Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes

Yi Kan Wang, Ali Bashashati, Michael S. Anglesio, Dawn R. Cochrane, Diljot S. Grewal, Gavin Ha, Andrew McPherson, Hugo M. Horlings, Janine Senz, Leah M. Prentice, Anthony Karnezis, Daniel Lai, Mohamed R. Aniba, Allen W. Zhang, Karey Shumansky, Celia Siu, Adrian Wan, Melissa K. McConechy, Hector Li-Chang, Alicia ToneDiane Provencher, Manon De Ladurantaye, Hubert Fleury, Aikou Okamoto, Satoshi Yanagida, Nozomu Yanaihara, Misato Saito, Andrew J. Mungall, Richard Moore, Marco A. Marra, C. Blake Gilks, Anne Marie Mes-Masson, Jessica N. McAlpine, Samuel Aparicio, David G. Huntsman, Sohrab P. Shah

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

We studied the whole-genome point mutation and structural variation patterns of 133 tumors (59 high-grade serous (HGSC), 35 clear cell (CCOC), 29 endometrioid (ENOC), and 10 adult granulosa cell (GCT)) as a substrate for class discovery in ovarian cancer. Ab initio clustering of integrated point mutation and structural variation signatures identified seven subgroups both between and within histotypes. Prevalence of foldback inversions identified a prognostically significant HGSC group associated with inferior survival. This finding was recapitulated in two independent cohorts (n = 576 cases), transcending BRCA1 and BRCA2 mutation and gene expression features of HGSC. CCOC cancers grouped according to APOBEC deamination (26%) and age-related mutational signatures (40%). ENOCs were divided by cases with microsatellite instability (28%), with a distinct mismatch-repair mutation signature. Taken together, our work establishes the potency of the somatic genome, reflective of diverse DNA repair deficiencies, to stratify ovarian cancers into distinct biological strata within the major histotypes.

Original languageEnglish (US)
Pages (from-to)856-864
Number of pages9
JournalNature Genetics
Volume49
Issue number6
DOIs
StatePublished - Jun 1 2017
Externally publishedYes

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Point Mutation
DNA Repair
Ovarian Neoplasms
DNA Repair-Deficiency Disorders
BRCA2 Gene
Genome
Microsatellite Instability
Deamination
Mutation
DNA Mismatch Repair
Granulosa Cells
Cluster Analysis
Neoplasms
Gene Expression
Transcend

ASJC Scopus subject areas

  • Genetics

Cite this

Wang, Y. K., Bashashati, A., Anglesio, M. S., Cochrane, D. R., Grewal, D. S., Ha, G., ... Shah, S. P. (2017). Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes. Nature Genetics, 49(6), 856-864. https://doi.org/10.1038/ng.3849

Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes. / Wang, Yi Kan; Bashashati, Ali; Anglesio, Michael S.; Cochrane, Dawn R.; Grewal, Diljot S.; Ha, Gavin; McPherson, Andrew; Horlings, Hugo M.; Senz, Janine; Prentice, Leah M.; Karnezis, Anthony; Lai, Daniel; Aniba, Mohamed R.; Zhang, Allen W.; Shumansky, Karey; Siu, Celia; Wan, Adrian; McConechy, Melissa K.; Li-Chang, Hector; Tone, Alicia; Provencher, Diane; De Ladurantaye, Manon; Fleury, Hubert; Okamoto, Aikou; Yanagida, Satoshi; Yanaihara, Nozomu; Saito, Misato; Mungall, Andrew J.; Moore, Richard; Marra, Marco A.; Gilks, C. Blake; Mes-Masson, Anne Marie; McAlpine, Jessica N.; Aparicio, Samuel; Huntsman, David G.; Shah, Sohrab P.

In: Nature Genetics, Vol. 49, No. 6, 01.06.2017, p. 856-864.

Research output: Contribution to journalArticle

Wang, YK, Bashashati, A, Anglesio, MS, Cochrane, DR, Grewal, DS, Ha, G, McPherson, A, Horlings, HM, Senz, J, Prentice, LM, Karnezis, A, Lai, D, Aniba, MR, Zhang, AW, Shumansky, K, Siu, C, Wan, A, McConechy, MK, Li-Chang, H, Tone, A, Provencher, D, De Ladurantaye, M, Fleury, H, Okamoto, A, Yanagida, S, Yanaihara, N, Saito, M, Mungall, AJ, Moore, R, Marra, MA, Gilks, CB, Mes-Masson, AM, McAlpine, JN, Aparicio, S, Huntsman, DG & Shah, SP 2017, 'Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes', Nature Genetics, vol. 49, no. 6, pp. 856-864. https://doi.org/10.1038/ng.3849
Wang YK, Bashashati A, Anglesio MS, Cochrane DR, Grewal DS, Ha G et al. Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes. Nature Genetics. 2017 Jun 1;49(6):856-864. https://doi.org/10.1038/ng.3849
Wang, Yi Kan ; Bashashati, Ali ; Anglesio, Michael S. ; Cochrane, Dawn R. ; Grewal, Diljot S. ; Ha, Gavin ; McPherson, Andrew ; Horlings, Hugo M. ; Senz, Janine ; Prentice, Leah M. ; Karnezis, Anthony ; Lai, Daniel ; Aniba, Mohamed R. ; Zhang, Allen W. ; Shumansky, Karey ; Siu, Celia ; Wan, Adrian ; McConechy, Melissa K. ; Li-Chang, Hector ; Tone, Alicia ; Provencher, Diane ; De Ladurantaye, Manon ; Fleury, Hubert ; Okamoto, Aikou ; Yanagida, Satoshi ; Yanaihara, Nozomu ; Saito, Misato ; Mungall, Andrew J. ; Moore, Richard ; Marra, Marco A. ; Gilks, C. Blake ; Mes-Masson, Anne Marie ; McAlpine, Jessica N. ; Aparicio, Samuel ; Huntsman, David G. ; Shah, Sohrab P. / Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes. In: Nature Genetics. 2017 ; Vol. 49, No. 6. pp. 856-864.
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AU - Karnezis, Anthony

AU - Lai, Daniel

AU - Aniba, Mohamed R.

AU - Zhang, Allen W.

AU - Shumansky, Karey

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AU - McConechy, Melissa K.

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AU - Fleury, Hubert

AU - Okamoto, Aikou

AU - Yanagida, Satoshi

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AU - Saito, Misato

AU - Mungall, Andrew J.

AU - Moore, Richard

AU - Marra, Marco A.

AU - Gilks, C. Blake

AU - Mes-Masson, Anne Marie

AU - McAlpine, Jessica N.

AU - Aparicio, Samuel

AU - Huntsman, David G.

AU - Shah, Sohrab P.

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