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:ImportanceNeuroblastoma accounts for 12% of childhood cancer deaths. The genetic contribution of rare pathogenic germline variation in patients without a family history remains unclear.ObjectiveTo define the prevalence, spectrum, and clinical significance of pathogenic germline variation in cancer predisposition genes (CPGs) in neuroblastoma patients.Design setting and participantsGermline DNA sequencing was performed on the peripheral blood from 786 neuroblastoma patients unselected for family history. Rare variants mapping to CPGs were evaluated for pathogenicity and the percentage of cases harboring pathogenic (P) or likely pathogenic (LP) variants was quantified. The frequency of CPG P-LP variants in neuroblastoma cases was compared to two distinct cancer-free control cohorts to assess enrichment. Matched tumor DNA sequencing was evaluated for "second hits" at CPGs and germline DNA array data from 5,585 neuroblastoma cases and 23,505 cancer-free control children was analyzed to identify rare germline copy number variants (CNVs) affecting genes with an excess burden of P-LP variants in neuroblastoma. Neuroblastoma patients with germline P-LP variants were compared to those without P-LP variants to test for association with clinical characteristics, tumor features, and patient survival.Main outcomes and measuresRare variant prevalence, pathogenicity, enrichment, and association with clinical characteristics, tumor features, and patient survival.ResultsWe observed 116 P-LP variants in CPGs involving 13.9% (109/786) of patients, representing a significant excess burden of P-LP variants compared to controls (9.1%; P = 5.14 × 10-5, Odds Ratio: 1.60, 95% confidence interval: 1.27-2.00). BARD1 harbored the most significant burden of P-LP variants compared to controls (1.0% vs. 0.03%; P = 8.18 × 10-7; Odds Ratio: 32.30, 95% confidence interval: 6.44-310.35). Rare germline CNVs disrupting BARD1 were also identified in neuroblastoma patients (0.05%) but absent in controls (P = 7.08 × 10-3; Odds Ratio: 29.47, 95% confidence interval: 1.52 - 570.70). Overall, P-LP variants in DNA repair genes in this study were enriched in cases compared to controls (8.1% vs. 5.7%; P = 0.01; Odds Ratio: 1.45, 95% confidence interval: 1.08-1.92). Neuroblastoma patients harboring a germline P-LP variant had a worse overall survival when compared to patients without P-LP variants (P = 8.6 × 10-3), and this remained significant in a multivariate Cox proportional-hazards model (P = 0.01).Conclusions and relevanceNeuroblastoma patients harboring germline P-LP variants in CPGs have worse overall survival and BARD1 is an important predisposition gene affected by both common and rare pathogenic variation. Germline sequencing should be performed for all neuroblastoma patients at diagnosis to inform genetic counseling and support future longitudinal and mechanistic studies. Patients with a germline P-LP variant should be closely monitored, regardless of risk group assignment.

Dataset Information

Pathogenic Germline Variants in 10,389 Adult Cancers.

Publications

Pathogenic Germline Variants in 10,389 Adult Cancers.

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