap‐ proach, based on published dose response data and its concentration in cigarette smoke of 0.014 μg per cigarette, benzo[a]pyrene is thought to be a much less important mutagen for lung tissue than acrolein and the other six highly likely carcinogens in tobacco smoke listed

DNA Damage, DNA Repair and Cancer http://dx.doi.org/10.5772/53919 421

The other agents in Table 3 cause DNA damages in different ways. Formaldehyde, the sec‐ ond agent in Table 3, primarily causes DNA damage by introducing DNA-protein crosslinks. These cross-links, in turn, cause mutagenic deletions or other small-scale chromosomal rearrangements [40] and may also cause mutations through single-nucleotide insertions [41]. Acrylonitrile, the third agent in Table 3, appears to cause DNA damage indi‐ rectly by increasing oxidative stress, leading to increased levels of 8'-hydroxyl-2-deoxygua‐ nosine (8-OHdG) in DNA [42]. Oxidative stress also causes lipid peroxidation that generates malondialdehyde (MDA), and MDA forms DNA adducts with guanine, adenine and cyto‐ sine [43]. The fourth agent in Table 3, 1, 3-butadiene, causes genotoxicity both directly by forming a DNA adduct as well as indirectly by causing global loss of DNA methylation and histone methylation leading to epigenetic alterations [44]. The fifth agent in Table 3, acetal‐ dehyde, reacts with 2'-deoxyguanosine in DNA to form DNA adducts [45]. The sixth agent in Table 3, ethylene oxide, forms mutagenic hydroxyethyl DNA adducts with adenine and guanine [46]. The seventh agent in Table 3, isoprene, is normally produced endogenously by humans, and is the main hydrocarbon of non-smoking human breath [47]. However, smok‐ ing one cigarette causes an increase of breath isoprene levels by an average of 70% [48]. Iso‐ prene, after being metabolized to mono-epoxides, causes DNA damage measured as single

A large number of studies have been published in which the levels and characteristics of DNA adducts in the lung and bronchus of smokers and non-smokers have been compared, as reviewed by Phillips [50]. In most of these studies, significantly elevated levels of DNA adducts were detected in the peripheral lung, bronchial epithelium or bronchioalveolar lav‐ age cells of the smokers, especially for total bulky DNA adducts. As further discussed by Phillips [50], mean levels of DNA adducts in ex-smokers (usually with at least a 1 year inter‐ val since smoking cessation) are found generally to be intermediate between the levels of smokers and life-long non-smokers. From these comparisons, the half-life of some DNA ad‐

Up to 20% of current colorectal cancers in the United States may be due to tobacco smoke [51].  These agents may be taken up in the blood and carried to or‐

in Table 3 [37].

and double strand breaks in DNA [49].

ducts in lung tissue are estimated to be ~1–2 years.

gans of the body.

**6. Exogenous DNA damaging agents in colorectal cancer**

**Table 3.** Weight, in μg per cigarette, of several likely carcinogenic DNA damaging agents in tobacco smoke (from [37] Cunningham et al., 2011])

Tobacco smoke is a complex mixture of over 5, 300 identified chemicals, of which 150 are known to have specific toxicological properties (see partial summary by Cunningham [37]). A "Margin of Exposure" approach has recently been established to determine the most im‐ portant exogenous carcinogenic factors in tobacco smoke [37]. This quantitative-type of measurement is based on published dose response data for mutagenicity or carcinogenicity and the concentrations of these components in tobacco smoke (Table 3). Using the "Margin of Exposure" approach, Cunningham et al. [37] found the most important tumorigenic com‐ pounds in tobacco smoke to be, in order of importance, acrolein, formaldehyde, acryloni‐ trile, 1, 3-butadiene, acetaldehyde, ethylene oxide and isoprene.

Acrolein, the first agent in Table 3, is the structurally simplest α, β-unsaturated aldehyde (Figure 2). It can rapidly penetrate through the cell membrane and bind to the nucleophilic N2 -amine of deoxyguanine (dG) followed by cyclization of N1, to give the exocyclic DNA adduct α-hydroxy-1, N2 -propano-2'-deoxyguanine (α-HOPdG) (shown in Figure 2) and an‐ other product designated γ-HOPdG. The adducts formed by acrolein are a major type of DNA damage caused by tobacco smoke, and acrolein has been found to be mutagenic [38].

