Adenoid Cystic Carcinoma (MGH, Nature Genetics 2016)

Overview

The acyc_mgh_2016 cohort was generated by Drier et al. at Massachusetts General Hospital and Dana-Farber Cancer Institute (published in Nature Genetics 2016). It comprises 20 adenoid cystic carcinomas (ACCs) analyzed by whole-genome sequencing and chromatin profiling to characterize the mechanism of recurrent MYB rearrangements. New sequencing data from this study are deposited at EGA under accession EGAS00001001457; 12 primary tumors were drawn from the previously published EGA dataset EGAS00001000030. PMID:26829750

Composition

  • 12 primary ACC tumors (from EGA EGAS00001000030).
  • 2 additional primary ACC tumors sequenced by targeted paired-end sequencing.
  • 6 patient-derived primagraft (PDX) models.
  • Cancer type: salivary-gland ACYC (adenoid cystic carcinoma).
  • Histologic grades: grade-2 (cribriform/tubular) and grade-3 (solid) represented.
  • Immunohistochemistry on 19 grade-2 ACCs and 8 grade-3 ACCs. PMID:26829750

Assays / panels (linked)

  • whole-genome-seq: Illumina HiSeq 2500, 100 bp paired-end; aligned to hg19 with BWA; rearrangements called with dRanger and BreakPointer.
  • chip-seq: H3K4me3, H3K27ac, BRD4 ChIP-seq in 13 ACCs (5 primary + 8 primagrafts); MYB and TP63 ChIP-seq in 3 primagrafts.
  • immunohistochemistry: MYB, TP63, ICN1 (active NOTCH1), KIT, Ki-67 across grade-2 and grade-3 ACC specimens.
  • In vivo drug testing (4 primagrafts in nude mice): BET inhibitor JQ1 at 50 mg/kg daily. PMID:26829750

Papers using this cohort

  • PMID:26829750 — Drier et al. 2016, Nature Genetics: Primary study demonstrating that MYB rearrangements act via super-enhancer hijacking rather than fusion-protein production; BET bromodomain inhibitor JQ1 effective in grade-2 but not grade-3 ACC primagrafts.

Notable findings derived from this cohort

  • 15/20 ACCs (75%) harbored MYB rearrangements: 12/20 via NFIB (6 with MYB 3′UTR loss, 6 with retained 3′UTR), 2/20 via TGFBR3, 1/20 via RAD51B. PMID:26829750
  • Rearrangements act by juxtaposing super-enhancers from NFIB, TGFBR3, or RAD51B to the MYB locus — not by producing a fusion protein — establishing a MYB-driven positive feedback loop confirmed by 3C and ChIP-seq. PMID:26829750
  • MYB ChIP-seq (3 primagrafts) identified 13,278 high-confidence MYB binding sites; second-ranked binding motif is TP53/TP63/TP73 (p<10⁻³⁴⁰); 81% of TP63 binding sites co-bound by MYB. PMID:26829750
  • NOTCH1 activating mutations or SPEN loss-of-function found in 7/9 grade-3 ACCs but none of the lower-grade tumors; TP63 and ICN1 IHC are mutually exclusive and stratify tumor grade. PMID:26829750
  • BET bromodomain inhibitor JQ1 significantly slowed tumor growth in 2 grade-2 ACC primagrafts; both grade-3 (Notch-activated) primagrafts failed to respond — supporting grade-stratified therapeutic strategy. PMID:26829750

Sources

  • cBioPortal study: acyc_mgh_2016 — https://www.cbioportal.org/study/summary?id=acyc_mgh_2016
  • EGA accession (new data): EGAS00001001457; prior primary tumors from EGAS00001000030.
  • PMID:26829750 — Drier et al. 2016, Nature Genetics.

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