Germline Variation in Cancer-Susceptibility Genes in a Healthy, Ancestrally Diverse Cohort: Implications for Individual Genome Sequencing

Abstract

Technological advances coupled with decreasing costs are bringing whole genome and whole exome sequencing closer to routine clinical use. One of the hurdles to clinical implementation is the high number of variants of unknown significance. For cancer-susceptibility genes, the difficulty in interpreting the clinical relevance of the genomic variants is compounded by the fact that most of what is known about these variants comes from the study of highly selected populations, such as cancer patients or individuals with a family history of cancer. The genetic variation in known cancer-susceptibility genes in the general population has not been well characterized to date. To address this gap, we profiled the nonsynonymous genomic variation in 158 genes causally implicated in carcinogenesis using high-quality whole genome sequences from an ancestrally diverse cohort of 681 healthy individuals. We found that all individuals carry multiple variants that may impact cancer susceptibility, with an average of 68 variants per individual. Of the 2,688 allelic variants identified within the cohort, most are very rare, with 75% found in only 1 or 2 individuals in our population. Allele frequencies vary between ancestral groups, and there are 21 variants for which the minor allele in one population is the major allele in another. Detailed analysis of a selected subset of 5 clinically important cancer genes, BRCA1, BRCA2, KRAS, TP53, and PTEN, highlights differences between germline variants and reported somatic mutations. The dataset can serve a resource of genetic variation in cancer-susceptibility genes in 6 ancestry groups, an important foundation for the interpretation of cancer risk from personal genome sequences.

Whole-Genome Sequencing of a Healthy Aging Cohort

“…These genomes were compared to 1,507 adult members of the Inova Translational Medicine Institute (ITMI) pre-term birth cohort also sequenced on the Complete Genomics platform (Bodian et al, 2014). Individuals from these cohorts were filtered to retain only individuals of 95+% European ancestry and a maximum relatedness of 12.5% (see Experimental Methods ).…”

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

“…The p.Arg621Ser variant was also found in an AA subject in an ancestrally diverse cohort of 681 healthy individuals [51]. A previous study involving Japanese patients with Rb found that a majority of the somatic mutations were found in the adenovirus early region 1A (ElA) binding sites [52]; however, the p.Arg621Ser and p. Leu819Val variants have not been reported in any domestic report in patients with Rb.…”

Utility of whole-genome sequencing for detection of newborn screening disorders in a population cohort of 1,696 neonates

“…Biological parentage was confirmed genomically, and ancestry was computed from the genomic data as described. 10 State NBS results, confirmatory tests, and clinical diagnoses of NBS disorders were manually extracted from the neonates' EHR. Data not available from the EHR were obtained from the pediatrician of record when possible and from longitudinal health surveys from the First 1,000 Days of Life Study.…”

“…10 The discordance rate of variant calls in the NBS genes in 66 infants sequenced by both CG and Illumina is 0.00277, 95% confidence interval (0.00258, 0.00295) for single-nucleotide polymorphisms and 0.0134, 95% confidence interval (0.0123, 0.0146) for indels (Supplementary Figure S1 online) (the Illumina genomes for these 66 infants were used only for the concordance-rate calculation, not the other analyses presented).…”