The success of these agents ultimately will depend on our basic knowledge of the various DNA repair processes present in a given cell type or tissue. Not all DNA repair pathways are present in all tissues, as evidenced by the fact that mutations in specific pathways give rise preferentially to certain tumour types and not others. Secondly, the success will also de‐ pend on the specific genomic and genetic landscape of each tumour, implying that different combinations of inhibitors and chemical agents shall have to be tailored to each tumour. We are still far from achieving this goal, but great strides have been taken in the past years. Thirdly, we shall have to redirect the strategy to discover a "cure for cancer" and instead follow strategies that allow us to accompany the inevitable and inexorable evolution of the cancer cell and consistently find and implement more and more targeted therapies, even if these strategies lead us to return to abandoned therapies. The resurgence of drug holidays, in which a therapy is abandoned temporarily to be taken up after a certain period, not un‐ like what can be adopted with antibiotics, is one such strategy. In this case the absence of a selective pressure imposed by a specific agent may lead cancer cells to lose resistance to this agent, making them again vulnerable to the same agent. This strategy has been followed in certain cancers and could be adapted in others, with the advantage of offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life [211, 212].

apoptosis, reversal of EMT phenotype, and increasing drug sensitivity [208].

therapy, and may prevent resistance to chemotherapy [188, 189, 208-210].

**10. Conclusion and future directions**

arising when we disrupt DNA repair processes.

Likewise, most plant derivatives can act as antioxidants and some of them can increase hu‐ man *MGMT* expression (e.g. curcumin, silymarin, sulforaphane and resveratrol) beyond its steady-state levels, having a role in cancer chemoprevention [202]. Additionally, both *BRCA1* and *MGMT* genes are susceptible to hypermethylation, and green tea polyphenols and bioflavonoids have been shown to reverse the effects of DNA hypermethylation [203].These results suggest that some dietary compounds may have a potential demethylat‐ ing effect, and could be promising adjuvants to chemotherapy in drug resistant settings.

Another issue in cancer chemotherapy is the use of monotherapy *vs* combined therapy, and several studies have been performed regarding possible combinatory chemotherapy with nat‐ ural compounds (less aggressive than the majority of chemotherapeutic drugs), albeit in pre‐ clinical settings, *e.g.* silibinin extract [204], ixabepilone [205] and curcumin [206]. Some of these agents are being evaluated in clinical trials. Silibinin strongly synergized the growth-inhibito‐ ry effect of doxorubicin in prostate carcinoma cells, which was associated with a strong G2-M arrest followed by apoptosis [204]. Ixabepilone, an analogue of the natural product epothilone B, is already indicated for the treatment of locally advanced or metastatic breast cancer in the US. In a phase III trial in women with locally advanced or metastatic breast cancer that were pretreated with, or resistant to, anthracyclines (e.g. doxorubicin) and resistant to taxanes, pro‐ gression-free survival was significantly longer in ixabepilone plus capecitabine recipients com‐ pared with recipients of capecitabine monotherapy [205]. Combination therapy using curcumin with gemcitabine-based chemotherapy, in a phase I/II study, in patients with pancre‐ atic cancer warrants further investigation into its efficacy [206].

Finally, an interesting recent development concerns the observation that miRs could be regu‐ lated by natural agents, leading to the inhibition of cancer cell growth, epithelial to mesenchy‐ mal transition (EMT), drug resistance, and metastasis [207]. For most epithelial tumors, progression toward malignancy is accompanied by a loss of epithelial differentiation and a shift toward mesenchymal phenotype [185]. During the acquisition of EMT characteristics, cancer cells lose the expression of proteins that promote cell-cell contact, such as E-cadherin and γ-catenin, and gain the expression of mesenchymal markers, such as vimentin, fibronectin, and N-cadherin, leading to enhanced cancer cell migration and invasion. It has been shown that down-regulation or the loss in the expression of the miR-200 family is associated with EMT. Gemcitabine-resistant pancreatic cells having EMT characteristics showed low expres‐ sion of the miR-200 family and miR-200 is lost in invasive breast cancer cell lines with mesen‐ chymal phenotype. Hence the interesting observation that isoflavone could induce miR-200 expression in gemcitabine-resistant pancreatic cells, resulting in altered cellular morphology from mesenchymal-to-epithelial appearance and induced E-cadherin distribution that is more similar to epithelial-like cells. Likewise, let-7 has been found to regulate cell proliferation and differentiation, and inhibit the expression of multiple oncogenes, including ras and myc, and again it was observed that isoflavone could significantly up-regulate the expression of let-7 family, suggesting that this phytochemical could reverse EMT characteristics in part due to the up-regulation of let-7 [207]. Other reports have shown that curcumin, isoflavone, indole-3-car‐ binol (I3C), 3,3′-diindolylmethane (DIM), (−)-epigallocatechin-3-gallate (EGCG) or resveratrol, can alter miRNA expression profiles, leading to the inhibition of cancer growth, induction of apoptosis, reversal of EMT phenotype, and increasing drug sensitivity [208].

It remains to be seen if phytochemicals can affect miRs that regulate DNA repair pathways, but since any given miR can target several transcripts, this regulation is highly likely. Over‐ all, natural compounds, may have an important role in chemoprevention and in combined therapy, and may prevent resistance to chemotherapy [188, 189, 208-210].

## **10. Conclusion and future directions**

*AKR* was observed. However genes associated with cell cycle, DNA replication, recombina‐ tion, and repair functions were down-regulated [200]. One study analysed 531 compounds derived from plants and found no correlation with genes involved in NER (*ERCC1, XPA, XPC, DDB2, ERCC4, ERCC5*) or BER (*MPG, APE1, OGG1, XRCC1, LIG3, POLB*). It is possible that natural compounds may target different molecular pathways from those of standard anti-tumor drugs, hence if DNA repair is involved in the development of resistance to estab‐ lished anticancer drugs, natural compounds may be attractive sources of novel drugs suita‐ ble to treat drug resistant tumours, with the advantage of having reduced side effects [201].

508 New Research Directions in DNA Repair

Likewise, most plant derivatives can act as antioxidants and some of them can increase hu‐ man *MGMT* expression (e.g. curcumin, silymarin, sulforaphane and resveratrol) beyond its steady-state levels, having a role in cancer chemoprevention [202]. Additionally, both *BRCA1* and *MGMT* genes are susceptible to hypermethylation, and green tea polyphenols and bioflavonoids have been shown to reverse the effects of DNA hypermethylation [203].These results suggest that some dietary compounds may have a potential demethylat‐ ing effect, and could be promising adjuvants to chemotherapy in drug resistant settings.

Another issue in cancer chemotherapy is the use of monotherapy *vs* combined therapy, and several studies have been performed regarding possible combinatory chemotherapy with nat‐ ural compounds (less aggressive than the majority of chemotherapeutic drugs), albeit in pre‐ clinical settings, *e.g.* silibinin extract [204], ixabepilone [205] and curcumin [206]. Some of these agents are being evaluated in clinical trials. Silibinin strongly synergized the growth-inhibito‐ ry effect of doxorubicin in prostate carcinoma cells, which was associated with a strong G2-M arrest followed by apoptosis [204]. Ixabepilone, an analogue of the natural product epothilone B, is already indicated for the treatment of locally advanced or metastatic breast cancer in the US. In a phase III trial in women with locally advanced or metastatic breast cancer that were pretreated with, or resistant to, anthracyclines (e.g. doxorubicin) and resistant to taxanes, pro‐ gression-free survival was significantly longer in ixabepilone plus capecitabine recipients com‐ pared with recipients of capecitabine monotherapy [205]. Combination therapy using curcumin with gemcitabine-based chemotherapy, in a phase I/II study, in patients with pancre‐

Finally, an interesting recent development concerns the observation that miRs could be regu‐ lated by natural agents, leading to the inhibition of cancer cell growth, epithelial to mesenchy‐ mal transition (EMT), drug resistance, and metastasis [207]. For most epithelial tumors, progression toward malignancy is accompanied by a loss of epithelial differentiation and a shift toward mesenchymal phenotype [185]. During the acquisition of EMT characteristics, cancer cells lose the expression of proteins that promote cell-cell contact, such as E-cadherin and γ-catenin, and gain the expression of mesenchymal markers, such as vimentin, fibronectin, and N-cadherin, leading to enhanced cancer cell migration and invasion. It has been shown that down-regulation or the loss in the expression of the miR-200 family is associated with EMT. Gemcitabine-resistant pancreatic cells having EMT characteristics showed low expres‐ sion of the miR-200 family and miR-200 is lost in invasive breast cancer cell lines with mesen‐ chymal phenotype. Hence the interesting observation that isoflavone could induce miR-200 expression in gemcitabine-resistant pancreatic cells, resulting in altered cellular morphology

atic cancer warrants further investigation into its efficacy [206].

As discussed in this chapter, the ultimate target of chemotherapy and radiotherapy is the cancer cell, and use of DNA damaging agents is justifiable since most of these cells are high‐ ly cycling cells. The targeting of DNA repair pathways is but one of the many strategies de‐ veloped in the fight against cancer. Cancer cells frequently possess altered DNA repair capacities, and this can be put to use in the clinic. Thus the quest for specific therapies that target DNA repair has produced many potentially useful agents (Table 1). Using such agents can theoretically increase the efficacy of existing chemotherapy and/or radiotherapy. Nevertheless, the same difficulties encountered by all other alternative strategies are also arising when we disrupt DNA repair processes.

