all families were identified through the gliogene consortium , and the exclusions were based on reported information obtained from the questionnaire in which we asked about the clinical criteria used for these hereditary conditions .
we excluded all families with a reported or confirmed diagnosis of neurofibromatosis i , neurofibromatosis ii , turcot 's syndrome , or tuberous sclerosis .
we identified 146 ( 34% ) families meeting the criteria of having both familial glioma and associated cancers out of 428 probands recruited from 14 569 screened cases of incident glioma cases .
the cases were initially screened for family history of glioma and had been diagnosed between 2007 and 2011 at one of our 14 recruitment centers .
biospecimen and clinicopathological information from probands and the above description of selected family members were collected after obtaining informed consent according to protocols approved by each center 's institutional review board in accordance with the declaration of helsinki .
the genomic areas covering tp53 , cdkn2a , mlh1 , and msh2 were selected because these genes have previously been reported to be associated with cancer pedigrees known to include glioma .
distributions of demographic characteristics of the probands , pathological characteristics of the glial tumors , and clinical variables of glioma in the families were described based on information derived from personal questionnaires ( table  1 ) .
glioma families were included from sweden ( n = 14 ) , denmark ( n = 36 ) , israel ( n = 10 ) , and the united states ( n = 86 ) ( table  2 ) .
the first category was families with at least 2 glioma cases verified and a third reported or verified in the same family ( n = 67 : sweden n = 7 , denmark n = 12 , israel n = 5 , united states n = 43 ) .
( international classification of diseases codes for oncology : low grade glioma [ who grades i and ii ] : juvenile pilocytic astrocytoma [ 9421/3 ] , fibrillary astrocytoma [ 9420/3 ] , protoplasmic astrocytoma [ 9410/3 ] , gemistocytic astrocytoma [ 9411/3 ] , diffuse astrocytoma [ 9400/3 ] , oligodendroglioma [ 9450/3 ] , oligoastrocytoma [ 9382/3 ] , ependymoma [ 9391/3 ] ; high - grade glioma [ who grades iii and iv ] : anaplastic astrocytoma [ 9401/3 ] , anaplastic oligodendroglioma [ 9451/3 ] , anaplastic oligoastrocytoma [ 9382/3 ] , anaplastic ependymoma [ 9392/3 ] , gliosarcoma [ 9442/3 ] , gliomatosis cerebri [ 9381/3 ] , and glioblastoma [ 9440/3 ] ) . the second category was families with  2 glioma cases plus a report of at least one family member affected with colon cancer , breast cancer , or malignant melanoma ( n = 128 : sweden n = 12 , denmark n = 38 , israel n = 8 , and united states n = 70 ) . some families belonged to both categories , having  3 cases of glioma , and another cancer in the family ( n = 37 : sweden n = 5 , denmark n = 9 , israel n = 3 , and united states n = 20 ) ( table  2 ) . 

table  1.demographic characteristics of the probands and pathological characteristics of the glial tumors from sweden , denmark , israel , and united states ascertained for multiplex ligation - dependent probe amplification analyses of tp53 , cdkn2a / b , mlh1 and msh2glial tumor ( pathological characteristics)number of affected individualsmedian age at diagnosis ( y)sexracemale / femalewhite / black / hispanic / arabicastrocytic tumors  astrocytoma , unclassified343.02/12/0/1/0  astrocytoma , fibrillary143.00/11/0/0/0  astrocytoma , gemistocytic131.00/11/0/0/0  astrocytoma , juvenile pilocytic12.00/11/0/0/0  astrocytoma , diffuse929.03/68/0/1/0  astrocytoma , anaplastic1847.011/718/0/0/0  ganglioglioma229.00/22/0/0/0  glioma , unclassified539.02/35/0/0/0  glioblastoma6456.035/2961/2/0/1oligodendroglial tumors  oligodendroglioma1742.09/816/0/1/0  oligodendroglioma , anaplastic1051.52/810/0/0/0  oligoastrocytoma334.01/23/0/0/0  oligoastrocytoma , anaplastic345.01/23/0/0/0eppendymal tumors  ependymoma , myxopapillary224.50/22/0/0/0  ependymoma328.00/33/0/0/0  ependymoma , anaplastic160.00/11/0/0/0neuronal and mixed neuronal - glial tumors  dysembryoplastic neuroepithelial tumor128.00/11/0/0/0  paraganglioma of spinal cord151.00/11/0/0/0median age at diagnosis of probands . 

