Broad/DeCOG BRAF-Inhibitor Resistance in Metastatic Melanoma WES 2012

Overview

The skcm_broad_brafresist_2012 cohort was assembled by Van Allen, Wagle, Schadendorf and colleagues through a collaboration between the Broad Institute and the Dermatologic Cooperative Oncology Group of Germany (DeCOG). The dataset comprises whole-exome sequencing of FFPE tumors from BRAF V600 metastatic cutaneous melanoma patients treated with single-agent RAF inhibitors (vemurafenib or dabrafenib), with matched pre-treatment and post-resistance biopsies available for the majority of patients. It was a landmark study characterizing the genetic landscape of clinical RAF-inhibitor resistance, revealing a “long tail” of MAPK-pathway alterations beyond the canonical resistance mechanisms.

Composition

  • Total samples: 45 patients (BRAF V600 metastatic SKCM)
  • Early resistance: 14/45 (31%) — progression in <12 weeks
  • Acquired resistance: 31/45 (69%)
  • Matched pre-/post-resistance pairs: 32/45 patients; remainder contributed either pre-treatment or resistance biopsy only
  • Treatment: single-agent vemurafenib or dabrafenib
  • Reference genome: hg19

Assays / panels (linked)

Papers using this cohort

  • PMID:24265153 — Van Allen et al., Cancer Discovery 2014: genetic landscape of clinical resistance to RAF inhibition

Notable findings derived from this cohort

  • Genetic alterations in known or putative RAF-inhibitor resistance genes observed in 23/45 (51%) patients PMID:24265153
  • MAPK-pathway resistance mechanisms (NRAS, BRAF amplification, MAP2K1, MAP2K2, MITF, NF1) accounted for 44.4% (20/45) of the cohort PMID:24265153
  • MAP2K2 (MEK2) mutations and MITF amplification identified as novel resistance mechanisms with experimental validation PMID:24265153
  • Three tumors carried multiple co-occurring resistance mechanisms within the same biopsy PMID:24265153
  • BRAF V600 mutations confirmed in 100% of pre-treatment biopsies; 44/45 at codon V600 plus one in-frame deletion (Val600_Lys601delinsGlu) predicted to phenocopy V600E PMID:24265153

Sources

This page was processed by crosslinker on 2026-05-09.