The success of these agents ultimately will depend on our basic knowledge of the various DNA repair processes present in a given cell type or tissue. Not all DNA repair pathways are present in all tissues, as evidenced by the fact that mutations in specific pathways give rise preferentially to certain tumour types and not others. Secondly, the success will also de‐ pend on the specific genomic and genetic landscape of each tumour, implying that different combinations of inhibitors and chemical agents shall have to be tailored to each tumour. We are still far from achieving this goal, but great strides have been taken in the past years. Thirdly, we shall have to redirect the strategy to discover a "cure for cancer" and instead follow strategies that allow us to accompany the inevitable and inexorable evolution of the cancer cell and consistently find and implement more and more targeted therapies, even if these strategies lead us to return to abandoned therapies. The resurgence of drug holidays, in which a therapy is abandoned temporarily to be taken up after a certain period, not un‐ like what can be adopted with antibiotics, is one such strategy. In this case the absence of a selective pressure imposed by a specific agent may lead cancer cells to lose resistance to this agent, making them again vulnerable to the same agent. This strategy has been followed in certain cancers and could be adapted in others, with the advantage of offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life [211, 212].

**Target Drug Condition or tumor Combination**

EGFR Erlotinib NSCLC Monotherapy or

**Table 1.** Targeted therapeutics in development, in clinical use or in clinical trials\*.

\* As of 10 September 2012, http://clinicaltrials.gov

Pathway

tient treatment.

from FCT.

**Author details**

Nuno G. Oliveira2

boa, Lisboa, Portugal

António S. Rodrigues1\*, Bruno Costa Gomes1

, Patrícia S. Guerreiro2

Pharmacy, Universidade de Lisboa, Lisboa, Portugal

\*Address all correspondence to<EMAIL_ADDRESS>
**Acknowledgements**

**therapy agent(s)**

combination

This leads to the final and perhaps most challenging problem in the development of agents that modulate DNA repair, which is toxicity to normal cells, in particular to the hematopoietic system and the gastrointestinal epithelia. Various strategies are being fol‐ lowed to minimize toxicity, which include the intermittent administration during thera‐ py, mentioned above, alternating with other therapies, using highly localized radiotherapy together with inhibitors to minimize collateral damage, and using inhibitors as single agents [213, 214]. Altogether, the combined use of the various weapons at our disposal in a coordinated, comprehensive fashion could effectively lead to improved pa‐

This work was supported by grants PTDC/SAUGMG/71720/2006 from Fundação de Ciência e Tecnologia (FCT), and PEst-OE/SAU/UI0009/2011-12 from FCT. M.G. was supported by CIENCIA 2008 (FCT). CIGMH is supported by FCT. B.G. (SFRH/BD/64131/2009), P.G. (SFRH/BD/70293/2010 ) and C.M. (SFRH/BD/ 81097/2011) are supported by Ph.D. grants

, Célia Martins1

and José Rueff1

1 CIGMH – Department of Genetics, Faculty of Medical Sciences, Universidade Nova de Lis‐

2 Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), UL, Faculty of

, Marta Gromicho1

,

Gefinitib www.astrazeneca.com

c-ABL Imatinib Various solid tumours Phase III www.novartis.com

**Phase of clinical trial planned, ongoing or recently completed\***

Phase II/III www.gene.com

**Reference**

http://dx.doi.org/10.5772/53952

511

DNA Repair and Resistance to Cancer Therapy

\* As of 10 September 2012, http://clinicaltrials.gov

**Target Drug Condition or tumor Combination**

Cell Neoplasm

Melanoma Colorectal Cancer

Cancer

Cancer

Solid tumors Melanoma

Multiple Myeloma and Plasma

Glioblastoma, Gliosarcoma

Triple Negative Breast Cancer Triple Negative Metastatic Breast

Known BRCA Ovarian Cancer or Known BRCA/ Triple Neg. Breast

Uterine Carcinosarcoma Carboplatin,

Breast Cancer Gemcitabine/

Breast cancer Carboplatin

MK4827 Solid BRCA Ovarian Single agent

Solid tumours TMZ

Advanced refractory solid cancers Hematological cancers

FA Curcumin Gastrointestinal cancers Phase II

CEP-9722 Solid tumours TMZ

LT673 Hematological cancers Solid tumours

MGMT O6-

PARP1 AZD-2281/ KU59436 (Olaparib)

Benzylguanine

510 New Research Directions in DNA Repair

AG014699/ PF-01367338 (Rucaparib)

BSI-201/ (Iniparib)

ABT-888/ (Veliparib)

GPI 1016/ E7016

BER Methoxyamine/ TRC-102

ATM Kinase **therapy agent(s)**

Carmustine Temodar Carmustine Carmustine

Cisplatin Paclitaxel

Temozolomide Various agents

INO-1001 Melanoma Temozolomide Phase I terminated www.inotekcorp.com

Paclitaxel,

Carboplatin

Temozolomide

Various agents

Various agents

Various agents

Pemetrexed TMZ Fludarabine

KU55933 Preclinical www.astrazeneca.com

CHK1 AZD7762 www.astrazeneca.com PF-00477736 www.pfizer.com XL844 www.exelixis.com

Prostate Cancer Temozolomide Phase I active Melanoma Temozolomide Phase II active Various cancers Various agents Phase I/II active

NMS-P118 Preclinical; highly selective

**Phase of clinical trial planned, ongoing or recently completed\***

Phase II completed Phase II completed Phase II completed Phase II completed

Phase I/II active Phase I/II completed

Phase I completed Phase II ongoing

Phase II completed Phase III active

**Reference**

www.cancer.gov

www.astrazeneca.com

www.pfizer.com

www.sanofi.com

www.tevapharm.com

www.nervianoms.com

www.traconpharma.co

m

Phase II active www.biparsciences.com

Phase II active www.abbott.com

Phase I ongoing www.merck.com

Phase I www.cephalon.com

Phase I www.eisai.com

Various agents Phase I ongoing www.bmrn.com

against PARP-5 (tankyrase)

Phase I active Phase I ongoing **Table 1.** Targeted therapeutics in development, in clinical use or in clinical trials\*.

This leads to the final and perhaps most challenging problem in the development of agents that modulate DNA repair, which is toxicity to normal cells, in particular to the hematopoietic system and the gastrointestinal epithelia. Various strategies are being fol‐ lowed to minimize toxicity, which include the intermittent administration during thera‐ py, mentioned above, alternating with other therapies, using highly localized radiotherapy together with inhibitors to minimize collateral damage, and using inhibitors as single agents [213, 214]. Altogether, the combined use of the various weapons at our disposal in a coordinated, comprehensive fashion could effectively lead to improved pa‐ tient treatment.

### **Acknowledgements**

This work was supported by grants PTDC/SAUGMG/71720/2006 from Fundação de Ciência e Tecnologia (FCT), and PEst-OE/SAU/UI0009/2011-12 from FCT. M.G. was supported by CIENCIA 2008 (FCT). CIGMH is supported by FCT. B.G. (SFRH/BD/64131/2009), P.G. (SFRH/BD/70293/2010 ) and C.M. (SFRH/BD/ 81097/2011) are supported by Ph.D. grants from FCT.

### **Author details**

António S. Rodrigues1\*, Bruno Costa Gomes1 , Célia Martins1 , Marta Gromicho1 , Nuno G. Oliveira2 , Patrícia S. Guerreiro2 and José Rueff1

\*Address all correspondence to<EMAIL_ADDRESS>
1 CIGMH – Department of Genetics, Faculty of Medical Sciences, Universidade Nova de Lis‐ boa, Lisboa, Portugal

2 Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), UL, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal

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**Chapter 19**

methyl guanine)

**DNA Base Excision Repair: Evolving**

Vivek Mohan and Srinivasan Madhusudan

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54607

**1. Introduction**

by MGMT (O6

therapeutic targets in cancer.

**2. Base excision repair pathway (BER)**

**Biomarkers for Personalized Therapies in Cancer**

DNA repair is critical for maintaining genomic integrity. The DNA damage such as those induced by endogenous processes (methylation, hydroxylation, oxidation by free radicals) or by exogenous agents such as ionizing radiation, environmental toxins, and chemotherapy is processed through the DNA repair machinery in cells. At least six distinct DNA repair pathways have been described. A detailed discussion of individual pathways is beyond the scope of this chapter as several recent excellent reviews on DNA repair are available [1-6].

corrects base-base mismatches and insertion-deletion loops (IDLs) erroneously generated during DNA replication and by exogenous DNA damage [11-13]. Bulky DNA adducts are processed through the nucleotide excision repair pathway (NER) [14-16]. DNA double strand breaks are repaired through the homologous recombination pathway (predominantly during S-phase of cell cycle) [17-19] or the non-homologous end joining pathway (NHEJ), that operates outside the S-phase of the cell cycle [20-22]. DNA base damage is processed by the base excision repair (BER) machinery. In the current chapter we focus on BER. Evolving preclinical and clinical data suggests that BER factors are likely to be important prognostic, predictive and

Exogenous as well as endogenously derived reactive metabolites cause DNA damage such as base oxidation, deamination and alkylation. If the damaged bases are left unrepaired, then dur‐

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

© 2013 Mohan and Madhusudan; 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,

methyl guanine DNA methyl transferases [7-10]. DNA mismatch repair (MMR)

Briefly, direct repair is involved in the repair of alkylated bases (such as O6

## **DNA Base Excision Repair: Evolving Biomarkers for Personalized Therapies in Cancer**

Vivek Mohan and Srinivasan Madhusudan

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54607

## **1. Introduction**

chymal Transition in Gemcitabine-Resistant Pancreatic Cancer Cells. Cancer Re‐

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[209] Sarkar FH, Li Y. Harnessing the fruits of nature for the development of multi-target‐

[210] Sarkar FH, Li Y, Wang Z, Kong D, Ali S. Implication of microRNAs in drug resist‐ ance for designing novel cancer therapy. Drug resistance updates : reviews and com‐

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[213] Kelley MR. Chapter 14 - Future Directions with DNA Repair Inhibitors: A Roadmap for Disruptive Approaches to Cancer Therapy. In: Mark RK, editor. DNA Repair in

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Cancer Therapy. San Diego: Academic Press; 2012. p. 301-10.

