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

Research output: Contribution to journalArticle

115 Scopus citations

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 languageEnglish (US)
Article number10086
JournalNature communications
Volume6
DOIs
StatePublished - Dec 22 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint Dive into the research topics of 'Patterns and functional implications of rare germline variants across 12 cancer types'. Together they form a unique fingerprint.

  • Cite this

    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, [10086]. https://doi.org/10.1038/ncomms10086