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; Li Ding

doi:10.1038/ncomms10086

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 KandothMaheetha 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, Li Ding

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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.

Original language	English
Article number	10086
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms10086
State	Published - Dec 22 2015

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Lu, C., Xie, M., Wendl, M. C., Wang, J., McLellan, M. D., Leiserson, M. D. M., Huang, K. L., Wyczalkowski, M. A., Jayasinghe, R., Banerjee, T., Ning, J., Tripathi, P., Zhang, Q., Niu, B., Ye, K., Schmidt, H. K., Fulton, R. S., McMichael, J. F., Batra, P., ... Ding, L. (2015). Patterns and functional implications of rare germline variants across 12 cancer types. Nature communications, 6, Article 10086. https://doi.org/10.1038/ncomms10086

@article{94fc300a9d324406b2e86d617f484c13,

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.",

author = "Charles Lu and Mingchao Xie and Wendl, {Michael C.} and Jiayin Wang and McLellan, {Michael D.} and Leiserson, {Mark D.M.} and Huang, {Kuan Lin} and Wyczalkowski, {Matthew A.} and Reyka Jayasinghe and Tapahsama Banerjee and Jie Ning and Piyush Tripathi and Qunyuan Zhang and Beifang Niu and Kai Ye and Schmidt, {Heather K.} and Fulton, {Robert S.} and McMichael, {Joshua F.} and Prag Batra and Cyriac Kandoth and Maheetha Bharadwaj and Koboldt, {Daniel C.} and Miller, {Christopher A.} and Kanchi, {Krishna L.} and Eldred, {James M.} and Larson, {David E.} and Welch, {John S.} and Ming You and Ozenberger, {Bradley A.} and Ramaswamy Govindan and Walter, {Matthew J.} and Ellis, {Matthew J.} and Mardis, {Elaine R.} and Graubert, {Timothy A.} and Dipersio, {John F.} and Ley, {Timothy J.} and Wilson, {Richard K.} and Goodfellow, {Paul J.} and Raphael, {Benjamin J.} and Feng Chen and Johnson, {Kimberly J.} and Parvin, {Jeffrey D.} and Li Ding",

note = "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.",

year = "2015",

month = dec,

day = "22",

doi = "10.1038/ncomms10086",

language = "English",

volume = "6",

journal = "Nature communications",

issn = "2041-1723",

}

Lu, C, Xie, M, Wendl, MC, Wang, J, McLellan, MD, Leiserson, MDM, Huang, KL, Wyczalkowski, MA , Jayasinghe, R, Banerjee, T, Ning, J, Tripathi, P, Zhang, Q, Niu, B, Ye, K, Schmidt, HK, Fulton, RS, McMichael, JF, Batra, P, Kandoth, C, Bharadwaj, M, Koboldt, DC, Miller, CA, Kanchi, KL, Eldred, JM, Larson, DE, Welch, JS, You, M, Ozenberger, BA, Govindan, R , Walter, MJ, Ellis, MJ, Mardis, ER, Graubert, TA, Dipersio, JF , Ley, TJ, Wilson, RK, Goodfellow, PJ, Raphael, BJ, Chen, F, Johnson, KJ, Parvin, JD & Ding, L 2015, 'Patterns and functional implications of rare germline variants across 12 cancer types', Nature communications, vol. 6, 10086. https://doi.org/10.1038/ncomms10086

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.

UR - http://www.scopus.com/inward/record.url?scp=84951293785&partnerID=8YFLogxK

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 -

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

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