Skin Cutaneous Melanoma (Yale, Nat Genet 2012)

Overview

The Yale melanoma dataset comprises 147 melanoma tumors with matched germline DNA subjected to whole-exome sequencing (Krauthammer et al., Nature Genetics 2012). The study is the discovery cohort for RAC1 P29S as a recurrent activating UV-signature mutation in cutaneous melanoma and for the comprehensive characterization of PPP6C as a melanoma driver gene. It also defines three molecular classes of melanoma based on mutation burden and copy-number alterations. The exome was expanded to 364 melanomas for RAC1 P29S validation via Sanger sequencing.

Composition

  • 147 melanoma primary and metastatic tumors with matched germline DNA
  • Cancer types: cutaneous melanoma (sun-exposed), acral melanoma, mucosal melanoma, UM (uveal)
  • Sun-exposed melanomas: median 171 somatic mutations per tumor
  • Sun-shielded melanomas: median 9 somatic mutations per tumor
  • Validation cohort: 76 Australian melanoma cell lines (independent)
  • Extended validation cohort: 364 melanomas (Sanger sequencing for RAC1 P29S)
  • Exome capture: Roche/NimbleGen SeqCap EZ; 22.4 Mb covering 15,714 genes
  • Sequencing: Illumina GAIIx and HiSeq 2000

Assays / panels (linked)

Papers using this cohort

  • PMID:22842228 — Krauthammer et al. Nat Genet 2012 primary analysis

Notable findings derived from this cohort

  • RAC1 P29S identified in 9.2% (20/217) of sun-exposed melanomas as a recurrent UV-signature activating mutation (third most frequent driver after BRAF and NRAS) PMID:22842228
  • PPP6C mutated in 12.4% of sun-exposed tumors; all co-occurring with BRAF or NRAS mutations (P=0.007); mutations cluster in catalytic active site suggesting loss-of-function PMID:22842228
  • NF1 inactivation in 30% of BRAF/NRAS-WT sun-exposed melanomas PMID:22842228
  • Three melanoma molecular classes: (1) sun-shielded/copy-gain-high/mutation-low; (2) sun-exposed/BRAF-NRAS-WT/mutation-high; (3) sun-exposed/BRAF-NRAS-mutant with frequent PTEN/CDKN2A losses PMID:22842228
  • RAC1 P29S significantly more prevalent in males (12.8%) vs females (2.4%, P=0.01), consistent with greater UV exposure in men PMID:22842228
  • BAP1 frameshift identified in 1 uveal melanoma case PMID:22842228

Sources

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