2011;10(11):1183-5. Epub 2011/10/04.

ed cancer therapeutics. Cancer Treatment Reviews. 2009;35(7):597-607.

search. 2009;69(16):6704-12.

528 New Research Directions in DNA Repair

research. 2010;27(6):1027-41.

DNA repair is critical for maintaining genomic integrity. The DNA damage such as those induced by endogenous processes (methylation, hydroxylation, oxidation by free radicals) or by exogenous agents such as ionizing radiation, environmental toxins, and chemotherapy is processed through the DNA repair machinery in cells. At least six distinct DNA repair pathways have been described. A detailed discussion of individual pathways is beyond the scope of this chapter as several recent excellent reviews on DNA repair are available [1-6]. Briefly, direct repair is involved in the repair of alkylated bases (such as O6 methyl guanine) by MGMT (O6 methyl guanine DNA methyl transferases [7-10]. DNA mismatch repair (MMR) corrects base-base mismatches and insertion-deletion loops (IDLs) erroneously generated during DNA replication and by exogenous DNA damage [11-13]. Bulky DNA adducts are processed through the nucleotide excision repair pathway (NER) [14-16]. DNA double strand breaks are repaired through the homologous recombination pathway (predominantly during S-phase of cell cycle) [17-19] or the non-homologous end joining pathway (NHEJ), that operates outside the S-phase of the cell cycle [20-22]. DNA base damage is processed by the base excision repair (BER) machinery. In the current chapter we focus on BER. Evolving preclinical and clinical data suggests that BER factors are likely to be important prognostic, predictive and therapeutic targets in cancer.

## **2. Base excision repair pathway (BER)**

Exogenous as well as endogenously derived reactive metabolites cause DNA damage such as base oxidation, deamination and alkylation. If the damaged bases are left unrepaired, then dur‐

© 2013 Mohan and Madhusudan; 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.

ing replication or transcription misincorporation of erroneous complementary bases usher mu‐ tagenesis. For example, reactive oxygen species (ROS) generated during cellular respiration, phagocytosis, inflammation and in tumour hypoxia milieu can lead to base oxidation and gen‐ eration of oxidised bases such as 8-hydroxyguanine (8-oxoG) [23]. DNA polymerase inserts ad‐ enine opposite to 8-oxoG, resulting in GC to AT transversion mutations after replication. Similarly, pyrimidine oxidation leads to the formation of 5-hydroxycytosine (5-OHC) which leads to the insertion of a thymine creating a potential mutagenic lesion [24]. Purine deamina‐ tion products such as hypoxanthine and xanthine generated from adenine and guanine respec‐ tively are highly mutagenic. Hypoxanthine in DNA can cause AT to GC mutations, whereas xanthine generate GC to AT mutations [25]. Deamination of cytosine generates uracil which can occur in DNA at a frequency of upto 100–500 per cell per day. Uracil misincorporation can in‐ duce CG to TA transition mutations [26]. Although endogenous *S*-adenosyl methionine (SAM) participates in targeted enzymatic DNA base methylation, non-enzymatic methylation of ring nitrogen of purine base adenine can be cytotoxic[26].  DNA bases damaged by oxidation, de‐ amination and alkylation produce a non-helix distorting, non-bulky base lesion. Such lesions are the prime repair target of BER [6, 28-30].

histological grade, neuro-lymphovascular invasion by cancer cells, presence or absence of certain signal protein expression (for example Her-2 in breast cancer is a poor prognostic marker). Predictive factors are those factors that help estimate the probability of a patient responding to a specific treatment. For example BRAF V 600 gene mutation in patients with

DNA Base Excision Repair: Evolving Biomarkers for Personalized Therapies in Cancer

http://dx.doi.org/10.5772/54607

531

**Figure 1.** DNA glycosylase initiates BER by excising the damaged base from DNA and generating an abasic site. APE 1 nicks the phosphodiester bond and hydrolyzes the phosphate bond 5' to the AP site leaving a 3'-OH group and a 5' dRP flanking the nucleotide gap. Pol β excises the 5'-dRP moiety generating a 5'-P. The short-patch (SP-BER) where pol β introduces a single nucleotide with the help of XRCC1. Ligase-IIIα subsequently seals the DNA nick establishing the phosphodiester DNA backbone. The long patch (LP-BER) processes those lesions that cannot be handled by the short patch such as oxidised AP sites. PCNA mediated Polymerase δ/ε introduces two to eight nucleotides past the abasic site. The resulting overhang DNA is excised by FEN1 endonuclease and the nick is then sealed by DNA ligase I.

Chemotherapeutic agents and ionizing radiation achieve cellular cytotoxicity by inducing DNA base damages [34]. However proficient BER in cancer cells results in therapeutic resist‐ ance and adversely impact patient outcomes. BER factors, therefore, are emerging as important prognostic factors as well as predictors of response to cytotoxic therapy in patients. For exam‐ ple, Temozolomide is an effective treatment for patients with high grade brain tumours. It indu‐ ces *O*6-meG, N3-meA and N7-meG base alkylation lesions which are processed by BER. [35]. Similarly, Melphalan which is used in the treatment of multiple myeloma induces N3-meA le‐ sions that is processed through BER [36]. Thiotepa is used with or without total body irradiation

metastatic melanoma predicts the response to treatment with Vemurafenib [33].

BER is a complex process and utilizes a number of enzymes and accessory scaffold proteins (Fig‐ ure 1). DNA glycosylases, AP endonuclease (APE-1) also called REF-1(Redox Effector Factor-1), DNA Polymerases, flap endonuclease (FEN-1), poly (ADP-ribose) polymerase 1(PARP-1) and DNA ligases are the key enzymes involved in BER. The core enzymes depend on accessory pro‐ teins such as X-ray cross complementation group 1 protein (XRCC1), proliferating cell nuclear antigen (PCNA), and protein 9-1-1 for coordinated action. DNA glycosylases initiate BER by ex‐ cising the damaged base from DNA and generating an abasic site. APE1 hydrolyzes the phos‐ phate bond 5' to the AP site leaving a 3'-OH group and a 5'-dRP flanking the nucleotide gap. Polymerase β (pol β) excises the 5'-dRP moiety generating a 5'-P. Members of the poly (ADP-ri‐ bose) polymerase (PARP) family of proteins get activated by single strand DNA breaks induced by APE1 and catalyze the addition of poly (ADP-ribose) polymers to target proteins, affecting protein-protein interactions. PARP may also be involved in the coordination of BER. At this point, BER can proceed through the short-patch (SP-BER) where pol β introduces a single nu‐ cleotide with the help of XRCC1. Ligase-IIIα subsequently seals the DNA nick establishing the phosphodiester DNA backbone. The long patch (LP-BER) processes those lesions that cannot be handled by the short patch such as oxidised AP sites. PCNA mediated Polymerase δ/ε introdu‐ ces two to eight nucleotides past the abasic site. The resulting overhang DNA is excised by FEN1 endonuclease and the nick is then sealed by DNA ligase I.[28-32]

#### **2.1. BER factors are promising biomarkers in cancer**

Prognostic factors are defined as patient and/or cancer characteristics that help to estimate patient survival independent of treatment. Conventionally these include patient age, fitness to withstand treatment toxicity (usually measured as performance status), tumour stage, histological grade, neuro-lymphovascular invasion by cancer cells, presence or absence of certain signal protein expression (for example Her-2 in breast cancer is a poor prognostic marker). Predictive factors are those factors that help estimate the probability of a patient responding to a specific treatment. For example BRAF V 600 gene mutation in patients with metastatic melanoma predicts the response to treatment with Vemurafenib [33].

ing replication or transcription misincorporation of erroneous complementary bases usher mu‐ tagenesis. For example, reactive oxygen species (ROS) generated during cellular respiration, phagocytosis, inflammation and in tumour hypoxia milieu can lead to base oxidation and gen‐ eration of oxidised bases such as 8-hydroxyguanine (8-oxoG) [23]. DNA polymerase inserts ad‐ enine opposite to 8-oxoG, resulting in GC to AT transversion mutations after replication. Similarly, pyrimidine oxidation leads to the formation of 5-hydroxycytosine (5-OHC) which leads to the insertion of a thymine creating a potential mutagenic lesion [24]. Purine deamina‐ tion products such as hypoxanthine and xanthine generated from adenine and guanine respec‐ tively are highly mutagenic. Hypoxanthine in DNA can cause AT to GC mutations, whereas xanthine generate GC to AT mutations [25]. Deamination of cytosine generates uracil which can occur in DNA at a frequency of upto 100–500 per cell per day. Uracil misincorporation can in‐ duce CG to TA transition mutations [26]. Although endogenous *S*-adenosyl methionine (SAM) participates in targeted enzymatic DNA base methylation, non-enzymatic methylation of ring nitrogen of purine base adenine can be cytotoxic[26].  DNA bases damaged by oxidation, de‐ amination and alkylation produce a non-helix distorting, non-bulky base lesion. Such lesions

