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
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.
UR - https://www.scopus.com/pages/publications/84951293785
U2 - 10.1038/ncomms10086
DO - 10.1038/ncomms10086
M3 - 文章
C2 - 26689913
AN - SCOPUS:84951293785
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 10086
ER -
SDG 3 Good Health and Well-being