Germline variation controls the architecture of somatic alterations in tumors

Autor: Dawn C. Allain, Amanda E. Toland, Amy M. Dworkin, O. Hans Iwenofu, Katie Ridd, Ritu Roy, Boris C. Bastian, Dianne Bautista
Rok vydání: 2010
Předmět:
Zdroj: PLoS Genetics
PLoS Genetics, Vol 6, Iss 9, p e1001136 (2010)
ISSN: 1553-7404
1328-1615
Popis: 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 ), 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.
Author Summary Tumors exhibit DNA copy number gains and losses, many of which alter the dosage of genes that promote or suppress tumorigenesis. Evidence from familial cancer syndromes and animal models have shown that DNA copy number changes acquired somatically during tumor progression can be controlled by the constitutional genotype. The genetic heterogeneity among humans makes it difficult to systematically assess the extent of this effect. We used a unique clinical scenario of squamous cell carcinoma (SCC), which can arise in high multiplicity within patients, to compare the pattern of somatic alterations on a homogeneous genetic background. We examined the genome-wide pattern of DNA copy number changes of tumors from individuals who had three or more independent SCCs. We identified multiple chromosomal regions that showed higher frequency of change in SCCs within patients than across patients, suggesting that the genetic background of the individual is important in driving these changes. We further confirmed this by identifying eight regions with strong evidence for a selection of loss or gain of a particular allele within patients. Together these data demonstrate that the genetic background of an individual influences the pattern of somatic alterations in tumors, offering a novel approach to map susceptibility alleles.
Databáze: OpenAIRE
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