Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pgen.1001136
Title: Germline variation controls the architecture of somatic alterations in tumors
Authors: Dworkin A.M.
Ridd K.
Bautista D. 
Allain D.C.
Iwenofu O.H.
Roy R.
Bastian B.C.
Toland A.E.
Keywords: allele
article
cancer risk
cancer susceptibility
chromosome 8q
chromosome aberration
comparative genomic hybridization
controlled study
cytoarchitecture
gene control
gene dosage
gene identification
gene locus
genetic predisposition
genetic variability
germ line
graft recipient
human
human tissue
microsatellite marker
mutational analysis
skin carcinoma
somatic mutation
squamous cell carcinoma
Allelic Imbalance
Chromosomes, Human, Pair 8
Comparative Genomic Hybridization
Genetic Loci
Germ-Line Mutation
Humans
Skin Neoplasms
Issue Date: 2010
Citation: Dworkin A.M., Ridd K., Bautista D., Allain D.C., Iwenofu O.H., Roy R., Bastian B.C., Toland A.E. (2010). Germline variation controls the architecture of somatic alterations in tumors. PLoS Genetics 6 (9) : e1001136. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pgen.1001136
Rights: Attribution 4.0 International
Abstract: Studies have suggested that somatic events in tumors can depend on an individual's constitutional genotype. We used squamous cell carcinomas (SCC) of the skin, which arise in high multiplicity in organ transplant recipients, as a model to compare the pattern of somatic alterations within and across individuals. Specifically, we performed array comparative genomic hybridization on 104 tumors from 25 unrelated individuals who each had three or more independently arisen SCCs and compared the profiles occurring within patients to profiles of tumors across a larger set of 135 patients. In general, chromosomal aberrations in SCCs were more similar within than across individuals (two-sided exact-test p-value <1×10-7), consistent with the notion that the genetic background was affecting the pattern of somatic changes. To further test this possibility, we performed allele-specific imbalance studies using microsatellite markers mapping to 14 frequently aberrant regions of multiple independent tumors from 65 patients. We identified nine loci which show evidence of preferential allelic imbalance. One of these loci, 8q24, corresponded to a region in which multiple single nucleotide polymorphisms have been associated with increased cancer risk in genome-wide association studies (GWAS). We tested three implicated variants and identified one, rs13281615, with evidence of allele-specific imbalance (p-value = 0.012). The finding of an independently identified cancer susceptibility allele with allele-specific imbalance in a genomic region affected by recurrent DNA copy number changes suggest that it may also harbor risk alleles for SCC. Together these data provide strong evidence that the genetic background is a key driver of somatic events in cancer, opening an opportunity to expand this approach to identify cancer risk alleles. © 2010 Dworkin et al.
Source Title: PLoS Genetics
URI: https://scholarbank.nus.edu.sg/handle/10635/161658
ISSN: 15537390
DOI: 10.1371/journal.pgen.1001136
Rights: Attribution 4.0 International
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