Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type

Nat Genet. 2014 May;46(5):438-43. doi: 10.1038/ng.2931. Epub 2014 Mar 23.

Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Carcinoma, Small Cell / genetics*
  • Cell Line, Tumor
  • DNA Helicases / genetics*
  • Exome / genetics
  • Female
  • Gene Components
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Molecular Sequence Data
  • Mutation / genetics*
  • Nuclear Proteins / genetics*
  • Ovarian Neoplasms / genetics*
  • Sequence Analysis, DNA
  • Transcription Factors / genetics*

Substances

  • Nuclear Proteins
  • Transcription Factors
  • SMARCA4 protein, human
  • DNA Helicases