Get access

Low-grade serous carcinomas of the ovary contain very few point mutations

Authors

  • Siân Jones,

    1. Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA
    Search for more papers by this author
    • Both authors contributed equally.

  • Tian-Li Wang,

    1. Departments of Pathology, Oncology, Gynaecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA
    Search for more papers by this author
    • Both authors contributed equally.

  • Robert J Kurman,

    1. Departments of Pathology, Oncology, Gynaecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA
    Search for more papers by this author
  • Kentaro Nakayama,

    1. Department of Gynaecology and Obstetrics, Shimane University, Izumo, Japan
    Search for more papers by this author
  • Victor E Velculescu,

    1. Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA
    Search for more papers by this author
  • Bert Vogelstein,

    1. Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA
    Search for more papers by this author
  • Kenneth W Kinzler,

    1. Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA
    Search for more papers by this author
  • Nickolas Papadopoulos,

    1. Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA
    Search for more papers by this author
  • Ie-Ming Shih

    Corresponding author
    1. Departments of Pathology, Oncology, Gynaecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA
    • Johns Hopkins Medical Institutions, 1550 Orleans Street, CRB-2 305 Baltimore, MD 21231, USA.
    Search for more papers by this author

  • Conflicts of interest. Under agreements between the Johns Hopkins University, Genzyme, Exact Sciences, Inostics, Qiagen, Invitrogen and Personal Genome Diagnostics, KWK, VEV, BV and NP are entitled to a share of the royalties received by the University on sales of products related to genes and technologies described in this manuscript. KWK, VEV, BV and NP are co-founders of Inostics and Personal Genome Diagnostics, are members of their Scientific Advisory Boards and own Inostics and Personal Genome Diagnostics stock, which is subject to certain restrictions under Johns Hopkins University policy

Abstract

It has been well established that ovarian low-grade and high-grade serous carcinomas are fundamentally different types of tumours. While the molecular genetic features of ovarian high-grade serous carcinomas are now well known, the pathogenesis of low-grade serous carcinomas, apart from the recognition of frequent somatic mutations involving KRAS and BRAF, is largely unknown. In order to comprehensively analyse somatic mutations in low-grade serous carcinomas, we applied exome sequencing to the DNA of eight samples of affinity-purified, low-grade, serous carcinomas. A remarkably small number of mutations were identified in seven of these tumours: a total of 70 somatic mutations in 64 genes. The eighth case displayed mixed serous and endometrioid features and a mutator phenotype with 783 somatic mutations, including a nonsense mutation in the mismatch repair gene, MSH2. We validated representative mutations in an additional nine low-grade serous carcinomas and 10 serous borderline tumours, the precursors of ovarian low-grade, serous carcinomas. Overall, the genes showing the most frequent mutations were BRAF and KRAS, occurring in 10 (38%) and 5 (19%) of 27 low-grade tumours, respectively. Except for a single case with a PIK3CA mutation, other mutations identified in the discovery set were not detected in the validation set of specimens. Our mutational analysis demonstrates that point mutations are much less common in low-grade serous tumours of the ovary than in other adult tumours, a finding with interesting scientific and clinical implications. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Ancillary