Ancestry-Specific Predisposing Germline Variants in Cancer

Abstract

Background: Cancer risk differs across ancestries and these differences may result from differing prevalence of inherited genetic predisposition. Yet, most germline genomic studies performed to date have focused on individuals of European ancestry.Ancestry-specific analyses of germline genomes are required to inform cancer genetic risk and prognosis for each ancestral group. Here, we investigate potentially germline pathogenic variants in cancer predisposition genes (CPG) and their somatic effects in patients across diverse ancestral backgrounds. Methods:We performed a retrospective analysis of germline genomic data of 9,899 patients from 33 cancer types generated by The Cancer Genome Atlas (TCGA) project along with matching somatic genomic and transcriptomic data. By collapsing pathogenic and likely pathogenic variants to the gene level, we analyzed the association between variants in CPGs and cancer types within each ancestry. We also identified ancestryspecific predisposing variants and their associated somatic two-hit events and gene expression levels.Results: Recent genetic ancestry analysis classified the cohort of 9,899 cancer cases into individuals of primarily European, (N = 8,184 , 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) along with the previously identified association of BRCA2 in ovarian serous cystadenocarcinoma (OR=8.5 [95% CI, 1.5-47.4];FDR=0.045). Similarly, in the East Asian ancestry, we discovered one previously known association of BRIP1 in stomach adenocarcinoma (OR=12.8 [95% CI, 1.8-90.84];FDR=0.038). Rare variant burden analysis further identified 7 suggestive associations for cancer-gene pairs in African ancestry individuals previously well 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. 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. Conclusions:While several predisposing genes are shared across patients, many pathogenic variants are found to be ancestry-specific and trigger somatic effects.Analysis of larger diverse ancestries genomic cohorts are required to pinpoint ancestryspecific genetic predisposition to inform personalized diagnosis and screening strategies.

Trans-ethnic variation in germline variants of patients with renal cell carcinoma

“…There were no significant differences in the allele frequency of FH germline alterations in Africans versus other ethnic populations. Using The Cancer Genome Atlas (TCGA) data, a suggestive association was reported between FH in pRCC and FH germline variants (Oak et al, 2020). Herein, we restricted our analysis to LOF FH variants reported in ClinVar and found that, in gnomAD, LOF variants in CHEK2 were enriched in NFEs compared to Africans, while there was no significant difference in the prevalence of P/LP variants in FH.…”

HSD17B7 gene in self‐renewal and oncogenicity of keratinocytes from Black versus White populations

“…A large-scale genomic analysis across tumor types has revealed significant ancestry-and tissue-specific differences of likely functional significance, such as higher FBXW7 mutation rates in patients of African descent (Carrot-Zhang et al, 2020). A recent study of a large panel of cancer cell lines has also yielded ancestry-specific genetic and transcriptomic differences (Kessler et al, 2019), and a spectrum of ancestry-specific germline variations with a possible involvement in cancer predisposition has also been reported (Oak et al, 2020). By contrast, integrated genomic and functional analysis of normal cells from which cancers originate is, to our knowledge, still missing.…”

Identification of Germline Genetic Variants that Increase Prostate Cancer Risk and Influence Development of Aggressive Disease

“…17 [271,281] PrCa sequencing studies reported to date have primarily been performed using men of European ancestry; however, large panel sequencing studies have also been conducted in African ancestry [285] and Japanese populations [144]. These studies have provided supporting evidence for pan-ethnic contributions towards PrCa risk for particular genes, especially ATM and BRCA2; however, ethnic specific differences in mutation carrier rates at individual genes were also observed, indicating that the allelic frequency spectrum of moderate penetrance PrCa risk genes could differ substantially across ancestral groups [297]. A sequencing study of aggressive PrCa cases and disease-free controls also implicated rare variants in the TET2 gene, a locus previously associated with overall PrCa through GWAS [185], as a prospective susceptibility gene for aggressiveness in African American men, with 24.4% of aggressive cases and only 9.6% of controls carrying a rare deleterious TET2 variant [298].…”