Adenoid Cystic Carcinoma — Sanger 2013

Overview

Whole-exome sequencing of 24 adenoid cystic carcinoma (ACC; ACYC) tumor/normal pairs performed by the Wellcome Sanger Institute in collaboration with MD Anderson Cancer Center, published by Stephens et al. 2013 in Journal of Clinical Investigation. Includes extension sequencing of SPEN (42 additional cases) and FGFR2 (25 additional cases) by Sanger sequencing. Sequence data deposited in the European Genome-phenome Archive (EGA00001064049); SNP6 data in ArrayExpress E-MTAB-1141; expression data in ArrayExpress E-MTAB-1397.

Composition

  • 24 ACYC cases: 23 pretreatment primary tumors + 1 local-regional lymph-node metastasis, with matched normal salivary-gland parenchyma.
  • Histology: roughly equal cribriform and predominantly solid forms; 19/24 MYB-positive.
  • Solution-phase exome capture + next-generation sequencing; Affymetrix SNP 6.0 copy-number profiling analyzed with ASCAT v2.1.
  • Extension cohorts: targeted Sanger sequencing of SPEN across 42 additional ACC cases and FGFR2 across 25 additional ACC cases.

Assays / panels (linked)

Papers using this cohort

  • PMID:23778141 — Stephens et al. 2013, “Whole exome sequencing of adenoid cystic carcinoma,” Journal of Clinical Investigation.

Notable findings derived from this cohort

  • 312 somatic mutations across 24 exomes (range 2–35; mean 13/exome) — lower than most adult solid tumors; mutation burden not significantly associated with histology or MYB status PMID:23778141.
  • Chromatin-biology genes mutated in 12/24 (50%) cases: ARID1A, ARID1B, ARID5B, CREBBP, EP300, KDM6A, KDM5A, KMT2C, SMARCA2, CHD2, BRD2 PMID:23778141.
  • SPEN nominated as a novel ACC cancer gene: 6 truncating mutations in 5 discovery cases (all solid histology) + 2 additional truncating mutations in extension cohort; mechanism is not simple loss-of-function (no consistent LOH) PMID:23778141.
  • Three likely activating FGFR2 mutations across discovery+extension cohorts (p.Y376C, p.I389_V393>M, p.K642R) nominating FGFR inhibition — e.g. dovitinib — as a therapeutic strategy; NCT01524692 trial cited PMID:23778141.
  • NOTCH1 and NOTCH2 mutations identified in 3 cases, co-occurring with SPEN truncations in one tumor, implicating Notch-pathway deregulation PMID:23778141.
  • Recurrent copy-number losses at 1p36, 6q, 9p, and 12q; MYB-positive cases showed copy-number breakpoints at MYB and NFIB loci PMID:23778141.

Sources

  • PMID:23778141
  • EGA: EGA00001064049
  • ArrayExpress: E-MTAB-1141 (SNP6), E-MTAB-1397 (expression)

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