Ancestry-specific predisposing germline variants in cancer

Abstract

Background: Distinct 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.

Methods: We 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.

Results: Genetic 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.

Conclusions: While 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.

Fig. 1

Cancer predisposing genes identified in each ancestry across 9899 TCGA cases across cancer types in the African ancestry, East Asian, and European ancestries. a Ancestry-specific cancer-gene pairs from TCGA dataset containing cancer predisposing variants as identified by multivariate logistic regression analyses. Each number represents carrier frequencies of predisposing genes within that cancer cohort. Genes with significant associations (Wald test FDR < 0.05) are highlighted with blue boxes. b Significant cancer-predisposing gene associations (FDR < 0.05) identified in the African and East Asian ancestries

Fig. 2

Ancestry-specific predisposing germline variants. Predisposing variants in the significant (regression analysis; a) and suggestive (rare variant burden testing; b) cancer-gene associations are shown. The variants are labeled with carrier counts and colored by their respective carriers’ ancestry (European Ancestry: blue, African ancestry: red, East Asian Ancestry: green). a Significant predisposing variants identified in the African and East Asian ancestries are shown across respective cancer types. For BRCA2, predisposing variants across all cancers are shown (top) in comparison with the two cancer types with significant associations in the African ancestry (LUSC and OV, bottom). Similarly, predisposing variants contributing to the significant association of BRIP1 in STAD in the East Asian ancestry are shown. b Suggestive predisposing variants identified in the African ancestry are shown for ATM, FH, and VHL genes within their associated cancer types. Bi-allelic events in each carrier are linked by a grey line bracket where the somatic second-hit mutations are marked with a box. c Borderline-suggestive predisposing variants identified in the East Asian ancestry are shown for RECQL in STAD and POLE in LIHC

Fig. 3

Loss of heterozygosity (LOH) and transcriptional effects associated with ancestry-specific predisposing germline variants. a LOH in ancestry-specific predisposing variants shown by comparing variant allele frequency in tumor vs. that in normal samples. Each dot denotes a variant and the affected genes are labeled in cases where showed both significant allelic imbalance and copy number deletion of the wild-type alleles (in purple). Variants showing significant allelic imbalance, yet no conclusive evidence of wild-type alleles are considered as other LOH and marked in yellow. All other variants are shown in grey. b Count distribution of each type of LOH events across genes in the African ancestry, the East Asian ancestry, and the European ancestry. Note given the larger number of events, the x-axis for the European ancestry is shown on a different scale

Fig. 4

Expression changes associated with the predisposing variants. a mRNA gene expression of the affected genes in the carriers of ancestry-specific variants as quantiles in their respective cancer cohort. Each dot denotes the gene expression level of a predisposing variant carrier colored by ancestry. Non-European variants corresponding to the bottom 25% expression in affected tumor suppressor genes and top 25% expression in affected oncogenes are further labeled. b Tumor RNA expression highlighting (red box) mis-spliced exon 5 with germline or somatic splice site variants in two cases with FH splice site variants as visualized using the integrated genome viewer (IGV). c Tumor RNA expression for the BRCA2 gene. The first two rows correspond to samples with a germline predisposing variant coupled with or without somatic LOH event, respectively. The third row corresponds to an unrelated sample without any BRCA2 alteration. All three coverage plots are group-scaled to show lower expression in the two samples harboring BRCA2 alterations