table  2.descriptive characteristics of glioma families from sweden , denmark , israel , and united states ascertained for multiplex ligation - dependent probe amplification analyses of tp53 , cdkn2a / b , mlh1 and msh2categoriesnumber of affected individualsmedian age at diagnosisnon - gbmgbmn ( % ) n ( % ) pedigrees available for mlpa analysis  united states8545.049 ( 57.0)36 ( 43.0 )  sweden1457.08 ( 57.1)6 ( 42.9 )  denmark3651.018 ( 50.0)18 ( 50.0 )  israel1049.55 ( 50.0)5 ( 50.0)pedigrees with 3 glioma  united states4348.020 ( 46.5)23 ( 53.5 )  sweden760.06 ( 85.7)1 ( 14.3 )  denmark1156.05 ( 45.5)6 ( 54.5 )  israel556.01 ( 20.0)4 ( 80.0)pedigrees with 2 glioma + colon cancer  united states5345.019 ( 35.2)34 ( 64.8 )  sweden1052.04 ( 40.0)6 ( 60.0 )  denmark2550.010 ( 40.0)15 ( 60.0 )  israel135.01 ( 100.0)napedigrees with 2 glioma + breast cancer  us3548.015 ( 42.9)20 ( 57.1 )  sweden560.03 ( 60.0)2 ( 40.0 )  denmark2445.012 ( 50.0)12 ( 50.0 )  israel841.05 ( 62.5)3 ( 37.5)pedigrees with 2 glioma + malignant melanoma  united states1651.510 ( 62.5)6 ( 37.5 )  sweden0nanana  denmark961.05 ( 55.6)4 ( 44.4 )  israel241.02 ( 100.0)namedian age at diagnosis of probands.overlap because some of the probands were included in several categories.abbreviations : mlpa , multiplex ligation - dependent probe amplification ; n , number of affected individuals ; na , not applicable .
demographic characteristics of the probands and pathological characteristics of the glial tumors from sweden , denmark , israel , and united states ascertained for multiplex ligation - dependent probe amplification analyses of tp53 , cdkn2a / b , mlh1 and msh2 median age at diagnosis of probands . descriptive characteristics of glioma families from sweden , denmark , israel , and united states ascertained for multiplex ligation - dependent probe amplification analyses of tp53 , cdkn2a / b , mlh1 and msh2 median age at diagnosis of probands .
abbreviations : mlpa , multiplex ligation - dependent probe amplification ; n , number of affected individuals ; na , not applicable .
the samples were screened for large deletions / duplications by multiplex ligation - dependent probe amplification ( mlpa ) .
small ( 5070 nt ) sequences are targeted , enabling mlpa to identify single exon aberrations .
the samples were ligated and amplified using the salsa mlpa p003 mlh1/msh2 probe mix version b2 according to the protocol manufacturer 's recommendation ( mrc - holland ) .
the p003 mlh1/msh2 probe mix version 2 contains probes for each of the 19 exons of the mlh1 gene and for each of the 16 exons of the msh2 gene .
also , 2 probes are included for the most 3 exon of epcam , a gene located just upstream of the msh2 gene .
deletions of the most 3 exon of the epcam gene can result in silencing of the msh2 gene .
in addition , the p003 mlh1/msh2 probe mix also covers 7 genes in the cdkn2a-9p21 region + pax5 ( 9p13 ) dock8 ( 9p24.3 ) , and gldc ( 9p21.1 ) .
