Abstract
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. 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. 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. 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.
Overview
- The study aims to investigate the difference in cancer risks across ancestries and the role of inherited genetic predisposition in these differences. The study uses germline and somatic sequencing data generated by The Cancer Genome Atlas (TCGA) to analyze the association between cancer predisposition genes (CPGs) and cancer types within ancestral groups. The study also identifies predisposition-associated two-hit events and gene expression effects in tumors. The cohort of 9899 cancer cases is classified into individuals of primarily European, African, East Asian, South Asian, Native/Latin American, and admixed ancestries. The study's primary objective is to identify ancestry-specific genetic predisposition and inform genetic screening strategies.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The study identifies several significant differences or similarities in the results between these conditions. The study discovers a potentially novel association of BRCA2 in lung squamous cell carcinoma in the African ancestry, along with a known association of BRCA2 in ovarian serous cystadenocarcinoma. The study also identifies one previously known association of BRIP1 in stomach adenocarcinoma in the East Asian ancestry. Rare variant burden analysis further identifies 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. While several CPGs are shared across patients, many pathogenic variants are found to be ancestry-specific and trigger somatic effects.
Implications and Future Directions
- The study's findings have significant implications for the field of research or clinical practice. The study highlights the importance of ancestry-specific analyses of germline genomes in informing cancer genetic risk and prognosis of diverse populations. The study identifies several ancestry-specific genetic predispositions that can inform genetic screening strategies. The study also suggests that larger cohorts of diverse ancestries are required to pinpoint ancestry-specific genetic predisposition and inform genetic screening strategies. The study identifies several limitations, such as the small sample size and the need for larger cohorts of diverse ancestries. Future research directions could include studies using larger cohorts of diverse ancestries, studies exploring the role of environmental factors in cancer risk across ancestries, and studies investigating the impact of ancestry-specific genetic predispositions on cancer outcomes.