In tobacco smoke, acrolein has a concentration >8, 000 fold higher than benzo[a]pyrene (re‐ viewed in [38]), with 122.4 μg of acrolein per cigarette. Benzo[a]pyrene has long been thought to be an important carcinogen in tobacco smoke [39]. As reviewed by Alexandrov et al. [39], benzo[a]pyrene damages DNA by forming DNA adducts at the N2 position of gua‐ nine (similar to where acrolein forms adducts). However, by the "Margin of Exposure" ap‐ proach, based on published dose response data and its concentration in cigarette smoke of 0.014 μg per cigarette, benzo[a]pyrene is thought to be a much less important mutagen for lung tissue than acrolein and the other six highly likely carcinogens in tobacco smoke listed in Table 3 [37].

**5. Exogenous DNA damaging agents in lung cancer**

Acrolein 122.4 Formaldehyde 60.5 Acrylonitrile 29.3 1,3-butadiene 105.0 Acetaldehyde 1448.0 Ethylene oxide 7.0 Isoprene 952.0 Benzo[a]pyrene 0.014

trile, 1, 3-butadiene, acetaldehyde, ethylene oxide and isoprene.

to 2%) [36].

420 New Research Directions in DNA Repair

Cunningham et al., 2011])

adduct α-hydroxy-1, N2

N2

In both developed and undeveloped countries, lung cancer is the most frequent cause of cancer mortality (Table 2, data for men and women combined). Lung cancer is large‐ ly caused by tobacco smoke, since risk estimates for lung cancer indicate that, in the United States, tobacco smoke is responsible for 90% of lung cancers. Also implicated in lung cancer (and somewhat overlapping with smoking) are occupational exposure to carcinogens (approximately 9 to 15%), radon (10%) and outdoor air pollution (perhaps 1

**Table 3.** Weight, in μg per cigarette, of several likely carcinogenic DNA damaging agents in tobacco smoke (from [37]

Tobacco smoke is a complex mixture of over 5, 300 identified chemicals, of which 150 are known to have specific toxicological properties (see partial summary by Cunningham [37]). A "Margin of Exposure" approach has recently been established to determine the most im‐ portant exogenous carcinogenic factors in tobacco smoke [37]. This quantitative-type of measurement is based on published dose response data for mutagenicity or carcinogenicity and the concentrations of these components in tobacco smoke (Table 3). Using the "Margin of Exposure" approach, Cunningham et al. [37] found the most important tumorigenic com‐ pounds in tobacco smoke to be, in order of importance, acrolein, formaldehyde, acryloni‐

Acrolein, the first agent in Table 3, is the structurally simplest α, β-unsaturated aldehyde (Figure 2). It can rapidly penetrate through the cell membrane and bind to the nucleophilic

other product designated γ-HOPdG. The adducts formed by acrolein are a major type of DNA damage caused by tobacco smoke, and acrolein has been found to be mutagenic [38].

In tobacco smoke, acrolein has a concentration >8, 000 fold higher than benzo[a]pyrene (re‐ viewed in [38]), with 122.4 μg of acrolein per cigarette. Benzo[a]pyrene has long been thought to be an important carcinogen in tobacco smoke [39]. As reviewed by Alexandrov et