the samples were analyzed on a ceqtm 8000 geneticanalysis system ( beckman coulter inc . ) .
data normalization and analysis were performed with genemarker software version 1.75 ( softgenetics ) using standard parameters .
standard mlpa analysis was performed following the manufacturer 's instructions ( mrc - holland ) , version 31 ; 17 - 06 - 211 .
one hundred nanograms of genomic dna were denatured and then hybridized with salsa mlpa probe mixes that covers 6 genes in the tp53 - 17p13.1 region + nf2 and chek2 ( included chek2 * 1100delc ) .
following ligation , pcr was performed in a bio - rad 1000series thermal cycler ( bio - rad laboratories ) .
fragment separation was carried out as suggested by mrc - holland on an abi 3100 sequencer using pop7 polymer and genescan-500 rox sizing standard ( applied biosystems ) .
8.75 l of hi - di formamide and 0.25 l of genescan-500 rox sizing standard were mixed with 1 l of the mlpa pcr product per sample for a total volume of 10 l .
since some of the variants found in this study were not standardized and clinically validated mutations , we used massively parallel sequencing of hybrid - captured dna to further evaluate preliminary findings from mlpa screening of genes in the 9p21 region .
agilent sureselect probes were designed to capture the genomic regions of cdkn2a and cdkn2b , including introns and 20 kb adjacent 5 and 3 regions , which covered the regions implicated by mlpa .
paired - end sequencing 2  100 bp was performed on the illumina hiseq2000 instrument to an average depth of > 100 reads , followed by alignment to the reference genome .
coverage over the suspected deleted / duplicated regions was not found to be different from coverage in control samples .
all families were identified through the gliogene consortium , and the exclusions were based on reported information obtained from the questionnaire in which we asked about the clinical criteria used for these hereditary conditions .
we excluded all families with a reported or confirmed diagnosis of neurofibromatosis i , neurofibromatosis ii , turcot 's syndrome , or tuberous sclerosis .
we identified 146 ( 34% ) families meeting the criteria of having both familial glioma and associated cancers out of 428 probands recruited from 14 569 screened cases of incident glioma cases .
the cases were initially screened for family history of glioma and had been diagnosed between 2007 and 2011 at one of our 14 recruitment centers .
biospecimen and clinicopathological information from probands and the above description of selected family members were collected after obtaining informed consent according to protocols approved by each center 's institutional review board in accordance with the declaration of helsinki .
the genomic areas covering tp53 , cdkn2a , mlh1 , and msh2 were selected because these genes have previously been reported to be associated with cancer pedigrees known to include glioma .
distributions of demographic characteristics of the probands , pathological characteristics of the glial tumors , and clinical variables of glioma in the families were described based on information derived from personal questionnaires ( table  1 ) .
glioma families were included from sweden ( n = 14 ) , denmark ( n = 36 ) , israel ( n = 10 ) , and the united states ( n = 86 ) ( table  2 ) .
the first category was families with at least 2 glioma cases verified and a third reported or verified in the same family ( n = 67 : sweden n = 7 , denmark n = 12 , israel n = 5 , united states n = 43 ) .
( international classification of diseases codes for oncology : low grade glioma [ who grades i and ii ] : juvenile pilocytic astrocytoma [ 9421/3 ] , fibrillary astrocytoma [ 9420/3 ] , protoplasmic astrocytoma [ 9410/3 ] , gemistocytic astrocytoma [ 9411/3 ] , diffuse astrocytoma [ 9400/3 ] , oligodendroglioma [ 9450/3 ] , oligoastrocytoma [ 9382/3 ] , ependymoma [ 9391/3 ] ; high - grade glioma [ who grades iii and iv ] : anaplastic astrocytoma [ 9401/3 ] , anaplastic oligodendroglioma [ 9451/3 ] , anaplastic oligoastrocytoma [ 9382/3 ] , anaplastic ependymoma [ 9392/3 ] , gliosarcoma [ 9442/3 ] , gliomatosis cerebri [ 9381/3 ] , and glioblastoma [ 9440/3 ] ) . the second category was families with  2 glioma cases plus a report of at least one family member affected with colon cancer , breast cancer , or malignant melanoma ( n = 128 : sweden n = 12 , denmark n = 38 , israel n = 8 , and united states n = 70 ) . some families belonged to both categories , having  3 cases of glioma , and another cancer in the family ( n = 37 : sweden n = 5 , denmark n = 9 , israel n = 3 , and united states n = 20 ) ( table  2 ) . 

