Patterns and functional implications of rare germline variants across 12 cancer types

Charles Lu, Mingchao Xie, Michael C. Wendl, Jiayin Wang, Michael D. McLellan, Mark D. M. Leiserson, Kuan-lin Huang, Matthew A. Wyczalkowski, Reyka Jayasinghe, Tapahsama Banerjee, Jie Ning, Piyush Tripathi, Qunyuan Zhang, Beifang Niu, Kai Ye, Heather K. Schmidt, Robert S. Fulton, Joshua F. McMichael, Prag Batra, Cyriac Kandoth, Maheetha Bharadwaj, Daniel C. Koboldt, Christopher A. Miller, Krishna L. Kanchi, James M. Eldred, David E. Larson, John S. Welch, Ming You, Bradley A. Ozenberger, Ramaswamy Govindan, Matthew J. Walter, Matthew J. Ellis, Elaine R. Mardis, Timothy A. Graubert, John F. Dipersio, Timothy J. Ley, Richard K. Wilson, Paul J. Goodfellow, Benjamin J. Raphael, Feng Chen, Kimberly J. Johnson, Jeffrey D. Parvin and Li Ding ()
Additional contact information
Charles Lu: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Mingchao Xie: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Michael C. Wendl: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Jiayin Wang: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Michael D. McLellan: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Mark D. M. Leiserson: Brown University
Kuan-lin Huang: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Matthew A. Wyczalkowski: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Reyka Jayasinghe: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Tapahsama Banerjee: The Ohio State University Comprehensive Cancer Center
Jie Ning: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Piyush Tripathi: Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Qunyuan Zhang: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Beifang Niu: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Kai Ye: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Heather K. Schmidt: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Robert S. Fulton: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Joshua F. McMichael: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Prag Batra: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Cyriac Kandoth: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Maheetha Bharadwaj: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Daniel C. Koboldt: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Christopher A. Miller: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Krishna L. Kanchi: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
James M. Eldred: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
David E. Larson: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
John S. Welch: Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Ming You: Medical College of Wisconsin
Bradley A. Ozenberger: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Ramaswamy Govindan: Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Matthew J. Walter: Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Matthew J. Ellis: Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Elaine R. Mardis: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Timothy A. Graubert: Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
John F. Dipersio: Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Timothy J. Ley: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Richard K. Wilson: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Paul J. Goodfellow: The Ohio State University Comprehensive Cancer Center
Benjamin J. Raphael: Brown University
Feng Chen: Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA
Kimberly J. Johnson: Brown School Master of Public Health Program, Washington University in St Louis
Jeffrey D. Parvin: The Ohio State University Comprehensive Cancer Center
Li Ding: The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms10086

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