BER is a complex process and utilizes a number of enzymes and accessory scaffold proteins (Fig‐ ure 1). DNA glycosylases, AP endonuclease (APE-1) also called REF-1(Redox Effector Factor-1), DNA Polymerases, flap endonuclease (FEN-1), poly (ADP-ribose) polymerase 1(PARP-1) and DNA ligases are the key enzymes involved in BER. The core enzymes depend on accessory pro‐ teins such as X-ray cross complementation group 1 protein (XRCC1), proliferating cell nuclear antigen (PCNA), and protein 9-1-1 for coordinated action. DNA glycosylases initiate BER by ex‐ cising the damaged base from DNA and generating an abasic site. APE1 hydrolyzes the phos‐ phate bond 5' to the AP site leaving a 3'-OH group and a 5'-dRP flanking the nucleotide gap. Polymerase β (pol β) excises the 5'-dRP moiety generating a 5'-P. Members of the poly (ADP-ri‐ bose) polymerase (PARP) family of proteins get activated by single strand DNA breaks induced by APE1 and catalyze the addition of poly (ADP-ribose) polymers to target proteins, affecting protein-protein interactions. PARP may also be involved in the coordination of BER. At this point, BER can proceed through the short-patch (SP-BER) where pol β introduces a single nu‐ cleotide with the help of XRCC1. Ligase-IIIα subsequently seals the DNA nick establishing the phosphodiester DNA backbone. The long patch (LP-BER) processes those lesions that cannot be handled by the short patch such as oxidised AP sites. PCNA mediated Polymerase δ/ε introdu‐ ces two to eight nucleotides past the abasic site. The resulting overhang DNA is excised by FEN1

Prognostic factors are defined as patient and/or cancer characteristics that help to estimate patient survival independent of treatment. Conventionally these include patient age, fitness to withstand treatment toxicity (usually measured as performance status), tumour stage,

are the prime repair target of BER [6, 28-30].

530 New Research Directions in DNA Repair

endonuclease and the nick is then sealed by DNA ligase I.[28-32]

**2.1. BER factors are promising biomarkers in cancer**

**Figure 1.** DNA glycosylase initiates BER by excising the damaged base from DNA and generating an abasic site. APE 1 nicks the phosphodiester bond and hydrolyzes the phosphate bond 5' to the AP site leaving a 3'-OH group and a 5' dRP flanking the nucleotide gap. Pol β excises the 5'-dRP moiety generating a 5'-P. The short-patch (SP-BER) where pol β introduces a single nucleotide with the help of XRCC1. Ligase-IIIα subsequently seals the DNA nick establishing the phosphodiester DNA backbone. The long patch (LP-BER) processes those lesions that cannot be handled by the short patch such as oxidised AP sites. PCNA mediated Polymerase δ/ε introduces two to eight nucleotides past the abasic site. The resulting overhang DNA is excised by FEN1 endonuclease and the nick is then sealed by DNA ligase I.

Chemotherapeutic agents and ionizing radiation achieve cellular cytotoxicity by inducing DNA base damages [34]. However proficient BER in cancer cells results in therapeutic resist‐ ance and adversely impact patient outcomes. BER factors, therefore, are emerging as important prognostic factors as well as predictors of response to cytotoxic therapy in patients. For exam‐ ple, Temozolomide is an effective treatment for patients with high grade brain tumours. It indu‐ ces *O*6-meG, N3-meA and N7-meG base alkylation lesions which are processed by BER. [35]. Similarly, Melphalan which is used in the treatment of multiple myeloma induces N3-meA le‐ sions that is processed through BER [36]. Thiotepa is used with or without total body irradiation as a conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation in haematological diseases in adult and paediatric patients. Thiotepa produces formamidopyrimidine, 7-Methyl-formamidopyrimidine base lesions [37] which is repaired by BER. Dacarbazine is used in the treatment of patients with advanced malignant melanoma and Procarbazine is used in the treatment of Hodgkin's disease. They both produce *O*6-meG, N7 meG alkylation lesions which are targets of BER [38]. Streptozotocin generates *O*6-meG, N3 meA, N7-meG metabolites and is used in the treatment of neuroendocrine tumours of the gastro-intestinal (GI) tract.[39]. Platinating agents usually cause DNA inter-strand lesions which are repaired via NER, MMR and HR pathways (see table 1). Cisplatin is used in the treat‐ ment of advanced and metastatic non-small cell lung cancer (NSCLC), small cell carcinoma (SCLC), head and neck squamous cell carcinoma (HNSCC), germ cell tumour (GCT), gastric, pancreatic, bladder and cervical cancer. In addition to the DNA inter-strand lesions it also gen‐ erates reactive oxygen species (ROS) that results in oxidative base damages. ROS derived base damages are also seen in patients with colorectal cancer (CRC) treated with Oxaliplatin. ROS in‐ duced base damages are also seen with anthracyclines (epirubicin and doxorubicin), used in the treatment of breast, gastric, ovarian, sarcoma and in haematological malignancy. The antimeta‐ bolite gemcitabine used in the treatment of NSCLC, pancreatico-biliary, bladder, breast and ovarian cancer also causes DNA base damage. Given the essential role of BER in cytotoxic thera‐ py induced base damage, it is perhaps not surprising to note that several components of BER are promising prognostic and predictive factors. The following section will review individual markers and their relevance to cancer therapy.

expression was also predictive of worse prognosis (log-rank test, P 0.02) in NSCLC patients with lymph node involvement, regardless of the histology [46]. In another study, high nuclear and cytoplasmic APE1 expression was demonstrated in prostate cancer biopsy samples [47].

**DNA damaging agents DNA Lesions DNA repair pathways [104,**

Non-bulky alkyl adducts, base oxidation,

Bulky alkyl adducts, helix distorting

Mismatched base pairs, insertion

DS DNA break HR

DNA cross-links NER

DS DNA break HR

Replication fork arrest BER

Base damages, replication fork arrest BER

Double-strand breaks, Replication lesions HR, NHEJ

Bulky adducts NER, MMR

deamination, AP sites

lesions

deletion loops

Double-strand breaks Single-strand breaks Replication lesions

Single-strand breaks Double-strand breaks Base damage

pathway, HR: homologous repair pathway, NHEJ: non homologous end joining repair pathway.

Abbreviations: BER : base excision repair pathway, NER: Nucleotide excision repair pathway, MMR: mis match repair

Small alkyl base adducts Direct reversal

DNA Base Excision Repair: Evolving Biomarkers for Personalized Therapies in Cancer

1 Mono-functional alkylators: temozolomide, nitrosurea,

alkylsulfonates

2 Bi-functional alkylators: cisplatin, mitomycin C, nitrogen mustards, psoralen

3 Anti-metabolites: 5-

Folate analogues

4 Topoisomerase inhibitors: Etoposide

5 Replication inhibitors: Hydroxyrea

6 Ionising Radiation and

Radiomimetics: Bleomycin

**Table 1.** Cytotoxic agents and DNA Repair pathways

Fluorouracil (5FU) Thiopurines

**105]**

http://dx.doi.org/10.5772/54607

533

BER

NER

MMR

HR, NHEJ

NHEJ, HR,BER

#### **2.2 APE1**

Human apurinic / apyrimidinic endonuclease 1 (APE1) is a major endonuclease accounting for > 95% of the cellular AP endonuclease activity in most of the human cell lines [40]. It is also involved in redox regulation of transcription factors [41-43]. APE1 may be expressed in the cytoplasm and/ or in the nucleus of cancer cells. Although the precise sub-cellular localization and regulation is not clearly known, altered localization may have prognostic or predictive significance in patients. Table 2 summarizes the current knowledge regarding the association between APE1 and its role as a biomarker. We recently demonstrated that APE1 is over expressed in Ovarian, Gastro-oesophageal and pancreatico-biliary cancers [44]. In ovarian cancers, nuclear APE1 expression was seen in 71.9% of tumours and correlated with tumour type (P 0.006), optimal debulking (P 0.009), and overall survival (P 0.05). In gastro-oesophageal cancers previously exposed to neoadjuvant chemotherapy, 34.8% of tumours were positive in the nucleus and this correlated with shorter overall survival (P 0.005), whereas cytoplasmic localisation correlated with tumour de-differentiation (P 0.034). In pancreatico-biliary cancer, nuclear staining was seen in 44% of tumours. Absence of cytoplasmic staining was associated with perineural invasion (P 0.007), vascular invasion (P 0.05), and poorly differentiated tumours (P 0.068). [45]. In another study, a cohort of ninety one NSCLC patients treated with radical resection, tumour samples were analyzed for expression of APE1 protein. In patients with adenocarcinoma, cytoplasmic expression of APE1 was significantly associated with poor survival rate in univariate (P 0.01) and multivariate (P 0.07) analyses. In addition, a cytoplasmic expression was also predictive of worse prognosis (log-rank test, P 0.02) in NSCLC patients with lymph node involvement, regardless of the histology [46]. In another study, high nuclear and cytoplasmic APE1 expression was demonstrated in prostate cancer biopsy samples [47].

Abbreviations: BER : base excision repair pathway, NER: Nucleotide excision repair pathway, MMR: mis match repair pathway, HR: homologous repair pathway, NHEJ: non homologous end joining repair pathway.