table  1.demographic characteristics of the probands and pathological characteristics of the glial tumors from sweden , denmark , israel , and united states ascertained for multiplex ligation - dependent probe amplification analyses of tp53 , cdkn2a / b , mlh1 and msh2glial tumor ( pathological characteristics)number of affected individualsmedian age at diagnosis ( y)sexracemale / femalewhite / black / hispanic / arabicastrocytic tumors  astrocytoma , unclassified343.02/12/0/1/0  astrocytoma , fibrillary143.00/11/0/0/0  astrocytoma , gemistocytic131.00/11/0/0/0  astrocytoma , juvenile pilocytic12.00/11/0/0/0  astrocytoma , diffuse929.03/68/0/1/0  astrocytoma , anaplastic1847.011/718/0/0/0  ganglioglioma229.00/22/0/0/0  glioma , unclassified539.02/35/0/0/0  glioblastoma6456.035/2961/2/0/1oligodendroglial tumors  oligodendroglioma1742.09/816/0/1/0  oligodendroglioma , anaplastic1051.52/810/0/0/0  oligoastrocytoma334.01/23/0/0/0  oligoastrocytoma , anaplastic345.01/23/0/0/0eppendymal tumors  ependymoma , myxopapillary224.50/22/0/0/0  ependymoma328.00/33/0/0/0  ependymoma , anaplastic160.00/11/0/0/0neuronal and mixed neuronal - glial tumors  dysembryoplastic neuroepithelial tumor128.00/11/0/0/0  paraganglioma of spinal cord151.00/11/0/0/0median age at diagnosis of probands . 

table  2.descriptive characteristics of glioma families from sweden , denmark , israel , and united states ascertained for multiplex ligation - dependent probe amplification analyses of tp53 , cdkn2a / b , mlh1 and msh2categoriesnumber of affected individualsmedian age at diagnosisnon - gbmgbmn ( % ) n ( % ) pedigrees available for mlpa analysis  united states8545.049 ( 57.0)36 ( 43.0 )  sweden1457.08 ( 57.1)6 ( 42.9 )  denmark3651.018 ( 50.0)18 ( 50.0 )  israel1049.55 ( 50.0)5 ( 50.0)pedigrees with 3 glioma  united states4348.020 ( 46.5)23 ( 53.5 )  sweden760.06 ( 85.7)1 ( 14.3 )  denmark1156.05 ( 45.5)6 ( 54.5 )  israel556.01 ( 20.0)4 ( 80.0)pedigrees with 2 glioma + colon cancer  united states5345.019 ( 35.2)34 ( 64.8 )  sweden1052.04 ( 40.0)6 ( 60.0 )  denmark2550.010 ( 40.0)15 ( 60.0 )  israel135.01 ( 100.0)napedigrees with 2 glioma + breast cancer  us3548.015 ( 42.9)20 ( 57.1 )  sweden560.03 ( 60.0)2 ( 40.0 )  denmark2445.012 ( 50.0)12 ( 50.0 )  israel841.05 ( 62.5)3 ( 37.5)pedigrees with 2 glioma + malignant melanoma  united states1651.510 ( 62.5)6 ( 37.5 )  sweden0nanana  denmark961.05 ( 55.6)4 ( 44.4 )  israel241.02 ( 100.0)namedian age at diagnosis of probands.overlap because some of the probands were included in several categories.abbreviations : mlpa , multiplex ligation - dependent probe amplification ; n , number of affected individuals ; na , not applicable .
