Uterine Carcinosarcoma — JHU 2014

Overview

Whole-exome sequencing study of gynaecologic carcinosarcomas (malignant mixed Müllerian tumours) generated by Jones et al. (2014) at Johns Hopkins University. Samples were sourced from the OHSU Knight BioLibrary. Exome data deposited at the European Genome-phenome Archive under accession EGAS00001000941.

Composition

  • Cancer types: UCS (17 uterine carcinosarcomas) and MXOV (5 ovarian carcinosarcomas).
  • Samples: 22 carcinosarcoma patients with matched tumor/normal exomes; one tumor (MM02) was a recurrence at the primary site; 11 patients received adjuvant chemotherapy or radiation after surgery.
  • Tissue preparation: 10 fresh-frozen; 12 FFPE; ~85% mean neoplastic cellularity after macrodissection.
  • Mismatch-repair status: 18 microsatellite-stable (MSS); 4 mismatch-repair–deficient (MMR-D) hypermutators.

Assays / panels (linked)

  • whole-exome-seq — Agilent SureSelect 51 Mb (v4) capture + Illumina HiSeq 2000 paired-end 100 bp; average 191× coverage with ≥90% of bases covered ≥10×; aligned to hg19 with Eland/CASAVA 1.7.

Papers using this cohort

  • PMID:25233892 — Jones et al. (2014), Nature Communications. Genomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes.

Notable findings derived from this cohort

  • 777 somatic mutations across 702 genes in 18 MSS tumors; 904–5,913 alterations each in 4 MMR-D hypermutators PMID:25233892.
  • TP53 mutated in 67% (16/22); PI3K pathway (PIK3CA, PTEN, PIK3R1) altered in >50% of cases; chromatin-remodelling genes (ARID1A 32%, KMT2C 27%, BAZ1A 18%, SPOP 14%, ARID1B 14%) mutated in ~two-thirds of cases PMID:25233892.
  • ARID1A mutations are restricted to ovarian-origin MSS carcinosarcomas (4/5 ovarian, 0/MSS uterine) in this cohort PMID:25233892.
  • More than three quarters of cases carry an alteration in a gene with potential clinical actionability (PI3K pathway, homologous recombination, MMR deficiency) PMID:25233892.
  • Biallelic MSH6 mutations (MM12T) and single truncating hits in MSH6 (MM04T, MM18T) and MLH1 (MM20T) drive the hypermutator phenotype PMID:25233892.

Sources

  • EGA: EGAS00001000941.
  • cBioPortal study: ucs_jhu_2014.

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