The other agents in Table 3 cause DNA damages in different ways. Formaldehyde, the sec‐ ond agent in Table 3, primarily causes DNA damage by introducing DNA-protein crosslinks. These cross-links, in turn, cause mutagenic deletions or other small-scale chromosomal rearrangements [40] and may also cause mutations through single-nucleotide insertions [41]. Acrylonitrile, the third agent in Table 3, appears to cause DNA damage indi‐ rectly by increasing oxidative stress, leading to increased levels of 8'-hydroxyl-2-deoxygua‐ nosine (8-OHdG) in DNA [42]. Oxidative stress also causes lipid peroxidation that generates malondialdehyde (MDA), and MDA forms DNA adducts with guanine, adenine and cyto‐ sine [43]. The fourth agent in Table 3, 1, 3-butadiene, causes genotoxicity both directly by forming a DNA adduct as well as indirectly by causing global loss of DNA methylation and histone methylation leading to epigenetic alterations [44]. The fifth agent in Table 3, acetal‐ dehyde, reacts with 2'-deoxyguanosine in DNA to form DNA adducts [45]. The sixth agent in Table 3, ethylene oxide, forms mutagenic hydroxyethyl DNA adducts with adenine and guanine [46]. The seventh agent in Table 3, isoprene, is normally produced endogenously by humans, and is the main hydrocarbon of non-smoking human breath [47]. However, smok‐ ing one cigarette causes an increase of breath isoprene levels by an average of 70% [48]. Iso‐ prene, after being metabolized to mono-epoxides, causes DNA damage measured as single and double strand breaks in DNA [49].

A large number of studies have been published in which the levels and characteristics of DNA adducts in the lung and bronchus of smokers and non-smokers have been compared, as reviewed by Phillips [50]. In most of these studies, significantly elevated levels of DNA adducts were detected in the peripheral lung, bronchial epithelium or bronchioalveolar lav‐ age cells of the smokers, especially for total bulky DNA adducts. As further discussed by Phillips [50], mean levels of DNA adducts in ex-smokers (usually with at least a 1 year inter‐ val since smoking cessation) are found generally to be intermediate between the levels of smokers and life-long non-smokers. From these comparisons, the half-life of some DNA ad‐ ducts in lung tissue are estimated to be ~1–2 years.

## **6. Exogenous DNA damaging agents in colorectal cancer**

Up to 20% of current colorectal cancers in the United States may be due to tobacco smoke [51].  These agents may be taken up in the blood and carried to or‐ gans of the body.

mitotic perturbations and reduced expression of spindle checkpoint proteins, giving rise to micro-nuclei, chromosome bridges and other structures that are precursors to aneuploidy [55]. Furthermore, at high physiological concentrations, bile acids cause frequent apoptosis, and those cells in the exposed populations with reduced apoptosis capability tend to survive and selectively proliferate [54, 56]. Cells with reduced ability to undergo apoptosis in re‐ sponse to DNA damage would tend to accumulate mutations when replication occurs past those damages, and such cells may give rise to colon cancers. In addition, 7 epidemiological studies between 1971 and 1990 (reviewed by Bernstein et al. [54]), found that fecal bile acid concentrations are increased in populations with a high incidence of colorectal cancer. A similar 2012 epidemiological study showed that concentrations of fecal LCA and DCA, re‐ spectively, were 4-fold and 5-fold higher in a population at 65-fold higher risk of colon can‐ cer compared to a population at lower risk of colon cancer [32]. This evidence points to bile acids DCA and LCA as centrally important DNA-damaging carcinogens in colon cancer.

 Increasing total fat or saturated fat in human diets results in increases in DCA and LCA in the feces [58, 59], indicating increased contact of the colonic epithelium with DCA and LCA. Bernstein et al. [60] added the bile acid DCA to the standard diet of wild-type mice. This supplement raised the level of DCA in the feces of mice from the stand‐ ard-diet fed mouse level of 0.3 mg DCA/g dry weight to 4.6 mg DCA/g dry weight, a level similar to that for humans on a high fat diet of 6.4 mg DCA/g dry weight. After 8 or 10 months on the DCA-supplemented diet, 56% of the mice developed invasive colon cancer. This directly indicates that DCA, a DNA damaging agent, at levels present in humans after a