demographic characteristics of the probands and pathological characteristics of the glial tumors from sweden , denmark , israel , and united states ascertained for multiplex ligation - dependent probe amplification analyses of tp53 , cdkn2a / b , mlh1 and msh2 median age at diagnosis of probands . descriptive characteristics of glioma families from sweden , denmark , israel , and united states ascertained for multiplex ligation - dependent probe amplification analyses of tp53 , cdkn2a / b , mlh1 and msh2 median age at diagnosis of probands .
abbreviations : mlpa , multiplex ligation - dependent probe amplification ; n , number of affected individuals ; na , not applicable .
the samples were screened for large deletions / duplications by multiplex ligation - dependent probe amplification ( mlpa ) .
small ( 5070 nt ) sequences are targeted , enabling mlpa to identify single exon aberrations .
the samples were ligated and amplified using the salsa mlpa p003 mlh1/msh2 probe mix version b2 according to the protocol manufacturer 's recommendation ( mrc - holland ) .
the p003 mlh1/msh2 probe mix version 2 contains probes for each of the 19 exons of the mlh1 gene and for each of the 16 exons of the msh2 gene .
also , 2 probes are included for the most 3 exon of epcam , a gene located just upstream of the msh2 gene .
deletions of the most 3 exon of the epcam gene can result in silencing of the msh2 gene .
in addition , the p003 mlh1/msh2 probe mix also covers 7 genes in the cdkn2a-9p21 region + pax5 ( 9p13 ) dock8 ( 9p24.3 ) , and gldc ( 9p21.1 ) .
the samples were analyzed on a ceqtm 8000 geneticanalysis system ( beckman coulter inc . ) .
data normalization and analysis were performed with genemarker software version 1.75 ( softgenetics ) using standard parameters .
standard mlpa analysis was performed following the manufacturer 's instructions ( mrc - holland ) , version 31 ; 17 - 06 - 211 .
one hundred nanograms of genomic dna were denatured and then hybridized with salsa mlpa probe mixes that covers 6 genes in the tp53 - 17p13.1 region + nf2 and chek2 ( included chek2 * 1100delc ) .
probe mixes used were p056-a2 for tp53 and me024-b1 9p21 for cdkn2a/2b . following ligation , pcr was performed in a bio - rad 1000series thermal cycler ( bio - rad laboratories ) .
fragment separation was carried out as suggested by mrc - holland on an abi 3100 sequencer using pop7 polymer and genescan-500 rox sizing standard ( applied biosystems ) .
8.75 l of hi - di formamide and 0.25 l of genescan-500 rox sizing standard were mixed with 1 l of the mlpa pcr product per sample for a total volume of 10 l .
the samples were screened for large deletions / duplications by multiplex ligation - dependent probe amplification ( mlpa ) .
small ( 5070 nt ) sequences are targeted , enabling mlpa to identify single exon aberrations .
the samples were ligated and amplified using the salsa mlpa p003 mlh1/msh2 probe mix version b2 according to the protocol manufacturer 's recommendation ( mrc - holland ) .
the p003 mlh1/msh2 probe mix version 2 contains probes for each of the 19 exons of the mlh1 gene and for each of the 16 exons of the msh2 gene .
also , 2 probes are included for the most 3 exon of epcam , a gene located just upstream of the msh2 gene .
deletions of the most 3 exon of the epcam gene can result in silencing of the msh2 gene .
in addition , the p003 mlh1/msh2 probe mix also covers 7 genes in the cdkn2a-9p21 region + pax5 ( 9p13 ) dock8 ( 9p24.3 ) , and gldc ( 9p21.1 ) .
the samples were analyzed on a ceqtm 8000 geneticanalysis system ( beckman coulter inc . ) .
