Dataset Information

Pathogenic Germline Variants in 10,389 Adult Cancers.

ABSTRACT: We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

SUBMITTER: Huang KL

PROVIDER: S-EPMC5949147 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Pathogenic Germline Variants in 10,389 Adult Cancers.

Huang Kuan-Lin KL Mashl R Jay RJ Wu Yige Y Ritter Deborah I DI Wang Jiayin J Oh Clara C Paczkowska Marta M Reynolds Sheila S Wyczalkowski Matthew A MA Oak Ninad N Scott Adam D AD Krassowski Michal M Cherniack Andrew D AD Houlahan Kathleen E KE Jayasinghe Reyka R Wang Liang-Bo LB Zhou Daniel Cui DC Liu Di D Cao Song S Kim Young Won YW Koire Amanda A McMichael Joshua F JF Hucthagowder Vishwanathan V Kim Tae-Beom TB Hahn Abigail A Wang Chen C McLellan Michael D MD Al-Mulla Fahd F Johnson Kimberly J KJ Lichtarge Olivier O Boutros Paul C PC Raphael Benjamin B Lazar Alexander J AJ Zhang Wei W Wendl Michael C MC Govindan Ramaswamy R Jain Sanjay S Wheeler David D Kulkarni Shashikant S Dipersio John F JF Reimand Jüri J Meric-Bernstam Funda F Chen Ken K Shmulevich Ilya I Plon Sharon E SE Chen Feng F Ding Li L

Cell 20180401 2

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) lo ...[more]

PMID: 29625052

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Project description:Pathogenic variants (PVs) in ATM are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate ATM PV cancer risks independent of family cancer history. This analysis included patients referred for hereditary cancer testing with a multi-gene panel (N = 627,742). Cancer risks for ATM PV carriers (N = 4,607) were adjusted for family history using multivariable logistic regression and reported as ORs with 95% confidence intervals (CIs). Subanalyses of the c.7271T>G missense PV were conducted. Moderate-to-high risks for pancreatic (OR, 4.21; 95% CI, 3.24-5.47), prostate (OR, 2.58; 95% CI, 1.93-3.44), gastric (OR, 2.97; 95% CI, 1.66-5.31), and invasive ductal breast (OR, 2.03; 95% CI, 1.89-2.19) cancers were estimated for ATM PV carriers. Notably, c.7271T>G was associated with higher invasive ductal breast cancer risk (OR, 3.76; 95% CI, 2.76-5.12) than other missense and truncating ATM PVs. Low-to-moderate risks were seen for ductal carcinoma in situ (OR, 1.80; 95% CI, 1.61-2.02), male breast cancer (OR, 1.72; 95% CI, 1.08-2.75), ovarian cancer (OR, 1.57; 95% CI, 1.35-1.83), colorectal cancer (OR, 1.49; 95% CI, 1.24-1.79), and melanoma (OR, 1.46; 95% CI, 1.18-1.81). ATM PVs are associated with multiple cancer risks and, while professional society guidelines support that carriers are eligible for increased breast and pancreatic cancer screening, increased screening for prostate and gastric cancer may also be warranted. c.7271T>G is associated with high risk for breast cancer, with a 3- to 4-fold risk increase that supports consideration of strategies for prevention and/or early detection. PREVENTION RELEVANCE: This study estimated risks for multiple cancers associated with ATM pathogenic variants independent of family history. These results indicate that some common variants may be associated with higher breast cancer risks than previously appreciated and increased screening for prostate and gastric cancer may be warranted for carriers of ATM pathogenic variants.

Dataset Information

Pathogenic Germline Variants in 10,389 Adult Cancers.

Publications

Pathogenic Germline Variants in 10,389 Adult Cancers.

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