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 ana...
Main Authors: | , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2020-05-01
|
Series: | Genome Medicine |
Online Access: | http://link.springer.com/article/10.1186/s13073-020-00744-3 |
_version_ | 1828760716320964608 |
---|---|
author | Ninad Oak Andrew D. Cherniack R. Jay Mashl TCGA Analysis Network Fred R. Hirsch Li Ding Rameen Beroukhim Zeynep H. Gümüş Sharon E. Plon Kuan-lin Huang |
author_facet | Ninad Oak Andrew D. Cherniack R. Jay Mashl TCGA Analysis Network Fred R. Hirsch Li Ding Rameen Beroukhim Zeynep H. Gümüş Sharon E. Plon Kuan-lin Huang |
author_sort | Ninad Oak |
collection | DOAJ |
description | 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. |
first_indexed | 2024-12-11T01:18:05Z |
format | Article |
id | doaj.art-de60882de0a144c695b5152ddc10189b |
institution | Directory Open Access Journal |
issn | 1756-994X |
language | English |
last_indexed | 2024-12-11T01:18:05Z |
publishDate | 2020-05-01 |
publisher | BMC |
record_format | Article |
series | Genome Medicine |
spelling | doaj.art-de60882de0a144c695b5152ddc10189b2022-12-22T01:25:48ZengBMCGenome Medicine1756-994X2020-05-0112111510.1186/s13073-020-00744-3Ancestry-specific predisposing germline variants in cancerNinad Oak0Andrew D. Cherniack1R. Jay Mashl2TCGA Analysis NetworkFred R. Hirsch3Li Ding4Rameen Beroukhim5Zeynep H. Gümüş6Sharon E. Plon7Kuan-lin Huang8Department of Oncology, St. Jude Children’s Research HospitalThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard UniversityDepartment of Medicine, Washington University in St. LouisDepartment of Oncological Sciences, Center for Thoracic Oncology, Tisch Cancer InstituteDepartment of Medicine, Washington University in St. LouisThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard UniversityDepartment of Genetics and Genomics, Icahn School of Medicine at Mount SinaiDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Genetics and Genomics, Icahn School of Medicine at Mount SinaiAbstract 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.http://link.springer.com/article/10.1186/s13073-020-00744-3 |
spellingShingle | Ninad Oak Andrew D. Cherniack R. Jay Mashl TCGA Analysis Network Fred R. Hirsch Li Ding Rameen Beroukhim Zeynep H. Gümüş Sharon E. Plon Kuan-lin Huang Ancestry-specific predisposing germline variants in cancer Genome Medicine |
title | Ancestry-specific predisposing germline variants in cancer |
title_full | Ancestry-specific predisposing germline variants in cancer |
title_fullStr | Ancestry-specific predisposing germline variants in cancer |
title_full_unstemmed | Ancestry-specific predisposing germline variants in cancer |
title_short | Ancestry-specific predisposing germline variants in cancer |
title_sort | ancestry specific predisposing germline variants in cancer |
url | http://link.springer.com/article/10.1186/s13073-020-00744-3 |
work_keys_str_mv | AT ninadoak ancestryspecificpredisposinggermlinevariantsincancer AT andrewdcherniack ancestryspecificpredisposinggermlinevariantsincancer AT rjaymashl ancestryspecificpredisposinggermlinevariantsincancer AT tcgaanalysisnetwork ancestryspecificpredisposinggermlinevariantsincancer AT fredrhirsch ancestryspecificpredisposinggermlinevariantsincancer AT liding ancestryspecificpredisposinggermlinevariantsincancer AT rameenberoukhim ancestryspecificpredisposinggermlinevariantsincancer AT zeynephgumus ancestryspecificpredisposinggermlinevariantsincancer AT sharoneplon ancestryspecificpredisposinggermlinevariantsincancer AT kuanlinhuang ancestryspecificpredisposinggermlinevariantsincancer |