data normalization and analysis were performed with genemarker software version 1.75 ( softgenetics ) using standard parameters .
standard mlpa analysis was performed following the manufacturer 's instructions ( mrc - holland ) , version 31 ; 17 - 06 - 211 .
one hundred nanograms of genomic dna were denatured and then hybridized with salsa mlpa probe mixes that covers 6 genes in the tp53 - 17p13.1 region + nf2 and chek2 ( included chek2 * 1100delc ) .
following ligation , pcr was performed in a bio - rad 1000series thermal cycler ( bio - rad laboratories ) .
fragment separation was carried out as suggested by mrc - holland on an abi 3100 sequencer using pop7 polymer and genescan-500 rox sizing standard ( applied biosystems ) .
8.75 l of hi - di formamide and 0.25 l of genescan-500 rox sizing standard were mixed with 1 l of the mlpa pcr product per sample for a total volume of 10 l .
since some of the variants found in this study were not standardized and clinically validated mutations , we used massively parallel sequencing of hybrid - captured dna to further evaluate preliminary findings from mlpa screening of genes in the 9p21 region .
agilent sureselect probes were designed to capture the genomic regions of cdkn2a and cdkn2b , including introns and 20 kb adjacent 5 and 3 regions , which covered the regions implicated by mlpa .
paired - end sequencing 2  100 bp was performed on the illumina hiseq2000 instrument to an average depth of > 100 reads , followed by alignment to the reference genome .
coverage over the suspected deleted / duplicated regions was not found to be different from coverage in control samples .
we were able to successfully analyze 127 out of 146 glioma cases for tp53 and cdkn2a / b .
one hundred thirty - seven out of 146 glioma cases were also successfully analyzed for mlh1 and msh2 .
one mutation found was a deletion of exon 1 - 6 in msh2 ; this mutation was present in the proband of a single family .
the family included 3 glioma cases and 1 relative with colon cancer ( table  3 ) .
the other affected relatives in this family were a maternal first cousin diagnosed with anaplastic astrocytoma at age 32 years , a maternal first cousin 's child diagnosed with oligodendroglioma at age 51 years , and a maternal aunt diagnosed with colon cancer at age 84 years ( table  3 ) .
another aberration found was the variant chek2 1100delc , and this aberration was present in one family that included 3 cases with glioma and one relative with breast cancer ( table  3 ) .
the other affected relatives were the proband 's mother , who was diagnosed with a glioblastoma at age 72 years , the child of the mother 's firstcousin diagnosed with a glioblastoma at age 41 years , and a maternal aunt diagnosed with breast cancer at age 38 years . 

table  3.description of aberrations detected in glioma families from sweden , denmark , israel , and united states by multiplex ligation - dependent probe amplificationfamily idmaternal / paternalgliomascolon cancerbreast cancermelanomagenemlpa status1bilineal31msh2del exon 1 - 62maternal31chek21100 delc3paternal411cdkn2aprom dupl1022 before exon 14paternal211cdkn2aprom dupl1022 before exon 15paternal312cdkn2aprom dupl1022 before exon 16maternal31efnb3del exon 27paternal212efnb3del exon 28bilineal31gldcdupl 9p24.1the maternal ( mother s side)/paternal ( father s side ) refer only to the glioma in the family.unconfirmed glioma on the maternal side.abbreviation : mlpa , multiplex ligation - dependent probe amplification .
description of aberrations detected in glioma families from sweden , denmark , israel , and united states by multiplex ligation - dependent probe amplification the maternal ( mother s side)/paternal ( father s side ) refer only to the glioma in the family .
in addition , we found , a duplication at the promoter of cdkn2aprom dupl1022before ex1 ( in 3 of the families ) , a deletion at exon 2 of efnb3 delex2 ( in 2 of the families ) and a duplication of gldc dupl9p24.1 ( in one family ) but these aberrations could not be verified by next - generation sequencing ( table  2 ) .
