Abstract
BackgroundDistinct prevalence of inherited genetic predisposition may partially explain the difference of cancer risks across ancestries. Ancestry-specific analyses of germline genomes are required to inform cancer genetic risk and prognosis of diverse populations.MethodsWe conducted analyses using germline and somatic sequencing data generated by The Cancer Genome Atlas. Collapsing pathogenic and likely pathogenic variants to cancer predisposition genes (CPG), we analyzed the association between CPGs and cancer types within ancestral groups. We also identified the predisposition-associated two-hit events and gene expression effects in tumors.ResultsGenetic ancestry analysis classified the cohort of 9899 cancer cases into individuals of primarily European (N = 8184, 82.7%), African (N = 966, 9.8%), East Asian (N = 649, 6.6%), South Asian (N = 48, 0.5%), Native/Latin American (N = 41, 0.4%), and admixed (N = 11, 0.1%) ancestries. In the African ancestry, we discovered a potentially novel association of BRCA2 in lung squamous cell carcinoma (OR = 41.4 [95% CI, 6.1–275.6]; FDR = 0.002) previously identified in Europeans, along with a known association of BRCA2 in ovarian serous cystadenocarcinoma (OR = 8.5 [95% CI, 1.5–47.4]; FDR = 0.045). In the East Asian ancestry, we discovered one previously known association of BRIP1 in stomach adenocarcinoma (OR = 12.8 [95% CI, 1.8–90.8]; FDR = 0.038). Rare variant burden analysis further identified 7 suggestive associations in African ancestry individuals previously described in European ancestry, including SDHB in pheochromocytoma and paraganglioma, ATM in prostate adenocarcinoma, VHL in kidney renal clear cell carcinoma, FH in kidney renal papillary cell carcinoma, and PTEN in uterine corpus endometrial carcinoma. Most predisposing variants were found exclusively in one ancestry in the TCGA and gnomAD datasets. Loss of heterozygosity was identified for 7 out of the 15 African ancestry carriers of predisposing variants. Further, tumors from the SDHB or BRCA2 carriers showed simultaneous allelic-specific expression and low gene expression of their respective affected genes, and FH splice-site variant carriers showed mis-splicing of FH.ConclusionsWhile several CPGs are shared across patients, many pathogenic variants are found to be ancestry-specific and trigger somatic effects. Studies using larger cohorts of diverse ancestries are required to pinpoint ancestry-specific genetic predisposition and inform genetic screening strategies.
Highlights
Distinct prevalence of inherited genetic predisposition may partially explain the difference of cancer risks across ancestries
These methods include those based on SNP-array genotypes used by Broad Institute, University of California San Francisco (UCSF), and Washington University (WashU), as well as those based on whole-exome sequencing data used by University of Trento and Exome aggregation consortium (ExAC)/Broad Institute
Ancestry demographics of the Cancer Genome Atlas Project (TCGA) cohort We classified the 9899 TCGA cases with pass-QC germline data across 33 cancer types by genotypedefined ancestries defined by the PanCanAtlas Ancestry Informative Markers (AIM) working group (Additional file 1: Fig. S1, the “Methods” section, Table 1)
Summary
Distinct prevalence of inherited genetic predisposition may partially explain the difference of cancer risks across ancestries. According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program, the cancer incidence per 100,000 ranges from 449 in race/ethnicity population self-identified as Whites, 453 in Blacks, 298 in Asian/Pacific Islanders, 315 in American Indian/Alaskan Natives, and 336 in Hispanics in the USA between 2011 and 2015 [1, 2]. While some of these differences may be attributed to non-genetic factors such as access to health care or diet, much can likely be explained by differences in the genomic architecture of these ancestries and differing frequencies of inherited genetic predisposition. Systematic cross-ancestry investigations of predisposing variants across cancer types are urgently needed to inform genetic testing for each ancestral group
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