Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

By Michael Krauthammer, Y. Kong, B. Ha, Perry Evans, A. Bacchiocchi, Jamie McCusker, E. Cheng, Matthew J. Davis, Gerald Goh, Murim Choi and 20 more. Nature Genetics, 2012

1,151 citations recorded by the source corpus.

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1P29S) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/cc6b61dcd2d772995bf6c3d813247928c4e2aff7

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Citations in the corpus

Tumor Exome Analysis Reveals Neoantigen-Specific T-Cell Reactivity in an Ipilimumab-Responsive Melanoma (2013, background): “A potential involvement of mutated epitopes in T cell control would fit well with the observation that the mutation load in sun-exposed melanomas is particularly high (8-10).”
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.”
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity (2015, neutral): “RAC1 P29S is an oncogenic hotspot in melanomas 12,33 that we also identified in head and neck and endometrial cancers (Fig.”
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).”
Whole-genome landscapes of major melanoma subtypes (2017, background): “The proportion of tumours with a mutation to a particular actionable gene was calculated and classified on the basis of mutation type into (1) SNV/indel, (2) SNV/indel and structural variant, (3) structural variant or (4) copy number variation only.”
Genomic Classification of Cutaneous Melanoma (2015, background): “Based on evidence that (1) BRAF/RAS (N/H/K) mutant melanomas are driven, at least in part, by MAPK signaling (Hodis et al., 2012; Krauthammer et al., 2012); (2) melanomas lacking NF1 expression are dependent on MAPK signaling and respond to MAPK inhibitors (Maertens et al.”
Multiplex Assessment of Protein Variant Abundance by Massively Parallel Sequencing (2018, methodology): “…analysis of enrichments of low-abundance, dominant negative, or p.Pro38Ser variants in different cancer types, we first used the rates of single nucleotide transitions and transversions observed in TCGA 42,59 to create mutational probabilities for every possible PTEN missense or nonsense variant.”
Integrative Annotation of Variants from 1092 Humans: Application to Cancer Genomics (2013, methodology): “Thus, we used cancer exome data sets for this analysis (275 melanoma samples from (85) and 61 prostate cancer samples from (86)).”