in this large family study of gliomas , we found one large deletion in exons 1 - 6 of msh2 in one of the swedish families with a family history of colon cancer .
the sequence of the breakpoints of the exon 1 - 6 deletions and the haplotypes surrounding the mutation were identical in all 9 kindred , suggesting a common origin of the mutation .
a similar mutation was reported as an american founder mutation in families with lynch syndrome , an autosomal - dominant cancer syndrome traced back to a single couple who migrated from germany , and settled in pennsylvania in the early 1700s .
lynch syndrome is known to be associated with hereditary colorectal cancer and several extracolonic cancers including endometrial , gastric , small - bowel , renal , ovarian , and brain . despite a low incidence ,
brain tumors were the third highest cancer - related cause of death in a large dutch cohort of patients with lynch syndrome .
germline mutations in msh2 have also been described in families with a syndrome diagnosis such as turcot 's syndrome , which is clinically characterized by occurrence of primary brain tumors and colorectal cancer .
mutations in msh2 result in production of a faulty , truncated , or absent protein , which impairs the ability of the mmr system to recognize and repair dna mismatches .
we also identified rearrangements in the promoter of chek2 , the variant chek2 1100delc , in one american family having a family history of breast cancer .
chek2 acts as a checkpoint gene , activated in response to dna damage , and encodes a serine / threonine - protein kinase that phosphorylates p53 .
the germline 1100delc variant of chek2 is a frameshift mutation , resulting in a truncated and nonfunctional protein . nevertheless , chek2 is a well - known median penetrant gene that is quite common in the population
to our knowledge , this specific aberration in the promoter has not been previously described in the literature .
the aberration in cdkn2a was present in 3 families , all of which have a family history of both breast and colon cancer .
unfortunately , we were unable to confirm this aberration by additional deep - sequencing methods .
because of the unusual structure of cdkn2a , mutations in this locus may affect both p16 and p14 depending on the localization and type of sequence alteration .
the p16 has been found to be inactivated in the vast majority of melanomas through mutation , deletion , or promoter hypermethylation of cdkn2a .
the cdkn2a has , as a low penetrant risk loci , been associated with risk of glioma and melanoma in genome - wide association studies .
the aberration discovered in cdkn2a supports the finding that germline mutations in cdkn2a / cdkn2b could cause the co - occurrence of the melanoma - astrocytoma syndrome reported previously .
however , we did not observe the cdkn2a aberration in our families with a family history of melanoma , so it might be possible that other low - penetrance genes contributed to the melanoma - astrocytoma syndrome in this study . in conclusion , candidate genes in known syndromes do not explain these glioma - prone families .
large rearrangements are uncommon events explaining cancer - prone glioma families , and novel strategies of exome and whole genome sequencing of glioma families with similar phenotypes are one likely strategy for the future .
this work was supported by grants from the nih , bethesda , maryland ( 5r01 ca119215 , 5r01 ca070917 , r01ca52689 , p50097257 , r01ca126831 , 5p30ca16672 ) .
additional support was provided by the american brain tumor association , the national brain tumor society , and the tug mcgraw foundation . for more information about the gliogene consortium ,
the analyses was supported by the swedish cancer foundation , swedish research council , the acta oncologica foundation through the royal swedish academy of science ( bm salary support ) , support from ka wallenberg , the northern sweden cancer foundation , and ume university young research awards , the ume university hospital cutting edge research funds .
the costs of publication of this article were defrayed in part by the payment of page charges .