**Table 1.** Cytotoxic agents and DNA Repair pathways

as a conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation in haematological diseases in adult and paediatric patients. Thiotepa produces formamidopyrimidine, 7-Methyl-formamidopyrimidine base lesions [37] which is repaired by BER. Dacarbazine is used in the treatment of patients with advanced malignant melanoma and Procarbazine is used in the treatment of Hodgkin's disease. They both produce *O*6-meG, N7 meG alkylation lesions which are targets of BER [38]. Streptozotocin generates *O*6-meG, N3 meA, N7-meG metabolites and is used in the treatment of neuroendocrine tumours of the gastro-intestinal (GI) tract.[39]. Platinating agents usually cause DNA inter-strand lesions which are repaired via NER, MMR and HR pathways (see table 1). Cisplatin is used in the treat‐ ment of advanced and metastatic non-small cell lung cancer (NSCLC), small cell carcinoma (SCLC), head and neck squamous cell carcinoma (HNSCC), germ cell tumour (GCT), gastric, pancreatic, bladder and cervical cancer. In addition to the DNA inter-strand lesions it also gen‐ erates reactive oxygen species (ROS) that results in oxidative base damages. ROS derived base damages are also seen in patients with colorectal cancer (CRC) treated with Oxaliplatin. ROS in‐ duced base damages are also seen with anthracyclines (epirubicin and doxorubicin), used in the treatment of breast, gastric, ovarian, sarcoma and in haematological malignancy. The antimeta‐ bolite gemcitabine used in the treatment of NSCLC, pancreatico-biliary, bladder, breast and ovarian cancer also causes DNA base damage. Given the essential role of BER in cytotoxic thera‐ py induced base damage, it is perhaps not surprising to note that several components of BER are promising prognostic and predictive factors. The following section will review individual

Human apurinic / apyrimidinic endonuclease 1 (APE1) is a major endonuclease accounting for > 95% of the cellular AP endonuclease activity in most of the human cell lines [40]. It is also involved in redox regulation of transcription factors [41-43]. APE1 may be expressed in the cytoplasm and/ or in the nucleus of cancer cells. Although the precise sub-cellular localization and regulation is not clearly known, altered localization may have prognostic or predictive significance in patients. Table 2 summarizes the current knowledge regarding the association between APE1 and its role as a biomarker. We recently demonstrated that APE1 is over expressed in Ovarian, Gastro-oesophageal and pancreatico-biliary cancers [44]. In ovarian cancers, nuclear APE1 expression was seen in 71.9% of tumours and correlated with tumour type (P 0.006), optimal debulking (P 0.009), and overall survival (P 0.05). In gastro-oesophageal cancers previously exposed to neoadjuvant chemotherapy, 34.8% of tumours were positive in the nucleus and this correlated with shorter overall survival (P 0.005), whereas cytoplasmic localisation correlated with tumour de-differentiation (P 0.034). In pancreatico-biliary cancer, nuclear staining was seen in 44% of tumours. Absence of cytoplasmic staining was associated with perineural invasion (P 0.007), vascular invasion (P 0.05), and poorly differentiated tumours (P 0.068). [45]. In another study, a cohort of ninety one NSCLC patients treated with radical resection, tumour samples were analyzed for expression of APE1 protein. In patients with adenocarcinoma, cytoplasmic expression of APE1 was significantly associated with poor survival rate in univariate (P 0.01) and multivariate (P 0.07) analyses. In addition, a cytoplasmic

markers and their relevance to cancer therapy.

**2.2 APE1**

532 New Research Directions in DNA Repair

**BER factor Key findings Year of**

patients treated with neo-adjuvant chemotherapy is associated

DNA Base Excision Repair: Evolving Biomarkers for Personalized Therapies in Cancer

23 APE1 APE1 is up-regulated in the NSCLC 2008 [115]

cancer-specific survival following radical radiotherapy in bladder

radiation and may be a useful predictor of progression after

outcome in patients with lung adenocarcinoma. Cytoplasmic expression of APE1 is a poor prognostic marker in node positive

responsible for resistance to treatment with chemotherapy and

Abbreviations: NSCLC: non small cell lung cancer, CRC: colorectal cancer, RCC: renal cell carcinoma, EOC: epithelial ovarian carcinoma, GCT: germ cell tumour, HNSCC: Head and neck Squamous cell carcinoma, BPH: benign prostatic hypertrophy.

resistance to chemoradiotherapy and poor survival

chemotherapy in Medulloblastomas and primitive

20 APE1 Nuclear expression of APE1 in gastro-oesophageal cancer

21 APE1 Polymorphism in APE1 gene may affect response to palliative

22 APE1 Altered APE1 expression found in platinum resistant ovarian

with poor prognosis.

cancer patients

cancer.

IR

osteosarcoma

chemotherapy in NSCLC.

24 APE1 APE1 activity promotes resistance to radiation plus

neuroectodermaltumours

26 APE1 APE1 over expression corresponds to poor prognosis in

27 APE1 APE 1 activity mediates resistance to alkylating agents and

adjuvant therapy in a subset of gliomas.

28 APE1 Cytoplasmic localization of APE1 seems to confer a poor survival

NSCLC regardless of the Histology.

29 APE1 Increased expression of APE1 is seen in GCT and may be

30 APE1 APE1 nuclear expression in HNSCC is directly related to

compared to BPH

resistance

**Table 2.** APE1

31 APE1 Increased APE1 cytoplasmic staining in prostate carcinoma as

32 APE1 APE1 expression in carcinompa of the cervix is a marker of radio-

25 APE1, XRCC1 High APE1 and XRCC1 protein expression levels predict better

**publication**

http://dx.doi.org/10.5772/54607

2010 [45]

2009 [113]

2009 [114]

2005 [116]

2005 [77]

2004 [117]

2004 [118]

2002 [46]

2001 [119]

2001 [120]

2001 [47]

1998 [121]

**Ref**

535

Abbreviations: NSCLC: non small cell lung cancer, CRC: colorectal cancer, RCC: renal cell carcinoma, EOC: epithelial ovarian carcinoma, GCT: germ cell tumour, HNSCC: Head and neck Squamous cell carcinoma, BPH: benign prostatic hypertrophy.

**Table 2.** APE1

**BER factor Key findings Year of**

predict poor survival and relapse in patients with NSCLC.

APE1 genetic variants may be associated with endometrial

development of gastric cancer in the Chinese population

on cancer risk particularly among Asian populations

Polymorphisms within BER genes may contribute to the

APE1 Asp148Glu and hOGG1 Ser326Cys polymorphisms might be associated with increasing risk of CRC in a Turkish population.

11 APE1 Polymorphisms of APE1 may confer susceptibility to RCC. 2011 [60]

progression and might be a valuable prognostic marker for EOC

16 APE1 Ape1 promotes radiation resistance in pediatric ependymomas 2011 [110]

18 APE1 APE1 may be a potential therapeutic target of MM. 2010 [112]

osteosarcoma local recurrence and/or metastasis.

1 APE1 Profound deregulation of APE1 acetylation status in triple negative breast cancer

2 APE1 Ape1 expression elevated by p53 aberration may be used to

cancer in Turkish women.

4 APE1 APE1 T1349G polymorphism may be a marker for the

the risk of colon cancer

5 APE1, XRCC1 APE1 allele and the 399Gln XRCC1 allele apparently increased

6 APE1 APE1-656 T "/> G polymorphism has a possible protective effect

8 APE1 Loss of APE1 expression causes cell growth arrest, mitochondrial

9 APE1 Genetic variant rs1760944 in APE1 was associated with gastric cancer survival in a Chinese population.

12 APE1 Cytoplasmic localization of APE1 is associated with tumor

13 APE1 Genetic variant in the APE1 promoter may modulate risk of

14 APE1 Changes in the expression of APE1 might contribute to lip

17 APE1 The APE1 expression had significant correlation with

15 APE1 APE1 inhibitors potentiated the cytotoxicity of alkylating agents in melanoma and glioma cell lines

19 APE1 APE1 is a potential drug target in ovarian, gastro-oesophageal, and pancreatico-biliary cancers.

glioblastoma.

carcinogenesis.

tumorigenesis of lung cancer.

impairment and apoptosis

3 APE1,

7 APE1, XRCC, OOG1

10 APE1, OGG1, XRCC1

XRCC1,HOGG1

534 New Research Directions in DNA Repair

**publication**

2012 [52]

2012 [53]

2012 [54]

2012 [55]

2012 [57]

2011 [106]

2011 [59]

2011 [107]

2011 [56]

2011 [58]

2011 [51]

2011 [61]

2011 [108]

2011 [109]

2010 [111]

2010 [44]

**Ref**

The commonly reported APE1 polymorphisms include Asp148Glu, Leu104Arg, Glu126Asp, Arg237Ala, Asp283Gly, Gln51His, Ile64Val, Gly306Glu and Thr141Gly [48-50]. In a cohort of epithelial ovarian cancer patients, cytoplasmic APE1 positivity was significantly associated with higher grade of tumour (P = 0.002), advanced stage (III + IV) compared to early stage (I + II) patients (40.7% vs. 11.8%; P = 0.002) and a lower survival rate compared to patients with cytoplasmic negative localization (P < 0.05) of APE1 [51]. Profound deregulation of APE1 acetylation status in triple negative breast cancer patients has recently been demonstrated. This may be a potential bio‐ marker for breast cancer aggressiveness [52]. In another study, one hundred and twen‐ ty five lung tumour samples were analysed for APE1 protein and mRNA expression by immunohistochemistry and real-time RT-PCR respectively. Cytoplasmic APE1 over‐ expression and p53 aberration was shown to be a potential predictor of poor survival and relapse in patients with NSCLC[53]. In a case control study of one hundred and four endometrial cancer patients with aged matched normal controls, APE1 Asp148Glu genotypes were determined by PCR-RFLP assays. Frequencies of Glu+ and Asp/Glu genotypes of APE1 were found to be more prevalent in patients than controls. This may represent a future diagnostic biomarker in endometrial cancer [54]. In a study in‐ volving three hundred and thirty eight newly diagnosed gastric cancer patients and matched control, APE1 genotype T1349G polymorphism was assessed. Compared with the APE1 TT genotype, individuals with the variant TG/GG genotypes had a signifi‐ cantly increased risk of gastric cancer (OR 1.69, 95% CI 1.19-2.40). Further analyses re‐ vealed that the variant genotypes were associated with an increased risk for diffusetype, low depth of tumour infiltration (T1 and T2), and lymph node metastatic gastric cancer. The APE1 T1349G polymorphism may be a biomarker for the development of aggressive gastric cancer [55]. Another cohort of nine hundred and twenty five gastric cancer patients was evaluated for the genetic variant rs1760944 in APE1. Survival anal‐ yses showed a statistically significant (P 0.025, log-rank test) differences in median sur‐ vival time between gastric cancer patients with APE1 rs1760944 TT (55 months) versus those with GT/GG (78 months). These studies suggest that APE1 polymorphism is a potential biomarker in patients with Gastric cancer [56]. In another study, significant differences in the distribution of APE1 genotype were found between colon cancer pa‐ tients and healthy individuals. The 148Asp APE1 allele apparently increased the risk of colon cancer (OR 1.9-2.3), suggesting it to be a biomarker in colorectal cancer (CRC) [57]. Polymorphisms of APE1 Asp148Glu (rs3136820) were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods in blood samples of seventy nine CRC patients at their initial staging and two hundred and forty seven healthy controls. Frequency of Glu allele of APE1 Asp148Glu was higher in CRC patients than in controls (P 0.006, OR 3.43; 95% CI 1.76-6.70)[58]. In a hospital-based case-control study of four hundred and fifty five lung cancer patients and four hundred and forty three controls, the single nucleotide polymorphisms (SNPs) of APE1 (Asp148Glu and -141T/G) were genotyped and analyzed. In a multi‐

