Germline variation controls the architecture of somatic alterations in tumors

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<1x10(-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.

Figure 1. Frequency of aCGH aberrations in skin tumors.

A frequency plot of somatic aberrations identified in 305 skin tumors by aCGH is shown. Each line is an individual BAC clone. Green indicates gain and red indicates loss. Clones are ordered from chromosome 1 through 22. Tumors profiled are from 181 patients with one or more independent SCCs and/or KAs.

Figure 2. aCGH profiles of independent tumors from two individuals.

aCGH profiles of three independent tumors from two individuals, A and B, are shown. Each dot represents a different BAC clone. The X-axis for each profile shows the BAC clones ordered from chromosomes 1 through 22. Chromosome boundaries are indicated by vertical lines and dotted lines indicate centromeres. The Y-axis is the log2ratio of the tumor genomic DNA compared to reference DNA. Blue lines indicate regions showing concordance for loss and orange lines indicate regions showing concordance for gain across tumors.

Figure 3. Loci with and without evidence of preferential allelic imbalance.

(A) Microsatellite marker showing evidence of preferential allelic imbalance. Four tumors from one individual were typed for microsatellite marker D3S3045. Compared to blood DNA, all four tumors showed respective loss of the 182 bp allele. A pattern of preferential allelic imbalance was observed in 8 of 9 informative individuals for this marker. (B) Microsatellite marker showing random allelic imbalance. Four tumors from one individual were typed for microsatellite marker D11S4463. Compared to the matched blood DNA, two tumors showed relative loss of the 118 bp allele and two tumors showed relative loss of the 122 bp allele.