Dana-Farber Metastatic Cutaneous SCC Cohort (2015)

Overview

A single-institution cohort from Dana-Farber Cancer Institute profiling 29 lymph-node metastases from patients with cutaneous squamous cell carcinoma (cSCC) — an FDA-orphaned subset with poor prognosis at the metastatic stage. All 29 samples were confirmed HPV-negative by p16 IHC and hybrid-capture sequencing of HPV E6/E7 (Pathogenica). The cohort showed a high UV-associated coding mutation rate (~33 mutations/Mb across the panel) dominated by C>T transitions at pyrimidine dinucleotides. BAM files were submitted to dbGaP. Published in 2015 by Li et al. in Clinical Cancer Research.

Composition

  • n = 29 patients; 19 male / 10 female; median age at metastatic diagnosis 74 (range 48–92); 4 immunocompromised; 12 smokers.
  • Primary tumor sites predominantly head and neck; parotid gland the most frequent nodal site.
  • 26 samples with matched normal skin; 3 unpaired (the unpaired set showed ~2× the SNV count of paired samples).
  • Median progression-free survival 37 months (range 1–130); median overall survival 60 months (range 7–155).
  • Cancer type: CSCC.

Assays / panels (linked)

  • DFCI-ONCOPANEL-1 — targeted Illumina hybrid-capture of 504 cancer-associated genes, sequenced 100 bp on HiSeq 2500. Mean tumor coverage 82× (range 25–166×); normal mean 69×. Reads aligned to b37 with Picard/Firehose pipeline.
  • Variant calling: mutect (SNVs/indels) with OxoG artifact filtering; oncotator annotation against dbSNP 134 and 1000 Genomes; significance via mutsig (1.5, 2.0, and CV). CNAs by Nexus 7.5 and gistic 2.0.

Papers using this cohort

  • PMID:25589618 — Li et al. (2015). Targeted sequencing of 504 cancer-associated genes on 29 lymph-node metastatic cSCC samples; identified RAS/RTK/PI3K pathway activation and chromatin-remodeling inactivation as independent prognostic markers.

Notable findings derived from this cohort

  • TP53 mutated in 23/29 (79%), consistent with HPV-negative status; CDKN2A altered by mutation and homozygous loss in 14/29 (48%). PMID:25589618
  • RAS/RTK/PI3K pathway activating mutations present in 11/29 (38%) samples spanning 12 oncogenes (BRAF, KRAS, HRAS, EGFR, FGFR3, KIT, ERBB4, MTOR, PIK3CA, EZH2, HGF, CARD11); events are nearly mutually exclusive. PMID:25589618
  • Chromatin-remodeling inactivation (CREBBP, EP300, KMT2D, ARID2, ARID1A) in 48% of samples; independently associated with shorter progression-free survival. PMID:25589618
  • Combined RAS/RTK/PI3K activation (excluding EGFR/ERBB4) and chromatin-remodeling inactivation was the strongest prognostic correlate: mean PFS 12 months (pathway-mutated) vs 50 months (non-mutated) vs 79 months (EGFR/ERBB4-mutated). PMID:25589618
  • TP63 amplified in 7/29 (24%); MYC in 10/29; recurrent 9p21 (CDKN2A/CDKN2B) homozygous deletions in 6/29 (21%). PMID:25589618

Sources

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