variate logistic regression model, individuals homozygous for the variants APE1 -141GG showed a protective effect for lung cancer (OR 0.62; 95% CI 0.42-0.91; p 0.02). This study indirectly suggests that polymorphism in APE1 genes may be a biomarker and contribute in the pathogenesis of lung cancer [59]. In a case-control study of six hundred and twelve renal cell carcinoma (RCC) patients and six hundred and thirty two age and sex matched healthy controls, APE1 polymorphisms (-656 T>G, rs1760944 and 1349 T>G, rs1130409) were assessed. Compared with 1349 TT/TG genotypes, the variant genotype 1349 GG had a significantly increased risk of RCC (adjusted odds ra‐ tio 1.47; 95% CI 1.10-1.95), suggesting a role for APE1 polymorphism as a biomarker in RCC [60]. In a case-control study of seven hundred and sixty six glioma patients and eight hundred and twenty four cancer-free controls APE1/Ref-1 promoter -141T/G variant (rs1760944) was evaluated. Allele G was associated with significant decreased glioblastoma risk (OR 0.80; 95% CI 0.65-0.98; P 0.032) [61].In conclusion emerging stud‐ ies of APE1 in tumours suggest that APE1 is a promising biomarker in cancer. How‐

DNA Base Excision Repair: Evolving Biomarkers for Personalized Therapies in Cancer

http://dx.doi.org/10.5772/54607

537

ever, large prospective studies are required to confirm these observations.

X-ray repair cross-complementing group 1 (XRCC1) is a scaffolding protein and coordi‐ nates BER [62]. Cells deficient in XRCC1 are hypersensitive to DNA damaging agents such as ionizing radiation and alkylating agents. Pre-clinically XRCC1 deficiency can induce mutagenesis [63]. Embryonic knock out of XRCC1 is lethal. The most extensive‐ ly studied polymorphisms of XRCC1 are Arg194Trp, Arg280His, Arg399Gln, Arg399Gln, Pro161Leu and Tyr576S. Ensembl data base records ten somatic mutations and six genetic variations of human XRCC1gene. Table 3 summarizes the current knowledge regarding the association between APE1 and its role as a biomarker. XRCC1 SNPs rs1799782 and rs25487 were investigated using the TaqMan assay in one hundred and eighty five pancreatic cancer cases and one thousand four hundred and sixty five controls. The minor allele, rs25487 was significantly associated with pancreat‐ ic cancer risk in the per-allele model (OR 1.29; CI 1.01-1.65; P 0.043). Haplotype analy‐ sis of XRCC1 also showed a statistically significant association with pancreatic cancer risk [64]. Endometrial biopsy samples in a case control study assessed the polymor‐ phisms Arg399Gln. Gln/Gln genotype of XRCC1was more prevalent in patients than in controls suggesting XRCC1 polymorphisms as a biomarker in endometrial cancer [54]. In a case control study, polymorphisms of XRCC1 Arg399Gln allele increased the risk of colon cancer (OR 1.5-2.1)[57]. In a cohort of ninety nine advanced colorectal cancer patients treated with oxaliplatin based chemotherapy, polymorphisms of XRCC1 Arg399Gln (G-->A) genotypes were detected by TaqMan-MGB probe allelic discrimina‐ tion method. Cox proportional hazards model, adjusted for stage, performance status, and chemotherapy regimen, showed that XRCC1 G/G genotype increased the OR sig‐ nificantly (OR 3.555; 95 % CI, 2.119 - 5.963; P < 0.01). The result suggests that XRCC1 Arg399Gln polymorphism is associated with response to chemotherapy and time to

**2.3.  This study indirectly suggests that polymorphism in APE1 genes may be a biomarker and contribute in the pathogenesis of lung cancer [59]. In a case-control study of six hundred and twelve renal cell carcinoma (RCC) patients and six hundred and thirty two age and sex matched healthy controls, APE1 polymorphisms (-656 T>G, rs1760944 and 1349 T>G, rs1130409) were assessed. Compared with 1349 TT/TG genotypes, the variant genotype 1349 GG had a significantly increased risk of RCC (adjusted odds ra‐ tio 1.47; 95% CI 1.10-1.95), suggesting a role for APE1 polymorphism as a biomarker in RCC [60]. In a case-control study of seven hundred and sixty six glioma patients and eight hundred and twenty four cancer-free controls APE1/Ref-1 promoter -141T/G variant (rs1760944) was evaluated. Allele G was associated with significant decreased glioblastoma risk (OR 0.80; 95% CI 0.65-0.98; P 0.032) [61].In conclusion emerging stud‐ ies of APE1 in tumours suggest that APE1 is a promising biomarker in cancer. How‐ ever, large prospective studies are required to confirm these observations.

#### **2.3. XRCC1**

The commonly reported APE1 polymorphisms include Asp148Glu, Leu104Arg, Glu126Asp, Arg237Ala, Asp283Gly, Gln51His, Ile64Val, Gly306Glu and Thr141Gly [48-50]. In a cohort of epithelial ovarian cancer patients, cytoplasmic APE1 positivity was significantly associated with higher grade of tumour (P = 0.002), advanced stage (III + IV) compared to early stage (I + II) patients (40.7% vs. 11.8%; P = 0.002) and a lower survival rate compared to patients with cytoplasmic negative localization (P < 0.05) of APE1 [51]. Profound deregulation of APE1 acetylation status in triple negative breast cancer patients has recently been demonstrated. This may be a potential bio‐ marker for breast cancer aggressiveness [52]. In another study, one hundred and twen‐ ty five lung tumour samples were analysed for APE1 protein and mRNA expression by immunohistochemistry and real-time RT-PCR respectively. Cytoplasmic APE1 over‐ expression and p53 aberration was shown to be a potential predictor of poor survival and relapse in patients with NSCLC[53]. In a case control study of one hundred and four endometrial cancer patients with aged matched normal controls, APE1 Asp148Glu genotypes were determined by PCR-RFLP assays. Frequencies of Glu+ and Asp/Glu genotypes of APE1 were found to be more prevalent in patients than controls. This may represent a future diagnostic biomarker in endometrial cancer [54]. In a study in‐ volving three hundred and thirty eight newly diagnosed gastric cancer patients and matched control, APE1 genotype T1349G polymorphism was assessed. Compared with the APE1 TT genotype, individuals with the variant TG/GG genotypes had a signifi‐ cantly increased risk of gastric cancer (OR 1.69, 95% CI 1.19-2.40). Further analyses re‐ vealed that the variant genotypes were associated with an increased risk for diffusetype, low depth of tumour infiltration (T1 and T2), and lymph node metastatic gastric cancer. The APE1 T1349G polymorphism may be a biomarker for the development of aggressive gastric cancer [55]. Another cohort of nine hundred and twenty five gastric cancer patients was evaluated for the genetic variant rs1760944 in APE1. Survival anal‐ yses showed a statistically significant (P 0.025, log-rank test) differences in median sur‐ vival time between gastric cancer patients with APE1 rs1760944 TT (55 months) versus those with GT/GG (78 months). These studies suggest that APE1 polymorphism is a potential biomarker in patients with Gastric cancer [56]. In another study, significant differences in the distribution of APE1 genotype were found between colon cancer pa‐ tients and healthy individuals. The 148Asp APE1 allele apparently increased the risk of colon cancer (OR 1.9-2.3), suggesting it to be a biomarker in colorectal cancer (CRC) [57]. Polymorphisms of APE1 Asp148Glu (rs3136820) were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods in blood samples of seventy nine CRC patients at their initial staging and two hundred and forty seven healthy controls. Frequency of Glu allele of APE1 Asp148Glu was higher in CRC patients than in controls (P 0.006, OR 3.43; 95% CI 1.76-6.70)[58]. In a hospital-based case-control study of four hundred and fifty five lung cancer patients and four hundred and forty three controls, the single nucleotide polymorphisms (SNPs) of APE1 (Asp148Glu and -141T/G) were genotyped and analyzed. In a multi‐

