TY - JOUR
T1 - Patterns and functional implications of rare germline variants across 12 cancer types
AU - Lu, Charles
AU - Xie, Mingchao
AU - Wendl, Michael C.
AU - Wang, Jiayin
AU - McLellan, Michael D.
AU - Leiserson, Mark D.M.
AU - Huang, Kuan Lin
AU - Wyczalkowski, Matthew A.
AU - Jayasinghe, Reyka
AU - Banerjee, Tapahsama
AU - Ning, Jie
AU - Tripathi, Piyush
AU - Zhang, Qunyuan
AU - Niu, Beifang
AU - Ye, Kai
AU - Schmidt, Heather K.
AU - Fulton, Robert S.
AU - McMichael, Joshua F.
AU - Batra, Prag
AU - Kandoth, Cyriac
AU - Bharadwaj, Maheetha
AU - Koboldt, Daniel C.
AU - Miller, Christopher A.
AU - Kanchi, Krishna L.
AU - Eldred, James M.
AU - Larson, David E.
AU - Welch, John S.
AU - You, Ming
AU - Ozenberger, Bradley A.
AU - Govindan, Ramaswamy
AU - Walter, Matthew J.
AU - Ellis, Matthew J.
AU - Mardis, Elaine R.
AU - Graubert, Timothy A.
AU - Dipersio, John F.
AU - Ley, Timothy J.
AU - Wilson, Richard K.
AU - Goodfellow, Paul J.
AU - Raphael, Benjamin J.
AU - Chen, Feng
AU - Johnson, Kimberly J.
AU - Parvin, Jeffrey D.
AU - Ding, Li
N1 - Funding Information:
This work was supported by the National Cancer Institute grants R01CA180006 and R01CA178383 to L.D., R01CA141090 to J.D.P. and PO1CA101937 to T.J.L., the National Human Genome Research Institute grants U01HG006517 to L.D., R01HG007069 to B.J.R. and U54HG003079 to R.K.W., the National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK087960 and DoD grant PC130118 to F.C., NHGRI Genome Analysis Training Program (T32 HG000045) to M.X., Ministry of Education in Taiwan Fellowship to K.-L.H. and CMB training grant (GM 007067) to R.J. We want to thank the Analysis Pipeline group at the McDonnell Genome Institute for developing the automated sequence analysis pipelines. We also acknowledge The Cancer Genome Atlas (cancergenome.nih.gov) as the source of primary data and members of the TCGA Research Network for helpful discussions.
PY - 2015/12/22
Y1 - 2015/12/22
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms10086
DO - 10.1038/ncomms10086
M3 - Article
C2 - 26689913
AN - SCOPUS:84951293785
SN - 2041-1723
VL - 6
JO - Nature communications
JF - Nature communications
M1 - 10086
ER -