**7. Exogenous DNA damaging agents implicated in other major cancers**

It is beyond the scope of this chapter to detail the evidence implicating DNA damaging agents as etiologic agents in all of the significant cancers. Therefore, in Table 4 we indicate with a single reference the major DNA damaging agent in five additional prevalent cancers, in order to illustrate the generality of exogenous DNA damaging agents as causes of cancer. In particular, we point out, as reviewed by Handa et al. [61], *Helicobacter pylori* infection in‐ creases the production of reactive oxygen and reactive nitrogen species (RNS) in the human stomach, which, in turn, significantly increases DNA damage in the gastric epithelial cells. Thus, *H. pylori* infection acts as a DNA damaging agent. In the case of human papillomavi‐ rus (HPV) infection, Wei et al. [62] showed that cervical cells could resist RNS stress when not infected with HPV. However, cervical cells infected by HPV and exposed to RNS had higher levels of DNA double strand breaks as well as a higher mutation rate. This appeared to occur due to the ability of HPV to greatly reduce protein expression of the DNA damage repair/response gene *P53* when infected cells were stressed by RNS. Since reduced *P53* ex‐ pression leads to greater RNS-induced DNA damage, HPV infection acts as a DNA damag‐

high fat diet, can cause colorectal cancer.

ing agent in the presence of RNS stress.

#### **Figure 2.** Reaction of acrolein with deoxyguanosine

The human colon is exposed to many compounds that are either of direct dietary origin or re‐ sult from digestive and/or microbial processes. Four different classes of colonic mutagenic compounds were analysed by de Kok and van Maanen [52] and evaluated for fecal mutagenici‐ ty. These included (1) pyrolysis compounds from food (heterocyclic aromatic amines and poly‐ cyclic aromatic hydrocarbons), (2) *N*-nitroso-compounds (from high meat diets, from drinking water with high nitrates or produced during ulcerative colitis), (3) fecapentaenes (produced by the colonic bacteria *Bacteriodes* in the presence of bile acids) and (4) bile acids (increased in the colon in response to a high fat diet and metabolized to genotoxic form by bacteria in the colon). Many of these diet-related mutagenic compounds were analysed by Pearson et al. [53] in terms of their presence in fecal water, and their effect on the cytotoxic or genotoxic activity of fecal water. Evidence in both of these studies was insufficient to evaluate the colorectal cancer risk as a result of specific exposures in quantitative terms.

However, substantial evidence implicates bile acids (the 4th possibility above) in colon caner. Bernstein et al. [54], summarized 12 studies indicating that the bile acids deoxycholic acid (DCA) and/or lithocholic acid (LCA) induce production of DNA damaging reactive oxygen species and/or reactive nitrogen species in colon cells of animal or human origin. They also tabulated 14 studies showing that DCA and LCA induce DNA damage in colon cells. In ad‐ dition to causing DNA damage, bile acids may also generate genomic instability by causing mitotic perturbations and reduced expression of spindle checkpoint proteins, giving rise to micro-nuclei, chromosome bridges and other structures that are precursors to aneuploidy [55]. Furthermore, at high physiological concentrations, bile acids cause frequent apoptosis, and those cells in the exposed populations with reduced apoptosis capability tend to survive and selectively proliferate [54, 56]. Cells with reduced ability to undergo apoptosis in re‐ sponse to DNA damage would tend to accumulate mutations when replication occurs past those damages, and such cells may give rise to colon cancers. In addition, 7 epidemiological studies between 1971 and 1990 (reviewed by Bernstein et al. [54]), found that fecal bile acid concentrations are increased in populations with a high incidence of colorectal cancer. A similar 2012 epidemiological study showed that concentrations of fecal LCA and DCA, re‐ spectively, were 4-fold and 5-fold higher in a population at 65-fold higher risk of colon can‐ cer compared to a population at lower risk of colon cancer [32]. This evidence points to bile acids DCA and LCA as centrally important DNA-damaging carcinogens in colon cancer.

 Increasing total fat or saturated fat in human diets results in increases in DCA and LCA in the feces [58, 59], indicating increased contact of the colonic epithelium with DCA and LCA. Bernstein et al. [60] added the bile acid DCA to the standard diet of wild-type mice. This supplement raised the level of DCA in the feces of mice from the stand‐ ard-diet fed mouse level of 0.3 mg DCA/g dry weight to 4.6 mg DCA/g dry weight, a level similar to that for humans on a high fat diet of 6.4 mg DCA/g dry weight. After 8 or 10 months on the DCA-supplemented diet, 56% of the mice developed invasive colon cancer. This directly indicates that DCA, a DNA damaging agent, at levels present in humans after a high fat diet, can cause colorectal cancer.

