title: Patterns and functional implications of rare germline variants across 12 cancer types.
abstract: Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C, PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes (ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2 and RAD51C/D). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine.
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Lu
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St. Louis, St Louis, Missouri 63108, USA.
authors.forename: Mingchao
authors.initials: M
authors.lastname: Xie
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St. Louis, St Louis, Missouri 63108, USA.|Department of Mathematics, Washington University in St. Louis, St Louis, Missouri 63108, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wendl
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Wang
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: McLellan
authors.affiliation: Department of Computer Science, Brown University, Providence, Rhode Island 02912, USA.|Center for Computational Molecular Biology, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: Mark D M
authors.initials: MD
authors.lastname: Leiserson
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Kuan-Lin
authors.initials: KL
authors.lastname: Huang
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Wyczalkowski
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Reyka
authors.identifier: http://orcid.org/0000-0003-2368-4890
authors.initials: R
authors.lastname: Jayasinghe
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Tapahsama
authors.initials: T
authors.lastname: Banerjee
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Ning
authors.affiliation: Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Piyush
authors.initials: P
authors.lastname: Tripathi
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Qunyuan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Beifang
authors.initials: B
authors.lastname: Niu
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St. Louis, St Louis, Missouri 63108, USA.
authors.forename: Kai
authors.identifier: http://orcid.org/0000-0002-2851-6741
authors.initials: K
authors.lastname: Ye
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Heather K
authors.initials: HK
authors.lastname: Schmidt
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St. Louis, St Louis, Missouri 63108, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Joshua F
authors.initials: JF
authors.lastname: McMichael
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Prag
authors.identifier: http://orcid.org/0000-0003-3482-0923
authors.initials: P
authors.lastname: Batra
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Cyriac
authors.initials: C
authors.lastname: Kandoth
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Maheetha
authors.initials: M
authors.lastname: Bharadwaj
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Koboldt
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Christopher A
authors.identifier: http://orcid.org/0000-0003-4266-6700
authors.initials: CA
authors.lastname: Miller
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Krishna L
authors.initials: KL
authors.lastname: Kanchi
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Eldred
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St. Louis, St Louis, Missouri 63108, USA.
authors.forename: David E
authors.identifier: http://orcid.org/0000-0001-7934-5906
authors.initials: DE
authors.lastname: Larson
authors.affiliation: Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, St Louis, Missouri 63108, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Welch
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: You
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
authors.forename: Bradley A
authors.identifier: http://orcid.org/0000-0002-2276-7013
authors.initials: BA
authors.lastname: Ozenberger
authors.affiliation: Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, St Louis, Missouri 63108, USA.
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Govindan
authors.affiliation: Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, St Louis, Missouri 63108, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walter
authors.affiliation: Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, St Louis, Missouri 63108, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St. Louis, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, St Louis, Missouri 63108, USA.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, St Louis, Missouri 63108, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.affiliation: Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, St Louis, Missouri 63108, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Dipersio
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St. Louis, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, St Louis, Missouri 63108, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St. Louis, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, St Louis, Missouri 63108, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Goodfellow
authors.affiliation: Department of Computer Science, Brown University, Providence, Rhode Island 02912, USA.|Center for Computational Molecular Biology, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Raphael
authors.affiliation: Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, St Louis, Missouri 63108, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: Brown School Master of Public Health Program, Washington University in St Louis, St Louis, Missouri 63130, USA.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Johnson
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.|Department of Biomedical Informatics and, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Parvin
authors.affiliation: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St. Louis, St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, St Louis, Missouri 63108, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000145:classification / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*; D014481:United States / Q000453:epidemiology; D055815:Young Adult