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Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes

Nature Genetics volume 44, pages 1310–1315 (2012)Cite this article

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Abstract

Endometrial cancer is the sixth most commonly diagnosed cancer in women worldwide, causing ∼74,000 deaths annually1. Serous endometrial cancers are a clinically aggressive subtype with a poorly defined genetic etiology2,3,4. We used whole-exome sequencing to comprehensively search for somatic mutations within ∼22,000 protein-encoding genes in 13 primary serous endometrial tumors. We subsequently resequenced 18 genes, which were mutated in more than 1 tumor and/or were components of an enriched functional grouping, from 40 additional serous tumors. We identified high frequencies of somatic mutations in CHD4 (17%), EP300 (8%), ARID1A (6%), TSPYL2 (6%), FBXW7 (29%), SPOP (8%), MAP3K4 (6%) and ABCC9 (6%). Overall, 36.5% of serous tumors had a mutated chromatin-remodeling gene, and 35% had a mutated ubiquitin ligase complex gene, implicating frequent mutational disruption of these processes in the molecular pathogenesis of one of the deadliest forms of endometrial cancer.

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Figure 1: Somatic mutations in CHD4, FBXW7 and SPOP cluster within important functional domains of the encoded proteins.
Figure 2: Distribution of nonsynonymous somatic mutations in endometrial cancers.
Figure 3: Somatic mutations in the consensus cancer genes EP300 and ARID1A relative to the functional domains of the encoded proteins.

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Acknowledgements

We thank our colleagues for critical reading of the manuscript; R.T. Moreland and N. Trivedi of the National Human Genome Research Institute Bioinformatics and Scientific Programming Core, respectively, for performing in silico PCR and giving advice on statistics; and J. Teer for sharing expertise on VarSifter. A. Santin (Yale School of Medicine) kindly provided the ARK1 and ARK2 cell lines. The study was funded in part by the Intramural Program of the National Human Genome Research Institute, US NIH (D.W.B., J.C.M. and M.J.M.); NIH grant R01CA112021 (D.C.S.); the Avon Foundation (D.C.S.); NIH grant R01CA140323 (A.K.G.); and the Ovarian Cancer Fund (A.K.G.). P.H. is supported by grants from the NIH (CA016519) and by the Canadian Institutes for Health Research (MOP-38096).

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Author notes

  1. Matthieu Le Gallo, Andrea J O'Hara and Maria J Merino: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Genetics Branch, National Human Genome Research Institute, US National Institutes of Health (NIH),, Bethesda, Maryland, USA

    Matthieu Le Gallo, Andrea J O'Hara, Meghan L Rudd, Mary Ellen Urick, Jessica C Price, Bryant M England & Daphne W Bell

  2. Genome Technology Branch, National Human Genome Research Institute, US NIH, Bethesda, Maryland, USA

    Nancy F Hansen, Suiyuan Zhang & James C Mullikin

  3. Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada

    Nigel J O'Neil & Philip Hieter

  4. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA

    Andrew K Godwin

  5. Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    Dennis C Sgroi

  6. Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    Dennis C Sgroi

  7. NISC, US NIH, Bethesda, Maryland, USA

    James C Mullikin

  8. National Cancer Institute, US NIH, Bethesda, Maryland, USA

    Maria J Merino

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NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program

Contributions

D.W.B. designed and directed the study and wrote the manuscript. A.K.G. contributed clinical specimens. M.J.M. and D.C.S. conducted pathological review of clinical specimens. M.L.R. prepared DNA samples and performed identity testing and microsatellite instability analysis. NISC performed library construction and whole-exome sequencing. NISC and N.F.H. performed variant calling. M.L.G. and A.J.O. curated and orthogonally validated exome sequencing data. M.L.G., A.J.O. and D.W.B. interpreted the exome data and established filtering criteria. M.L.G., A.J.O., M.L.R., J.C.P., B.M.E., S.Z. and D.W.B. designed, performed, analyzed and interpreted the mutation prevalence screens. A.J.O. and M.L.G. analyzed MSH6. M.E.U. and M.L.G. generated sequence conservation alignments. M.E.U. performed cell culture and immunoblotting. N.F.H., M.L.G. and J.C.M. performed statistical analyses. N.F.H. performed the power calculation. D.W.B., M.E.U., M.L.G., M.L.R., A.J.O., N.F.H., J.C.M., A.K.G., P.H. and N.J.O. edited and commented on the manuscript.

Corresponding author

Correspondence to Daphne W Bell.

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The authors declare no competing financial interests.

Additional information

A list of members appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10, Supplementary Tables 2, 3, 6–10, 12, 14 and 15 and Supplementary Note (PDF 2801 kb)

Supplementary Table 1

Characteristics of endometrial tumors included in the discovery and prevalence screens (XLS 34 kb)

Supplementary Table 4

Filtered exonic and splice junction somatic mutations in a hypermutated tumor (T155) in the discovery screen (XLS 506 kb)

Supplementary Table 5

Filtered exonic and splice junction somatic mutations among 12 tumors in the discovery screen (XLS 272 kb)

Supplementary Table 11

Microsatellite instability (MSI) status and MSH6 status of 160 tumors included in the discovery and prevalence screens of CHD4, FBXW7, and SPOP (XLS 29 kb)

Supplementary Table 13

Enriched functional groupings identified by DAVID analysis (XLS 285 kb)

Supplementary Table 16

All exonic and splice junction somatic mutations among 12 tumors in the discovery screen (XLS 396 kb)

Supplementary Table 17

All exonic and splice junction somatic mutations in a hypermutated tumor (T155) in the discovery screen (XLS 518 kb)

Supplementary Table 18

Primers used for PCR amplification (XLS 219 kb)

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Le Gallo, M., O'Hara, A., Rudd, M. et al. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet 44, 1310–1315 (2012). https://doi.org/10.1038/ng.2455

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