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 ancestry- specific 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 ofBRCA2in lung squamous cell carcinoma (OR = 41.4 [95% CI, 6.1-275.6]; FDR = 0.002) along with the previously identified association ofBRCA2in 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 ofBRIP1in 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 includingSDHBin pheochromocytoma and paraganglioma,ATMin prostate adenocarcinoma,VHLin kidney renal clear cell carcinoma,FHin kidney renal papillary cell carcinoma, andPTENin uterine corpus endometrial carcinoma. Loss of heterozygosity was identified for 7 out of the 15 African ancestry carriers of predisposing variants. Further, tumors from theSDHBorBRCA2carriers showed simultaneous allelic specific expression and low gene expression of their respective affected genes; andFHsplice-site variant carriers showed mis-splicing ofFH.
Conclusion
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 ancestry- specific genetic predisposition to inform personalized diagnosis and screening strategies.
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