the members of the gliogene consortium : department of pediatrics , section of hematology and oncology , dan l. duncan cancer center , baylor college of medicine , houston , texas ( melissa l. bondy , ching c. lau , michael e. scheurer , georgina n. armstrong , yanhong liu ) ; department of biostatistics , the university of texas md anderson cancer center , houston , texas ( sanjay shete , robert k. yu ) ; department of pathology , the university of texas md anderson cancer center , houston , texas ( kenneth d. aldape ) ; department of neuro - oncology , the university of texas md anderson cancer center , houston , texas ( mark r. gilbert ) ; department of neurosurgery , the university of texas md anderson cancer center , houston , texas ( jeffrey weinberg ) ; section of cancer genetics , institute of cancer research , sutton , surrey , united kingdom ( richard s. houlston , fay j. hosking , lindsay robertson , elli papaemmanuil ) ; department of epidemiology and public health , yale university school of medicine , new haven , connecticut ( elizabeth b. claus ) ; department of neurosurgery , brigham and women 's hospital , boston , massachusetts ( elizabeth b. claus ) ; case comprehensive cancer center , case western reserve university school of medicine , cleveland , ohio ( jill barnholtz - sloan , andrew e. sloan , gene barnett , karen devine , yingli wolinsky ) ; departments of neurology , neurosurgery , and preventive medicine , university of southern california , keck school of medicine , los angeles , california ( rose lai , roberta mckean - cowdin ) ; cancer control and prevention program , department of community and family medicine , duke university medical center , durham , north carolina ( dora il'yasova , joellen schildkraut ) ; cancer and radiation epidemiology unit , gertner institute , chaim sheba medical center , tel hashomer , israel ( siegal sadetzki , galit hirsh yechezkel , revital bar - sade bruchim , lili aslanov ) ; sackler school of medicine , tel - aviv university , tel - aviv , israel ( siegal sadetzki ) ; cancer late effects research , oncology , finsencenteret , rigshospitalet , university of copenhagen and head , survivorship , danish cancer society research center , copenhagen , denmark ( christoffer johansen , ) ; neurosurgery department , rigshospitalet , university copenhagen ( michael kosteljanetz ) , neuropathology department , rigshospitalet , university of copenhagen , copenhagen , denmark ( helle broholm ) ; department of epidemiology and biostatistics , memorial sloan - kettering cancer center , new york , new york ( jonine l. bernstein , sara h. olson , erica schubert ) , department of neurology , memorial sloan - kettering cancer center , new york , new york ( lisa deangelis ) ; mayo clinic comprehensive cancer center , mayo clinic , rochester , minnesota ( robert b. jenkins , ping yang , amanda rynearson ) ; department of radiation sciences oncology , ume university , ume , sweden ( ulrika andersson , carl wibom , roger henriksson , beatrice s. melin ) ; computational life science cluster ( clic ) , ume university , ume , sweden ( carl wibom ) ; department of medical biosciences , pathology , ume university , ume , sweden ( kristina cederquist ) ; department of oncology , clinical science , lund university , lund , sweden ( steina aradottir , ke borg ) ; evanston kellogg cancer care center , north shore university health system , evanston , illinois ( ryan merrell , patricia lada ) ; departments of neurological surgery and epidemiology and biostatistics , university of california , san francisco , california ( margaret wrensch , john wiencke , joe wiemels , lucie mccoy ) ; division of epidemiology and biostatistics , university of illinois at chicago , chicago , illinois ( bridget j. mccarthy , faith g. davis ) .
 backgroundalthough familial susceptibility to glioma is known , the genetic basis for this susceptibility remains unidentified in the majority of glioma - specific families . 
 an alternative approach to identifying such genes is to examine cancer pedigrees , which include glioma as one of several cancer phenotypes , to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers.methodsgermline rearrangements in 146 glioma families ( from the gliogene consortium ; http://www.gliogene.org/ ) were examined using multiplex ligation - dependent probe amplification . 
 these families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma , colon , or breast cancer.the genomic areas covering tp53 , cdkn2a , mlh1 , and msh2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma.resultswe detected a single structural rearrangement , a deletion of exons 1 - 6 in msh2 , in the proband of one family with 3 cases with glioma and one relative with colon cancer.conclusionslarge deletions and duplications are rare events in familial glioma cases , even in families with a strong family history of cancers that may be involved in known cancer syndromes . 