Comprehensive genomic profiling reveals inactivating SMARCA4 mutations and low tumor mutational burden in small cell carcinoma of the ovary, hypercalcemic-type

Gynecol Oncol. 2017 Dec;147(3):626-633. doi: 10.1016/j.ygyno.2017.09.031. Epub 2017 Nov 6.


Objective: Small cell carcinoma of the ovary, hypercalcemic-type (SCCOHT) is a rare, extremely aggressive neoplasm that usually occurs in young women and is characterized by deleterious germline or somatic SMARCA4 mutations. We performed comprehensive genomic profiling (CGP) to potentially identify additional clinically and pathophysiologically relevant genomic alterations in SCCOHT.

Methods: CGP assessment of all classes of coding alterations in up to 406 genes commonly altered in cancer and intronic regions for up to 31 genes commonly rearranged in cancer was performed on 18 SCCOHT cases (16 exhibiting classic morphology and 2 cases exhibiting exclusive a large cell variant morphology). In addition, a retrospective database search for clinically advanced ovarian tumors with genomic profiles similar to SCCOHT yielded 3 additional cases originally diagnosed as non-SCCOHT.

Results: CGP revealed inactivating SMARCA4 alterations and low tumor mutational burden (TMB) (<6mutations/Mb) in 94% (15/16) of SCCOHT with classic morphology. In contrast, both (2/2) cases exhibiting only large cell variant morphology were hypermutated (TMB scores of 90 and 360mut/Mb) and were wildtype for SMARCA4. In our retrospective search, an index ovarian cancer patient harboring inactivating SMARCA4 alterations, initially diagnosed as endometrioid carcinoma, was re-classified as SCCOHT and responded to an SCCOHT chemotherapy regimen.

Conclusion: The vast majority of SCCOHT demonstrate genomic SMARCA4 loss with only rare co-occurring alterations. Our data support a role for CGP in the diagnosis and management of SCCOHT and of other lesions with overlapping histological and clinical features, since identifying the former by genomic profile suggests benefit from an appropriate regimen and treatment decisions, as illustrated by an index patient.

Keywords: BRG1; Hypercalcemia; Ovarian small cell carcinoma; SMARCA4; SWI/SNF.

MeSH terms

  • Adolescent
  • Adult
  • Carcinoma, Small Cell / blood
  • Carcinoma, Small Cell / enzymology
  • Carcinoma, Small Cell / genetics*
  • Carcinoma, Small Cell / pathology
  • Cohort Studies
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism
  • Female
  • Gene Silencing
  • Germ-Line Mutation
  • Humans
  • Hypercalcemia / enzymology
  • Hypercalcemia / genetics*
  • Hypercalcemia / pathology
  • Middle Aged
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Ovarian Neoplasms / blood
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcriptome
  • Young Adult


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