## **7. Exogenous DNA damaging agents implicated in other major cancers**

**Figure 2.** Reaction of acrolein with deoxyguanosine

422 New Research Directions in DNA Repair

a result of specific exposures in quantitative terms.

The human colon is exposed to many compounds that are either of direct dietary origin or re‐ sult from digestive and/or microbial processes. Four different classes of colonic mutagenic compounds were analysed by de Kok and van Maanen [52] and evaluated for fecal mutagenici‐ ty. These included (1) pyrolysis compounds from food (heterocyclic aromatic amines and poly‐ cyclic aromatic hydrocarbons), (2) *N*-nitroso-compounds (from high meat diets, from drinking water with high nitrates or produced during ulcerative colitis), (3) fecapentaenes (produced by the colonic bacteria *Bacteriodes* in the presence of bile acids) and (4) bile acids (increased in the colon in response to a high fat diet and metabolized to genotoxic form by bacteria in the colon). Many of these diet-related mutagenic compounds were analysed by Pearson et al. [53] in terms of their presence in fecal water, and their effect on the cytotoxic or genotoxic activity of fecal water. Evidence in both of these studies was insufficient to evaluate the colorectal cancer risk as

However, substantial evidence implicates bile acids (the 4th possibility above) in colon caner. Bernstein et al. [54], summarized 12 studies indicating that the bile acids deoxycholic acid (DCA) and/or lithocholic acid (LCA) induce production of DNA damaging reactive oxygen species and/or reactive nitrogen species in colon cells of animal or human origin. They also tabulated 14 studies showing that DCA and LCA induce DNA damage in colon cells. In ad‐ dition to causing DNA damage, bile acids may also generate genomic instability by causing It is beyond the scope of this chapter to detail the evidence implicating DNA damaging agents as etiologic agents in all of the significant cancers. Therefore, in Table 4 we indicate with a single reference the major DNA damaging agent in five additional prevalent cancers, in order to illustrate the generality of exogenous DNA damaging agents as causes of cancer. In particular, we point out, as reviewed by Handa et al. [61], *Helicobacter pylori* infection in‐ creases the production of reactive oxygen and reactive nitrogen species (RNS) in the human stomach, which, in turn, significantly increases DNA damage in the gastric epithelial cells. Thus, *H. pylori* infection acts as a DNA damaging agent. In the case of human papillomavi‐ rus (HPV) infection, Wei et al. [62] showed that cervical cells could resist RNS stress when not infected with HPV. However, cervical cells infected by HPV and exposed to RNS had higher levels of DNA double strand breaks as well as a higher mutation rate. This appeared to occur due to the ability of HPV to greatly reduce protein expression of the DNA damage repair/response gene *P53* when infected cells were stressed by RNS. Since reduced *P53* ex‐ pression leads to greater RNS-induced DNA damage, HPV infection acts as a DNA damag‐ ing agent in the presence of RNS stress.

methylation and transcriptional silencing [73]. As pointed out above, the enzyme Parp1 (poly(ADP)-ribose polymerase) and its product poly(ADP)-ribose (PAR) accumulate at sites of DNA damage as part of a repair process [9], recruiting chromatin remodeling protein ALC1, causing nucleosome remodeling [10] that has been shown to direct epigenetic silenc‐ ing of DNA repair gene *MLH1* [11]. If silencing of genes necessary for DNA repair occurs, the repair of further DNA damages will be deficient and more damages will accumulate. Such additional DNA damages will cause increased errors during DNA synthesis, leading

Homologous Recombinational Repair (HRR) 21,21

Non-homologous End Joining (NHEJ) 8,7

Nucleotide Excision Repair (NER) 30,29

Base Excision Repair (including PARP enzymes) (BER) 19,20

Mis-Match Repair (MMR) 11,10

Fanconi Anemia (FANC) [affects HRR (above) and translesion synthesis (TLS)] 10,16

Direct reversal of damage 3,3

DNA polymerases (act in various pathways) 17,15

Editing and processing nucleases (act in various pathways) 6,8

Ubiquitination and modification/Rad6 pathway including TLS 11,5

DNA damage response 12,14

Modulation of nucleotide pools 3,3

Chromatin structure 2,3

Defective in diseases and syndromes 4,5

DNA-topoisomerase crosslinks 2,1

Other genes 8,9

**Table 5.** DNA repair pathways and other processes affecting DNA repair [67, 68]

**Number of genes listed in the two databases**

DNA Damage, DNA Repair and Cancer http://dx.doi.org/10.5772/53919 425

to mutations that can give rise to cancer.

