Pathogenic Germline Variants in 10,389 Adult Cancers

Authors

Kuan lin Huang, Washington University in St. Louis
R. Jay Mashl, Washington University in St. Louis
Yige Wu, Washington University in St. Louis
Deborah I. Ritter, Texas Children's Hospital Houston
Jiayin Wang, Xi'an Jiaotong University
Clara Oh, Washington University in St. Louis
Marta Paczkowska, Ontario Institute for Cancer Research
Sheila Reynolds, Institute for Systems Biology
Matthew A. Wyczalkowski, Washington University in St. Louis
Ninad Oak, Baylor College of Medicine
Adam D. Scott, Washington University in St. Louis
Michal Krassowski, Ontario Institute for Cancer Research
Andrew D. Cherniack, Broad Institute
Kathleen E. Houlahan, Ontario Institute for Cancer Research
Reyka Jayasinghe, Washington University in St. Louis
Liang Bo Wang, Washington University in St. Louis
Daniel Cui Zhou, Washington University in St. Louis
Di Liu, Washington University in St. Louis
Song Cao, Washington University in St. Louis
Young Won Kim, Baylor College of Medicine
Amanda Koire, Baylor College of Medicine
Joshua F. McMichael, Washington University School of Medicine in St. Louis
Vishwanathan Hucthagowder, Molecular Pathology Laboratory Network, Inc.
Tae Beom Kim, University of Texas MD Anderson Cancer Center
Abigail Hahn, Institute for Systems Biology
Chen Wang, Mayo Medical School
Michael D. McLellan, Washington University School of Medicine in St. Louis
Fahd Al-Mulla, University of Kuwait
Kimberly J. Johnson, Washington University in St. Louis, George Warren Brown School of Social Work
Samantha J. Caesar-Johnson
John A. Demchok
Ina Felau
Melpomeni Kasapi

Document Type

Journal Article

Publication Date

4-5-2018

Journal

Cell

Volume

173

Issue

2

DOI

10.1016/j.cell.2018.03.039

Keywords

cancer predisposition; germline and somatic genomes; LOH; variant pathogenicity

Abstract

© 2018 The Authors 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. A pan-cancer analysis identifies hundreds of predisposing germline variants.

This document is currently not available here.

Share

COinS