{"doi":"10.17615/n84y-5q28","title":"The prognostic significance of low-frequency somatic mutations in metastatic cutaneous melanoma","abstract":"Background: Little is known about the prognostic significance of somatically mutated genes in metastatic melanoma (MM). We have employed a combined clinical and bioinformatics approach on tumor samples from cutaneous melanoma (SKCM) as part of The Cancer Genome Atlas project (TCGA) to identify mutated genes with potential clinical relevance. Methods: After limiting our DNA sequencing analysis to MM samples (n = 356) and to the CANCER CENSUS gene list, we filtered out mutations with low functional significance (snpEFF). We performed Cox analysis on 53 genes that were mutated in ≥3% of samples, and had ≥50% difference in incidence of mutations in deceased subjects versus alive subjects. Results: Four genes were potentially prognostic [RAC1, FGFR1, CARD11, CIITA; false discovery rate (FDR) < 0.2]. We identified 18 additional genes (e.g., SPEN, PDGFRB, GNAS, MAP2K1, EGFR, TSC2) that were less likely to have prognostic value (FDR < 0.4). Most somatic mutations in these 22 genes were infrequent (< 10%), associated with high somatic mutation burden, and were evenly distributed across all exons, except for RAC1 and MAP2K1. Mutations in only 9 of these 22 genes were also identified by RNA sequencing in >75% of the samples that exhibited corresponding DNA mutations. The low frequency, UV signature type and RNA expression of the 22 genes in MM samples were confirmed in a separate multi-institution validation cohort (n = 413). An underpowered analysis within a subset of this validation cohort with available patient follow-up (n = 224) showed that somatic mutations in SPEN and RAC1 reached borderline prognostic significance [log-rank favorable (p = 0.09) and adverse (p = 0.07), respectively]. Somatic mutations in SPEN, and to a lesser extent RAC1, were not associated with definite gene copy number or RNA expression alterations. High (>2+) nuclear plus cytoplasmic expression intensity for SPEN was associated with longer melanoma-specific overall survival (OS) compared to lower (≤ 2+) nuclear intensity (p = 0.048). We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., BRAF, RAS, CDKN2A, PTEN, TP53), such as RAC1 and SPEN, may have prognostic significance in MM.","journal":"UNC Libraries","year":2021,"id":229983,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.863,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":835813,"name":"W. 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Bouchard","orcid":null,"position":12,"is_corresponding":false},{"id":535951,"name":"D.B. Johnson","orcid":null,"position":13,"is_corresponding":false},{"id":450387,"name":"H.S. Earp","orcid":null,"position":14,"is_corresponding":false},{"id":835821,"name":"Newsom-Davis Thomas","orcid":null,"position":15,"is_corresponding":false},{"id":835822,"name":"J.S. Wilmott","orcid":null,"position":16,"is_corresponding":false},{"id":835823,"name":"M.P. Papakonstantinou","orcid":null,"position":17,"is_corresponding":false},{"id":835824,"name":"J.S. Frank","orcid":null,"position":18,"is_corresponding":false},{"id":786344,"name":"K.A. Hoadley","orcid":null,"position":19,"is_corresponding":false},{"id":801396,"name":"S.J. Moschos","orcid":null,"position":20,"is_corresponding":false},{"id":834917,"name":"M.G. Soloway","orcid":null,"position":21,"is_corresponding":false},{"id":835825,"name":"J.S Parker","orcid":null,"position":22,"is_corresponding":false},{"id":834620,"name":"Hoon Gil Jo","orcid":"0000-0002-0947-7185","position":23,"is_corresponding":false},{"id":835826,"name":"N.E. Sharpless","orcid":null,"position":24,"is_corresponding":false},{"id":835827,"name":"G.J. Pegna","orcid":null,"position":25,"is_corresponding":false},{"id":835828,"name":"S.R. Jefferys","orcid":null,"position":26,"is_corresponding":false},{"id":396585,"name":"A. Ivanova","orcid":null,"position":27,"is_corresponding":false},{"id":835829,"name":"R.A. Scolyer","orcid":null,"position":28,"is_corresponding":false},{"id":835830,"name":"N. Waddell","orcid":null,"position":29,"is_corresponding":false},{"id":835831,"name":"D.W. Ollila","orcid":null,"position":30,"is_corresponding":false},{"id":835832,"name":"N.K. Hayward","orcid":null,"position":31,"is_corresponding":false},{"id":835833,"name":"Chun Hian Quek","orcid":null,"position":32,"is_corresponding":false},{"id":835834,"name":"A.P. Hoyle","orcid":null,"position":33,"is_corresponding":false},{"id":835835,"name":"G.J. Mann","orcid":null,"position":34,"is_corresponding":false},{"id":834621,"name":"Xiaobei Zhao","orcid":"0000-0002-5277-0846","position":35,"is_corresponding":false},{"id":835836,"name":"D.L. Marron","orcid":null,"position":36,"is_corresponding":false},{"id":450371,"name":"D.N. Hayes","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:55:01.675482Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}