Adenoid Cystic Carcinoma — MSKCC 2013

Overview

Whole-exome (n=55) or whole-genome (n=5) sequencing of 60 adenoid cystic carcinoma (ACC; ACYC) tumor/normal pairs collected at Memorial Sloan Kettering Cancer Center. At the time of publication this was the largest genomic cohort for this salivary-gland malignancy. Deposited in dbGaP under accession phs000612.v1.p1.

Composition

  • 60 ACC tumor/normal pairs: 55 whole-exome (Agilent SureSelect 51 MB) + 5 whole-genome (Illumina HiSeq 2000).
  • Cancer type: ACYC (adenoid cystic carcinoma — salivary gland).
  • Samples microdissected to >70% tumor purity; aligned to hg19/GRCh37 with BWA.
  • Mean exome coverage 106×; mean genome coverage 37×; 92.4% of target covered at ≥10×.
  • Subset of 23 samples profiled by Illumina HumanHT-12 expression arrays.
  • Affymetrix SNP 6.0 arrays used for copy-number profiling (ExomeCNV + GISTIC2.0).
  • MYB-NFIB translocation status determined by 3-color BAC FISH on tissue microarrays.

Assays / panels (linked)

Papers using this cohort

  • PMID:23685749 — Ho et al. 2013, “The mutational landscape of adenoid cystic carcinoma,” Nature Genetics.

Notable findings derived from this cohort

  • Remarkably low somatic mutation rate (mean 0.31 non-silent mutations/Mb; mean 22 somatic mutations per sample), comparable to neuroblastoma and hematologic malignancies PMID:23685749.
  • MYB-NFIB translocation detected by FISH in 57% (34/60) of cases; additional MYB-pathway lesions in 8% PMID:23685749.
  • Pathway-level convergence: chromatin-state regulators mutated in 35% (SMARCA2, CREBBP, KDM6A; q=4.5×10⁻³), DNA-damage response genes (TP53, UHRF1, ATM, BRCA1; q=5.6×10⁻³), PKA-pathway (RYR2/3, PTPRG/H/J/K; 27%; q=4.2×10⁻³), and FGF/IGF/PI3K axis (PIK3CA, PTEN, FGFR4, FGF16, IGFBP2; 30%; q=2.4×10⁻²) PMID:23685749.
  • PI3K-altered tumors enriched for solid histology, the most aggressive ACC variant (Fisher p<1.6×10⁻³); p-AKT and p-PRAS40 IHC confirmed functional PI3K activation PMID:23685749.
  • KDM6A H3K27me3 demethylase activity abolished by missense mutations; some mutants showed a dominant pro-growth phenotype in cell-based assays PMID:23685749.
  • CHASM nominated drivers in PIK3CA, TP53, PTEN, SMARCA2, KDM6A, and CREBBP; 8 tumors lacked any CHASM driver call PMID:23685749.

Sources

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