47
IRUS Total
Downloads

Pathogenic germline variants in 10,389 adult cancers

File Description SizeFormat 
1-s2.0-S0092867418303635-main.pdfPublished version5.99 MBAdobe PDFView/Open
Title: Pathogenic germline variants in 10,389 adult cancers
Authors: Huang, K-L
Mashl, RJ
Wu, Y
Ritter, DI
Wang, J
Oh, C
Paczkowska, M
Reynolds, S
Wyczalkowski, MA
Oak, N
Scott, AD
Krassowski, M
Cherniack, AD
Houlahan, KE
Jayasinghe, R
Wang, L-B
Zhou, DC
Liu, D
Cao, S
Kim, YW
Koire, A
McMichael, JF
Hucthagowder, V
Kim, T-B
Hahn, A
Wang, C
McLellan, MD
Al-Mulla, F
Johnson, KJ
Lichtarge, O
Boutros, PC
Raphael, B
Lazar, AJ
Zhang, W
Wendl, MC
Govindan, R
Jain, S
Wheeler, D
Kulkarni, S
Dipersio, JF
Reimand, J
Meric-Bernstam, F
Chen, K
Shmulevich, I
Plon, SE
Chen, F
Ding, L
Item Type: Journal Article
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.
Issue Date: 5-Apr-2018
Date of Acceptance: 15-Mar-2018
URI: http://hdl.handle.net/10044/1/71219
DOI: https://doi.org/10.1016/j.cell.2018.03.039
ISSN: 0092-8674
Publisher: Elsevier
Start Page: 355
End Page: 370.e14
Journal / Book Title: Cell
Volume: 173
Issue: 2
Copyright Statement: © 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Sponsor/Funder: SAIC-F-Frederick, Inc
Leidos Biomedical Research, Inc.
Funder's Grant Number: TCGA Pilot Program
15Y011ST
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
MUTATIONS
KINASE
DISCOVERY
BRCA1
GUIDELINES
GENOMICS
SITES
RISK
LOH
cancer predisposition
germline and somatic genomes
variant pathogenicity
DNA Copy Number Variations
Databases, Genetic
Gene Deletion
Gene Frequency
Genetic Predisposition to Disease
Genotype
Germ Cells
Germ-Line Mutation
Humans
Loss of Heterozygosity
Mutation, Missense
Neoplasms
Polymorphism, Single Nucleotide
Proto-Oncogene Proteins c-met
Proto-Oncogene Proteins c-ret
Tumor Suppressor Proteins
Cancer Genome Atlas Research Network
Germ Cells
Humans
Neoplasms
Genetic Predisposition to Disease
Tumor Suppressor Proteins
Gene Deletion
Gene Frequency
Genotype
Loss of Heterozygosity
Germ-Line Mutation
Mutation, Missense
Polymorphism, Single Nucleotide
Databases, Genetic
Proto-Oncogene Proteins c-met
Proto-Oncogene Proteins c-ret
DNA Copy Number Variations
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
MUTATIONS
KINASE
DISCOVERY
BRCA1
GUIDELINES
GENOMICS
SITES
RISK
06 Biological Sciences
11 Medical and Health Sciences
Developmental Biology
Publication Status: Published
Open Access location: https://www.cell.com/cell/fulltext/S0092-8674(18)30363-5?_returnURL=https:%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867418303635%3Fshowall%3Dtrue
Online Publication Date: 2018-04-05
Appears in Collections:Department of Surgery and Cancer