Small Cell Carcinoma of the Ovary (MSKCC 2014)

Overview

Targeted sequencing cohort of 12 paired tumor/normal samples from small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) — a rare, aggressive ovarian malignancy predominantly affecting young women. Collected at MSKCC (1998–2012) plus collaborating centers; formalin-fixed, paraffin-embedded tissue. Sequenced with the MSK-IMPACT panel (279 cancer-associated genes) on Illumina HiSeq 2000 (2×75 bp; mean depth 442×; ≥100× at 97% of targeted exons). Mutations validated by Sanger sequencing of genomic DNA and cDNA; protein loss confirmed by immunohistochemistry and immunoblot.

Composition

  • 12 paired tumor–normal SCCOHT samples (SCCO).
  • FFPE tissue sourced from MSKCC and collaborating institutions.
  • All 12 tumors with biallelic SMARCA4 inactivation; 4 non-recurrent somatic mutations found across all other 278 sequenced genes combined.

Assays / panels (linked)

Papers using this cohort

  • PMID:24658004 — Jelinic et al. (2014): recurrent SMARCA4 mutations establish SCCOHT as a SWI/SNF-driven malignancy.

Notable findings derived from this cohort

  • Biallelic inactivating SMARCA4 mutations detected in 100% (12/12) of SCCOHT tumors (P < 2.22×10⁻¹⁶); mutation classes included nonsense, frameshift, splice-site, and homozygous intragenic deletions — no missense mutations observed PMID:24658004.
  • Only 4 additional non-recurrent somatic mutations found across all other 278 sequenced genes combined — strikingly low mutational burden compared to TCGA non-hypermutated cancers PMID:24658004.
  • Loss of SMARCA4 (BRG1) protein confirmed by IHC and immunoblot; one case with in-frame deletion retained protein expression but is predicted to encode a catalytically dead helicase PMID:24658004.
  • One case harbored a heterozygous germline SMARCA4 nonsense mutation with somatic loss of the wild-type allele, supporting a hereditary component to SCCOHT PMID:24658004.
  • Synthetic-lethal vulnerability proposed: mutual exclusivity of SMARCA2 and SMARCA4 inactivation suggests SMARCA2 ATPase inhibition as a therapeutic strategy PMID:24658004.

Sources

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