536 New Research Directions in DNA Repair

X-ray repair cross-complementing group 1 (XRCC1) is a scaffolding protein and coordi‐ nates BER [62]. Cells deficient in XRCC1 are hypersensitive to DNA damaging agents such as ionizing radiation and alkylating agents. Pre-clinically XRCC1 deficiency can induce mutagenesis [63]. Embryonic knock out of XRCC1 is lethal. The most extensive‐ ly studied polymorphisms of XRCC1 are Arg194Trp, Arg280His, Arg399Gln, Arg399Gln, Pro161Leu and Tyr576S. Ensembl data base records ten somatic mutations and six genetic variations of human XRCC1gene. Table 3 summarizes the current knowledge regarding the association between APE1 and its role as a biomarker. XRCC1 SNPs rs1799782 and rs25487 were investigated using the TaqMan assay in one hundred and eighty five pancreatic cancer cases and one thousand four hundred and sixty five controls. The minor allele, rs25487 was significantly associated with pancreat‐ ic cancer risk in the per-allele model (OR 1.29; CI 1.01-1.65; P 0.043). Haplotype analy‐ sis of XRCC1 also showed a statistically significant association with pancreatic cancer risk [64]. Endometrial biopsy samples in a case control study assessed the polymor‐ phisms Arg399Gln. Gln/Gln genotype of XRCC1was more prevalent in patients than in controls suggesting XRCC1 polymorphisms as a biomarker in endometrial cancer [54]. In a case control study, polymorphisms of XRCC1 Arg399Gln allele increased the risk of colon cancer (OR 1.5-2.1)[57]. In a cohort of ninety nine advanced colorectal cancer patients treated with oxaliplatin based chemotherapy, polymorphisms of XRCC1 Arg399Gln (G-->A) genotypes were detected by TaqMan-MGB probe allelic discrimina‐ tion method. Cox proportional hazards model, adjusted for stage, performance status, and chemotherapy regimen, showed that XRCC1 G/G genotype increased the OR sig‐ nificantly (OR 3.555; 95 % CI, 2.119 - 5.963; P < 0.01). The result suggests that XRCC1 Arg399Gln polymorphism is associated with response to chemotherapy and time to progression in advanced colorectal cancer patients. This study pointed XRCC1 poly‐ morphism as a predictive biomarker in advanced CRC patients treated with oxaliplatin based chemotherapy [65].

**BER factor Key findings Year of**

colorectal cancer in the Chinese population.

prognostic factor in unresected NSCLC treated with

cancer risk, and individuals with XRCC1-77C variant have a significantly higher cancer risk, particularly in

candidate prognostic markers and predictive factor for benefit from adjuvant platinum-based chemotherapy in resectable gastric carcinoma.

associated with overall survival and response to platinum-based chemotherapy in lung cancer

development breast cancer, especially among Asian

post radiotherapy for localized prostate cancer.

may predict OS and response to palliative chemotherapy with FOLFOX / XELOX in metastatic

increased risk of acute skin reactions to radiotherapy in breast cancer patients

13 XRCC1 The 751 Lys/Gln polymorphism of the ERCC2 gene

14 XRCC1, XRCC3 XRCC1 and XRCC3 gene polymorphisms for risk of

15 XRCC1 XRCC1 399Gln is an independent unfavourable

16 XRCC1 XRCC1-Arg399Cln polymorphism is associated with

17 XRCC1 XRCC1 -77T"/>C polymorphism is associated with

the Asian population

19 XRCC1 Genetic polymorphisms in XRCC1 gene might be

20 XRCC1 XRCC1 T-77C and eNOS G874T may confer an

22 XRCC1 XRCC1 Arg399Gln allele is a risk factor for the

and African populations.

24 XRCC1 Combined polymorphisms of ERCC1 and XRCC1

CRC patients

23 XRCC1 genetic polymorphisms in XRCC1 may affect survival

21 XRCC1 XRCC1 399Gln/Gln genotype have an increased risk of colorectal cancer

patients.

18 XRCC1 XRCC1 protein expressions in tumor is novel

associations.

may be linked to endometrial cancer

radiotherapy and chemoradiotherapy

susceptibility to HCC, and XRCC1 Gln allele genotype showed significant prognostic

**publication**

DNA Base Excision Repair: Evolving Biomarkers for Personalized Therapies in Cancer

**Ref**

http://dx.doi.org/10.5772/54607

539

#1050][123]

2012 [Sobczuk, 2012

2012 [124]

2012 [125]

2012 [126]

2012 [67]

2012 [75]

2012 [127]

2012 [128]

2012 [129]

2011 [130]

2010 [131]

2010 [132]

progression in advanced colorectal cancer patients. This study pointed XRCC1 poly‐ morphism as a predictive biomarker in advanced CRC patients treated with oxaliplatin

**publication**

2012 [64]

2012 [66]

2012 [68]

2012 [69]

2012 [70]

2012 [76]

2012 [64]

2012 [71]

2012 [72]

2012 [73]

2012 [65]

2012 [Chiyomaru,

2012 #1047] [122]

**Ref**

**BER factor Key findings Year of**

the susceptibility and survival of ovarian cancer

significantly increased risk of gastric cancer

associated with poor survival in gastric cancer

sensitivity to platinum based chemotherapy in

contributed to individual susceptibility to lung

nonmelanoma skincancer and extramammary Paget's disease risk in a Japanese population.

candidate for contributing to the difference in the OS of gemcitabine/platinum-treated advanced

chemotherapy and time to progression in advanced

1 XRCC1 XRCC1 polymorphisms affect pancreatic cancer risk

in Japanese.

patients.

5 XRCC1 XRCC1 polymorphism is associated with

in Japanese.

9 XRCC1 Polymorphisms of XRCC1 gene might have

NSCLC

cancer.

6 XRCC1 High XRCC1 and low ATM were independently

7 XRCC1 XRCC1 polymorphisms affect pancreatic cancer risk

8 XRCC1 Genetic variations in XRCC1 exhibit variation in the

10 XRCC1 Arg194Trp polymorphism could be associated with

11 XRCC1 Polymorphism of XRCC1 Arg399Gln may be a

NSCLC patients.

12 XRCC1 XRCC1 Arg399Gln polymorphisms is associated

with a response to oxaliplantin-based

colorectal cancer in Chinese population.

2 XRCC1 Elevated cancer risk associated with XRCC1 polymorphism.

3 XRCC1 XRCC1 polymorphism might influence the risk of developing glioma

4 XRCC1, XRCC3 Polymorphisms in DNA repair genes have roles in

based chemotherapy [65].

538 New Research Directions in DNA Repair

**BER factor Key findings Year of**

advantage for SCLC and NSCLC patients after

palliative FOLFOX and can also be a prognostic survival factor in metastatic colorectal cancer.

absence of pathologic complete response and poor

factor in advanced NSCLC patients treated with

XRCC1 polymorphism may be a prognostic factor in

with MBC treated with high dose chemotherapy.

prognostic factors in muscle-invasive bladder cancer

response to platinum-based NAC in bulky cervical

with resistance to oxaliplatin/5-FU chemotherapy in

Abbreviations:ATM: ataxia telangiectasia mutated protein, FOLFOX: oxaliplatin and 5FU based chemotherapy, XELOX: oxliplatin and Capecitabine based chemotherapy, TCC: transitional cell carcinoma, BCG: Bacillus Calmette–Guérin, CRT:

Meta-analysis of fifty three case-control studies with twenty one thousand three hundred and forty nine cases and twenty three thousand six hundred forty nine controls for XRCC1 Arg280His polymorphism and its cancer risk were estimated using fixed or random effect

response rate to platinum based palliative chemotherapy in NSCLC patients.

37 XRCC1 XRCC1 polymorphism may predict survival

platinum based treatment

survival in oesophageal cancer

palliative Cisplatin and Gemcitabine.

40 XRCC1 XRCC1 polpmorphism may represent a prognostic

42 XRCC1 XRCC1-01may predict survival outcome in patients

43 XRCC1 Combined XPD and XRCC1 genotypes might be

patients treated with CRT.

44 XRCC1 Polymorphism of XRCC1 R399Q is associated with

45 XRCC1 Polymorphisms in the XRCC1 gene may impact the

46 XRCC1 Polymorphism of XRCC1 gene may be associated

advanced colorectal cancer.

cancer

chemoradiotherapy, MBC: metastatic breast cancer.

**Table 3.** XRCC1

38 XRCC1 XRCC1 polymorphism may predict response to

39 XRCC1 Variant alleles of XRCC1 associated with the

patients with CRC

41 OGG1, LIG3, APE1, POLB, XRCC1, PCNA **publication**

DNA Base Excision Repair: Evolving Biomarkers for Personalized Therapies in Cancer

2007 [145]

2006 [146]

2006 [147]

2006 [148]

2006 [95]

2006 [74]

2006 [149]

2006 [150]

2004 [151]

2001 [152]

**Ref**

http://dx.doi.org/10.5772/54607

541

Abbreviations:ATM: ataxia telangiectasia mutated protein, FOLFOX: oxaliplatin and 5FU based chemotherapy, XELOX: oxliplatin and Capecitabine based chemotherapy, TCC: transitional cell carcinoma, BCG: Bacillus Calmette–Guérin, CRT: chemoradiotherapy, MBC: metastatic breast cancer.

