The prognostic significance of low-frequency somatic mutations in metastatic cutaneous melanoma

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  • Zhao, X.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Little, P.
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
  • Hoyle, A.P.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Pegna, G.J.
    • Affiliation: School of Medicine, Division of Hematology/Oncology
  • Hayward, M.C.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Ivanova, A.
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
  • Parker, J.S.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Marron, D.L.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Soloway, M.G.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Jo, H.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Salazar, A.H.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Papakonstantinou, M.P.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Bouchard, D.M.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Jefferys, S.R.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Hoadley, K.A.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Ollila, D.W.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Frank, J.S.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Thomas, N.E.
    • Affiliation: School of Medicine, Department of Dermatology
  • Googe, P.B.
    • Affiliation: School of Medicine, Department of Dermatology
  • Ezzell, A.J.
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
  • Collichio, F.A.
    • Affiliation: School of Medicine, Division of Hematology/Oncology
  • Lee, C.B.
    • Affiliation: School of Medicine, Division of Hematology/Oncology
  • Earp, H.S.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Sharpless, N.E.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Hugo, W.
    • Other Affiliation: University of California, Los Angeles
  • Wilmott, J.S.
    • Other Affiliation: University of Sydney
  • Quek, C.
    • Other Affiliation: University of Sydney
  • Waddell, N.
    • Other Affiliation: Queensland Institute of Medical Research
  • Johansson, P.A.
    • Other Affiliation: Queensland Institute of Medical Research
  • Thompson, J.F.
    • Other Affiliation: University of Sydney
  • Hayward, N.K.
    • Other Affiliation: Queensland Institute of Medical Research
  • Mann, G.J.
    • Other Affiliation: University of Sydney
  • Lo, R.S.
    • Other Affiliation: University of California, Los Angeles
  • Johnson, D.B.
    • Other Affiliation: Vanderbilt-Ingram Cancer Center
  • Scolyer, R.A.
    • Other Affiliation: Queensland Institute of Medical Research
  • Hayes, D.N.
    • Affiliation: School of Medicine, Division of Hematology/Oncology
  • Moschos, S.J.
    • Affiliation: School of Medicine, Division of Hematology/Oncology
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.
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  • Article
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  • In Copyright
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  • Attribution 3.0 United States
Journal title
  • Frontiers in Oncology
Journal volume
  • 9
Journal issue
  • JAN
ISSN
  • 2234-943X
Publisher
  • Frontiers Media S.A.

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