**Table 4.** Selected cancers and relevant implicated exogenous DNA damaging agents

## **8. Deficient DNA repair due to a germ line mutation allows DNA damages to increase, leading to increased frequencies of mutation, epimutation and cancer**

Expression of DNA repair genes may be reduced by inherited germ line mutations or genet‐ ic polymorphisms, or by epigenetic alterations or mutations in somatic cells, and these re‐ ductions may substantially increase the risk of cancer. Overall, about 30% of cancers are considered to be familial (largely due to inherited germ line mutations or genetic polymor‐ phisms) and 70% are considered to be sporadic [66].

In 2 overlapping databases [67, 68] 167 and169 human genes (depending on the database) are listed that are directly employed in DNA repair or influence DNA repair processes. The lists were originally devised by Wood et al. [69, 70]. The genes are distributed in groups of DNA repair pathways and in related functions that affect DNA repair (Table 5). Bernstein et al. [71] illustrate many of the steps and order of action of the gene products involved for the first five DNA repair pathways listed in Table 5.

Individuals with an inherited impairment in DNA repair capability are often at considerably increased risk of cancer. If an individual has a germ line mutation in a DNA repair gene or a DNA damage response gene (that recognizes DNA damage and activates DNA repair), usu‐ ally one abnormal copy of the gene is inherited from one of the parents and then the other copy is inactivated at some later point in life in a somatic cell. The inactivation may be due, for example, to point mutation, deletion, gene conversion, epigenetic silencing or other mechanisms [72]. The protein encoded by the gene will either not be expressed or be ex‐ pressed in a mutated form. Consequently the DNA repair or DNA damage response func‐ tion will be deficient or impaired, and damages will accumulate. Such DNA damages can cause errors during DNA replication or inaccurate repair, leading to mutations that can give rise to cancer.

Increased oxidative DNA damages also cause increased gene silencing by CpG island hy‐ permethylation, a form of epimutation. These oxidative DNA damages induce formation and relocalization of a silencing complex that may result in cancer-specific aberrant DNA methylation and transcriptional silencing [73]. As pointed out above, the enzyme Parp1 (poly(ADP)-ribose polymerase) and its product poly(ADP)-ribose (PAR) accumulate at sites of DNA damage as part of a repair process [9], recruiting chromatin remodeling protein ALC1, causing nucleosome remodeling [10] that has been shown to direct epigenetic silenc‐ ing of DNA repair gene *MLH1* [11]. If silencing of genes necessary for DNA repair occurs, the repair of further DNA damages will be deficient and more damages will accumulate. Such additional DNA damages will cause increased errors during DNA synthesis, leading to mutations that can give rise to cancer.

**Cancer Exogenous DNA damaging agent Ref.** Esophagus Bile acids [63] Stomach *Helicobacter pylori* infection [61] Liver *Aspergillus* metabolite aflatoxin B(1) [64]

Cervix/Uterus Human papillomavirus plus increased nitric oxide from tobacco smoke or

**Table 4.** Selected cancers and relevant implicated exogenous DNA damaging agents

phisms) and 70% are considered to be sporadic [66].

first five DNA repair pathways listed in Table 5.

**epimutation and cancer**

424 New Research Directions in DNA Repair

rise to cancer.