#### **Table 3.** XRCC1

**BER factor Key findings Year of**

treated with Cisplatin-Taxane combined

overall survival in advanced gastric cancer patients

may predict the sensitivity of advanced NSCLC to palliative chemotherapy treatment with vinorelbine

rate to palliative Cisplatin based chemotherapy in

25 XRCC1 XRCC1 194 CT genotype associated with inferior

26 XRCC1 XRCC1 codon 194 and codon 399 polymorphisms

27 XRCC1 XRCC 1 polymorphism may predict higher response

28 XRCC1 XRCC1 polymorphism in clinical stage III may be a

29 XRCC1 SNP of XRCC1 gene at codon 399 influences the

30 XRCC1, APE1 Polymorphism in APE1 and XRCC1 may represent

31 XRCC1 A rarely occurring XRCC1 variant may predict

32 XRCC1 XRCC1 variant alleles may be associated with

33 XRCC1 Genotypes of XRCC1 Arginine194Tryptophan and

34 XRCC1 XRCC1 variant may predict the risk of recurrence of bladder TCC post BCG treatment.

35 XRCC1 XRCC1 gene polymorphism may predict survival in

36 XRCC1 Polymorphism in XRCC1 gene is a potential

prognostic survival marker in HNSCC.

response to platinum based neo-adjuvant chemotherapy treatment in patients with cervical

prognostic factors in metastatic melanoma.

the treatment of oesophageal cancer.

response to Neoadjuvant chemo-radiotherapy for

shorter overall survival in lung cancer patients

GGH-401Cytosine/Thymine associated with the response to platinum based neo-adjuvant chemotherapy treatment in patients with cervical

good PS advanced Gastric cancer patients treated with Oxalipaltin based palliative chemotherapy.

prognostic and predictive marker in breast cancer patients treated with adjuvant CMF chemotherapy

chemotherapy.

540 New Research Directions in DNA Repair

and Cisplatin.

NSCLC patients

cancer.

cancer

**publication**

2010 [133]

2009 [134]

2009 [135]

2009 [136]

2009 [137]

2009 [138]

2009 [139]

2008 [140]

2008 [141]

2008 [142]

2007 [143]

2007 [144]

**Ref**

Meta-analysis of fifty three case-control studies with twenty one thousand three hundred and forty nine cases and twenty three thousand six hundred forty nine controls for XRCC1 Arg280His polymorphism and its cancer risk were estimated using fixed or random effect models. Minor variant His allele and Arg-His/His-His genotypes showed a statistical associa‐ tion with the risk of cancer (OR 1.16; 95% CI 1.08-1.25) [66]. Meta-analysis of thirteen studies in‐ volving a total of eleven thousand six hundred and seventy eight individuals showed that there was significant association between the C variant of XRCC1-77T>C polymorphism and cancer risk in all four genetic comparison models (OR C vs. T 1.19; 95% CI 1.07-1.31; P 0.001; OR homozygote model 1.28; 95% CI 1.07-1.52; P 0.007; OR recessive genetic model 1.22; 95% CI 1.04-1.44; P 0.015; OR dominant model 1.21; 95% CI 1.07-1.35, P 0.001). XRCC1 -77T>C polymor‐ phism is associated with cancer risk, and individuals with XRCC1 -77C variant have a signifi‐ cantly higher cancer risk, particularly in the Asian population [67]. Using a PCR-RFLP method, XRCC1 Arg194Trp, Arg280His and Arg399Gln were genotyped in six hundred and twenty four glioma patients and five hundred and eighty healthy controls. Significant differences in the distribution of the Arg399Gln allele were detected between glioma patients and healthy controls by a logistic regression analysis (OR 1.35; 95% CI 1.17-1.68; P 0.001). Arg399Gln var‐ iant (allele A) carriers had an increased glioma risk compared to the wild-type (allele G) homo‐ zygous carriers (OR 1.40, 95%CI 1.12-1.76, P 0.003)[68]. In a prospective follow-up study, a cohort of three hundred and ten ovarian cancer patients treated with platinum-based chemo‐ therapy between January 2005 to January 2007 were followed up to 2010. Genotyping of XRCC1 and XRCC3 polymorphisms was conducted by TaqMan Gene Expression assays. Low‐ er survival rate in XRCC1 399 Arg/Arg genotype than in Gln/ Gln, with a significant increased risk of death (HR 1.69; 95% CI 1.07-2.78) were observed. However no significant association be‐ tween XRCC1 Arg194Trp and XRCC1 Arg280His gene polymorphisms and ovarian cancer death was observed. [69]. A multicenter 1:1 matched case- control study of three hundred and seven pairs of gastric cancers patients and controls between October 2010 and August 2011 was undertaken. XRCC1 Arg194Trp and ADPRT Val762Ala were sequenced. Demographic data collected using a self-designed questionnaire. Individuals carrying XRCC1 Trp/Trp or Arg/Trp variant genotype had a significantly increased risk of gastric cancer (OR 1.718; 95% CI, 1.190-2.479). [70]. In a cohort of advanced NSCLC patients treated with platinum based chemo‐ therapy, XRCC1 polymorphism was evaluated. XRCC1 Arg194Arg, FAS-1377GG, and FASL-844T allele displayed no response to platinum, whereas patients with XRCC1 194Trp al‐ lele and XPC PAT +/+ had 68.8% response rate to platinum. In Logistic Regression analysis, a significant gene-dosage effect was detected along with the increasing number of favourable genotypes of these four polymorphisms (P 0.00002). Multi-loci analysis showed the impor‐ tance of genetic variations involved in BER repair and apoptotic pathways in sensitivity of plat‐ inum-based chemotherapy in NSCLC [71]. In a meta-analysis of forty four published casecontrol studies demonstrated that codon 194, codon 399 and -77 T > C polymorphisms of XRCC1 gene might have contributed to individual susceptibility to lung cancer [72]. In a anoth‐ er study, sixty two advanced NSCLC patients in a training set and forty five patients in a vali‐ dation set treated with gemcitabine/platinum were genotyped for XRCC1 polymorphism. Wild-type genotype of XRCC1 Arg399Gln (G/G) was associated with decreased median over‐ all survival than those carrying variant genotypes (G/A+A/A). In addition, there was a statisti‐ cally significant longer median OS in patients carrying wild-type ERCC2 Asp312Asn genotype (G/G) (51 months, 95% CI, 19-82 months versus 10 months, log-rank test, P < 0.001) than those carrying heterozygous variant genotypes (G/A). This points out the predictive biomarker sta‐ tus of XRCC1 in platinum treated NSCLC patients[73]. XRCC1 polymorphism is a potential predictive marker of platinum based treatment response in non-small cell lung carcinoma, col‐

orectal carcinoma, advanced gastric, advanced cervical, advanced operable oesophageal can‐ cer. It may also predict response to adjuvant CMF chemotherapy and high dose chemotherapy

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http://dx.doi.org/10.5772/54607

543

In a training and validating cohort of Gastric cancer patients, XRCC1 protein levels were signif‐ icantly downregulated in gastric cancers compared to adjacent non-cancerous tissues. Low tu‐ mour XRCC1 expression significantly correlated with shorter overall survival as well as with clinic-pathologic characteristics in patients without adjuvant treatment. Multivariate regres‐ sion analysis showed that low XRCC1 expressions, separately and together, were independent negative markers of OS. Adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) significantly im‐ proved OS compared with surgery alone (log-rank test, P 0.01). However, this effect was evi‐ dent only in the XRCC1 low expression group (HR 0.44, 95% CI 0.26-0.75; P 0.002); Adjuvant fluorouracil-leucovorin-platinum (FLP) did not improve OS, except in the patients with low XRCC1 expressions (P 0.024). XRCC1 protein expressions in tumour are novel candidate prog‐ nostic markers and predictive factors for benefit from adjuvant platinum-based chemotherapy (FLO or FLP) in patients with resectable gastric carcinoma [75]. SMUG1, FEN1, XRCC1 and ATM are involved in ROS induced oxidative DNA damage repair in gastric cancer patients. High expression of SMUG1, FEN1 and XRCC1 correlated to high T-stage (T3/T4) (P 0.001, 0.005 & 0.02 respectively). High expression of XRCC1 and FEN1 also correlated to lymph node posi‐ tive disease (P 0.009 and 0.02 respectively). High expression of XRCC1, FEN1 & SMUG1 corre‐ lated with poor disease specific survival (P 0.001, 0.006 and 0.05 respectively) and poor disease free survival (P 0.001, 0.001 & 0.02 respectively) [76]. Muscle-invasive transitional cell carcino‐ ma tumour samples from ninety patients treated with radical radiotherapy was evaluated for XRCC1 protein expression. Nuclear staining of XRCC1 was 96.5% (range, 0.6-99.6%). High ex‐ pression levels of XRCC1 (> or = 95% positivity) were associated with improved patient cancer-

XRCC1 has shown to be a promising prognostic biomarker in a majority of cancer groups including HNSCC, breast, ovarian, endometrial, cervical, lung, gastric, oesophageal, pancre‐ atic, glial, colorectal, hepatocellular, bladder transitional cell carcinoma, metastatic melanoma

FEN1 is a structure-specific 5′ endo/exonuclease with a range of functions during DNA repair and replication. It is a BER long patch protein. FEN1 also has a role in the processing of the okazaki lagging DNA strand synthesis. As an endonuclease, FEN1 recognizes double-stranded DNA with a 5′-unannealed flap and makes an endonucleolytic cleavage at the base of the flap. As a 5′ exonuclease, it degrades nucleotides from a nick or a gap. It may also be involved in maintaining stability of telomeres, inhibiting repeat sequence expansion and involved in creation of double-stranded DNA breaks when mammalian cells are subjected to X-ray irradiation[78]. Human flap endonuclease 1 gene has been shown to have 4 somatic mutations, one polymorphism, and two transcripts in the Ensembl data base. In the following section we will review the potential of FEN1 as a prognostic, predictive biomarker and its feasibility as a

in breast cancer [74].

specific survival (log-rank, P 0.006) [77].

and non melanomatous skin cancer.

drug target in cancer treatment (See Table 4).

**2.4. FEN1**

orectal carcinoma, advanced gastric, advanced cervical, advanced operable oesophageal can‐ cer. It may also predict response to adjuvant CMF chemotherapy and high dose chemotherapy in breast cancer [74].