AUTHOR=Zhao Xiaobei , Little Paul , Hoyle Alan P. , Pegna Guillaume J. , Hayward Michele C. , Ivanova Anastasia , Parker Joel S. , Marron David L. , Soloway Matthew G. , Jo Heejoon , Salazar Ashley H. , Papakonstantinou Michael P. , Bouchard Deeanna M. , Jefferys Stuart R. , Hoadley Katherine A. , Ollila David W. , Frank Jill S. , Thomas Nancy E. , Googe Paul B. , Ezzell Ashley J. , Collichio Frances A. , Lee Carrie B. , Earp H. Shelton , Sharpless Norman E. , Hugo Willy , Wilmott James S. , Quek Camelia , Waddell Nicola , Johansson Peter A. , Thompson John F. , Hayward Nicholas K. , Mann Graham J. , Lo Roger S. , Johnson Douglas B. , Scolyer Richard A. , Hayes D. Neil , Moschos Stergios J. 

TITLE=The Prognostic Significance of Low-Frequency Somatic Mutations in Metastatic Cutaneous Melanoma

JOURNAL=Frontiers in Oncology

VOLUME=8

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2018.00584

DOI=10.3389/fonc.2018.00584

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Methods:</bold> After limiting our DNA sequencing analysis to MM samples (<italic>n</italic> = 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.</p><p><bold>Results:</bold> Four genes were potentially prognostic [<italic>RAC1, FGFR1, CARD11, CIITA</italic>; false discovery rate (FDR) &lt; 0.2]. We identified 18 additional genes (e.g., <italic>SPEN, PDGFRB, GNAS, MAP2K1, EGFR, TSC2</italic>) that were less likely to have prognostic value (FDR &lt; 0.4). Most somatic mutations in these 22 genes were infrequent (&lt; 10%), associated with high somatic mutation burden, and were evenly distributed across all exons, except for <italic>RAC1</italic> and <italic>MAP2K1</italic>. Mutations in only 9 of these 22 genes were also identified by RNA sequencing in &gt;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 (<italic>n</italic> = 413). An underpowered analysis within a subset of this validation cohort with available patient follow-up (<italic>n</italic> = 224) showed that somatic mutations in <italic>SPEN</italic> and <italic>RAC1</italic> reached borderline prognostic significance [log-rank favorable (<italic>p</italic> = 0.09) and adverse (<italic>p</italic> = 0.07), respectively]. Somatic mutations in <italic>SPEN</italic>, and to a lesser extent <italic>RAC1</italic>, were not associated with definite gene copy number or RNA expression alterations. High (&gt;2+) nuclear plus cytoplasmic expression intensity for SPEN was associated with longer melanoma-specific overall survival (OS) compared to lower (≤ 2+) nuclear intensity (<italic>p</italic> = 0.048). We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., <italic>BRAF, RAS, CDKN2A, PTEN, TP53</italic>), such as <italic>RAC1</italic> and <italic>SPEN</italic>, may have prognostic significance in MM.</p>