Melanoma UV light from solar radiation [65]

**8. Deficient DNA repair due to a germ line mutation allows DNA damages to increase, leading to increased frequencies of mutation,**

Expression of DNA repair genes may be reduced by inherited germ line mutations or genet‐ ic polymorphisms, or by epigenetic alterations or mutations in somatic cells, and these re‐ ductions may substantially increase the risk of cancer. Overall, about 30% of cancers are considered to be familial (largely due to inherited germ line mutations or genetic polymor‐

In 2 overlapping databases [67, 68] 167 and169 human genes (depending on the database) are listed that are directly employed in DNA repair or influence DNA repair processes. The lists were originally devised by Wood et al. [69, 70]. The genes are distributed in groups of DNA repair pathways and in related functions that affect DNA repair (Table 5). Bernstein et al. [71] illustrate many of the steps and order of action of the gene products involved for the

Individuals with an inherited impairment in DNA repair capability are often at considerably increased risk of cancer. If an individual has a germ line mutation in a DNA repair gene or a DNA damage response gene (that recognizes DNA damage and activates DNA repair), usu‐ ally one abnormal copy of the gene is inherited from one of the parents and then the other copy is inactivated at some later point in life in a somatic cell. The inactivation may be due, for example, to point mutation, deletion, gene conversion, epigenetic silencing or other mechanisms [72]. The protein encoded by the gene will either not be expressed or be ex‐ pressed in a mutated form. Consequently the DNA repair or DNA damage response func‐ tion will be deficient or impaired, and damages will accumulate. Such DNA damages can cause errors during DNA replication or inaccurate repair, leading to mutations that can give

Increased oxidative DNA damages also cause increased gene silencing by CpG island hy‐ permethylation, a form of epimutation. These oxidative DNA damages induce formation and relocalization of a silencing complex that may result in cancer-specific aberrant DNA

other infection [62]

**Table 5.** DNA repair pathways and other processes affecting DNA repair [67, 68]

## **9. Inherited mutations in genes employed in DNA repair that give rise to syndromes characterized by increased risk of cancer.**

**DNA repair gene(s)**

breast cancer 1 & 2 BRCA1,

ataxia telangiectasia mutated ATM

Rothman Thomson syndrome Rapadilino syndrome Baller Gerold syndrome

Fanconi's anemia gene FANC A,B,C,D1,D2,E,F,G,I,J,L,M,N

xeroderma pigmentosa C, E [DNA damage binding protein 2 (DDB2)]

xeroderma pigmentosa

called polymerase H)

xeroderma pigmentosa V (also

A, B, D, F, G

**Encoded protein**

BRCA2

**Repair pathway(s) affected**

HRR of double strand breaks

Different mutations in ATM reduce HRR, single strand annealing (SSA), NHEJ or homology directed double strand break rejoining

Nijmegen breakage syndrome NBS NHEJ [89] Lymphoid cancers [89] meiotic recombination 11 MRE11 HRR and NHEJ [90] Breast [91]

RECQ4 Helicase likely active in HRR [96]

FANCA etc. HRR and TLS [98]

Global genomic NER repairs damage in both transcribed and untranscribed DNA

Transcription coupled NER repairs the transcribed strands of transcriptionally

active genes

(HDR)

Bloom's Syndrome (helicase) BLM HRR [92]

Werner Syndrome (helicase) WRN HRR, NHEJ, long patch BER [94]

XPC XPE

XPA XPB XPD XPF XPG

XPV

**Ref.**

and daughter strand gaps [85] Breast, Ovarian [86]

**Cancers with increased risk**

DNA Damage, DNA Repair and Cancer http://dx.doi.org/10.5772/53919

[87] Leukemia, Lymphoma, Breast

> Leukemia, Lymphoma, Colon, Breast, Skin, Auditory canal, Tongue, Esophagus, Stomach, Tonsil, Larynx, Lung,

Soft tissue sarcoma, Colorectal, Skin, Thyroid, Pancreatic

Basal cell carcinoma, Squamous cell carcinoma, Intraepidemial carcinoma

Leukemia, Liver tumors, Solid tumors many

Skin cancer (melanoma and non-melanoma)

Skin cancer (melanoma and non-melanoma), Central nervous system

and non-melanoma) [102]

Uterus

areas

cancers

[100, 101]

[102]

(POLH) Translesion Synthesis (TLS) [102] Skin cancer (melanoma

**Ref.**

427

[87,88]

[93]

[95]

[97]

[99]

[100, 101]

[102]