A Landscape of Driver Mutations in Melanoma

By Eran Hodis, I. Watson, G. Kryukov, S. Arold, Marcin Imielinski, Jean-Philippe P. Theurillat, E. Nickerson, D. Auclair, Liren Li, Chelsea S. Place and 30 more. Cell, 2012

2,528 citations recorded by the source corpus.

SUMMARY Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic ultraviolet (UV) light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19 and ARID2), three of which - RAC1, PPP6C and STK19 - harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.

Subfields: Computational Theory and Mathematics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/bd7104f269c2680f45f7cb31d86a7c39acb65f51

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Citations in the corpus

Lessons from the cancer genome. (2013, neutral): “, 2012; CGAN, 2012), RAC1 in melanoma (a GTPase involved in the RAC/PAK-signaling module involved in focal adhesion) (Hodis et al., 2012; Krauthammer et al., 2012), ELMO1 and DOCK2 in esophageal cancer (two genes that activate RAC/PAK signaling) (A.”
Variation Interpretation Predictors: Principles, Types, Performance, and Choice (2016, background): “MutSigCV [Lawrenceetal.,2013],MuSiC[Deesetal.,2012],andInVEx[Hodis etal.,2012]identifygenescontainingasigniﬁcantlyhighervariation frequencycomparedwiththebackgroundmutationrate.”
KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer (2018, background): “The subsequent identification of RAC1 missense mutations (P29S), primarily in cutaneous melanomas, provided strong evidence for a driver role for RAC1 activation in cancer (Hodis et al. 2012; Krauthammer et al. 2012).”
Genomic correlates of response to CTLA-4 blockade in metastatic melanoma (2015, neutral): “The median nonsynonymous mutational load was 197 per sample (range: 7 to 5854), which is consistent with the known high mutational loads in cutaneous melanoma (13, 20).”