Adenoid Cystic Carcinoma (JHU, Cancer Prevention Research 2016)

Overview

The acyc_jhu_2016 cohort was generated by Rettig et al. at Johns Hopkins University and published in Cancer Prevention Research 2016. It comprises 25 fresh-frozen surgically resected adenoid cystic carcinomas (ACCs) with matched blood/normal tissue, accrued under IRB at Johns Hopkins Hospital and the Salivary Gland Tumor Biorepository. The study performed whole-genome sequencing on all 25 tumor/normal pairs and mRNA expression analysis on 17 tumors, cataloguing the complete landscape of structural rearrangements and somatic mutations. Genomic and mRNA data were noted as in-process for deposition at time of publication. PMID:26862087

Composition

  • 25 fresh-frozen surgically resected ACC tumors with matched blood/normal tissue.
  • Cancer type: salivary-gland ACYC (adenoid cystic carcinoma).
  • Tumor sites: parotid, submandibular, sublingual, and minor salivary glands of palate, maxilla, lip, nasal septum, and ear.
  • Neoplastic cellularity ≥60% (mean) achieved via macro-dissection from frozen-section histology. PMID:26862087

Assays / panels (linked)

  • whole-genome-seq: All 25 tumor/normal pairs; mean coverage 65.2× tumor / 38.1× normal; 98.2% of targets ≥10×; Illumina HiSeq 2000, 100×100 bp paired-end reads aligned to hg19.
  • rna-seq: 17 tumors; Illumina HiSeq 2000, ≥50M paired 100×100 bp reads/sample; RSEM for transcript quantification; TopHat-Fusion for fusion-transcript discovery.
  • Bioinformatics: VariantDx custom somatic-mutation caller, snpEff for functional annotation, Ingenuity Pathway Analysis (IPA) for pathway enrichment. PMID:26862087

Papers using this cohort

  • PMID:26862087 — Rettig et al. 2016, Cancer Prevention Research: Primary study revealing pan-NFIB rearrangement landscape (60% of tumors), fusion-independent NFIB overexpression, and Rho-family GTPase and axon-guidance pathway disruption as novel recurrent features of ACC.

Notable findings derived from this cohort

  • NFIB translocations in 15/25 tumors (60%, 95% CI 41–77%) with five distinct partners: MYB (11), MAP3K5 (2), MYBL1 (2), RPS6KA2 (1), MYO6 (1), RIMS1 (1); plus intrachromosomal rearrangements in 3 additional tumors. PMID:26862087
  • NFIB mRNA overexpressed in tumors vs. normal (p=0.002) with no difference between NFIB-fusion-positive and -negative tumors (p=0.91), implicating a fusion-independent oncogenic role. PMID:26862087
  • MYB-NFIB canonical t(6;9) fusion detected in 11/25 tumors (44%, 95% CI 27–63%); MYBL1-NFIB fusions (2 tumors) were mutually exclusive with MYB expression, supporting an MYB/MYBL1 functional equivalence model. PMID:26862087
  • Rho-family GTPase signaling disrupted in 11/25 tumors (44%, p=3.9×10⁻⁶), including recurrent RHOA mutations (2 tumors); axon-guidance signaling disrupted in 14/25 tumors (56%, p=8.3×10⁻⁵) — first systematic report of these pathways in ACC. PMID:26862087
  • NOTCH1 most-frequently mutated gene (4 mutations in 3 tumors, 12%); chromatin-regulator mutations in KMT2D, KMT2C, EP300, SMARCA2, SMARCC1, KDM6A; truncating-mutation enrichment p=3.8×10⁻⁶. PMID:26862087
  • 253 chromosomal rearrangements total (median 7/tumor); breakpoint hotspots at chromosome 6q (28%) and 9p (14%); median somatic mutation burden 14/tumor (range 2–36). PMID:26862087

Sources

  • cBioPortal study: acyc_jhu_2016 — https://www.cbioportal.org/study/summary?id=acyc_jhu_2016
  • Accrual site: Johns Hopkins Hospital and the Salivary Gland Tumor Biorepository.
  • PMID:26862087 — Rettig et al. 2016, Cancer Prevention Research.

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