Frontiers in Oncology (Jan 2019)
The Prognostic Significance of Low-Frequency Somatic Mutations in Metastatic Cutaneous Melanoma
- Xiaobei Zhao,
- Paul Little,
- Alan P. Hoyle,
- Guillaume J. Pegna,
- Michele C. Hayward,
- Anastasia Ivanova,
- Anastasia Ivanova,
- Joel S. Parker,
- David L. Marron,
- Matthew G. Soloway,
- Heejoon Jo,
- Ashley H. Salazar,
- Michael P. Papakonstantinou,
- Deeanna M. Bouchard,
- Stuart R. Jefferys,
- Katherine A. Hoadley,
- David W. Ollila,
- David W. Ollila,
- David W. Ollila,
- Jill S. Frank,
- Jill S. Frank,
- Nancy E. Thomas,
- Nancy E. Thomas,
- Nancy E. Thomas,
- Paul B. Googe,
- Paul B. Googe,
- Paul B. Googe,
- Ashley J. Ezzell,
- Frances A. Collichio,
- Frances A. Collichio,
- Frances A. Collichio,
- Carrie B. Lee,
- Carrie B. Lee,
- Carrie B. Lee,
- H. Shelton Earp,
- Norman E. Sharpless,
- Willy Hugo,
- James S. Wilmott,
- Camelia Quek,
- Nicola Waddell,
- Peter A. Johansson,
- John F. Thompson,
- Nicholas K. Hayward,
- Graham J. Mann,
- Roger S. Lo,
- Douglas B. Johnson,
- Richard A. Scolyer,
- D. Neil Hayes,
- D. Neil Hayes,
- Stergios J. Moschos,
- Stergios J. Moschos,
- Stergios J. Moschos
Affiliations
- Xiaobei Zhao
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Paul Little
- Department of Biostatistics, Gillings School of Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Alan P. Hoyle
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Guillaume J. Pegna
- Division of Hematology/Oncology, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Michele C. Hayward
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Anastasia Ivanova
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Anastasia Ivanova
- Department of Biostatistics, Gillings School of Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Joel S. Parker
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- David L. Marron
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Matthew G. Soloway
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Heejoon Jo
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Ashley H. Salazar
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Michael P. Papakonstantinou
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Deeanna M. Bouchard
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Stuart R. Jefferys
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Katherine A. Hoadley
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- David W. Ollila
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- David W. Ollila
- Division of Surgical Oncology, Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- David W. Ollila
- Melanoma Program, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Jill S. Frank
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Jill S. Frank
- Melanoma Program, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Nancy E. Thomas
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Nancy E. Thomas
- Melanoma Program, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Nancy E. Thomas
- Department of Dermatology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Paul B. Googe
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Paul B. Googe
- Melanoma Program, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Paul B. Googe
- Department of Dermatology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Ashley J. Ezzell
- Department of Cell Biology & Physiology, Histology Research Core Facility, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Frances A. Collichio
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Frances A. Collichio
- Division of Hematology/Oncology, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Frances A. Collichio
- Melanoma Program, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Carrie B. Lee
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Carrie B. Lee
- Division of Hematology/Oncology, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Carrie B. Lee
- Melanoma Program, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- H. Shelton Earp
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Norman E. Sharpless
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Willy Hugo
- Division of Dermatology, Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, United States
- James S. Wilmott
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Camelia Quek
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Nicola Waddell
- 0Queensland Institute of Medical Research-QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
- Peter A. Johansson
- 0Queensland Institute of Medical Research-QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
- John F. Thompson
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Nicholas K. Hayward
- 0Queensland Institute of Medical Research-QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
- Graham J. Mann
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Roger S. Lo
- Division of Dermatology, Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, United States
- Douglas B. Johnson
- 1Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, United States
- Richard A. Scolyer
- 0Queensland Institute of Medical Research-QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
- D. Neil Hayes
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- D. Neil Hayes
- Division of Hematology/Oncology, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Stergios J. Moschos
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Stergios J. Moschos
- Division of Hematology/Oncology, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Stergios J. Moschos
- Melanoma Program, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- DOI
- https://doi.org/10.3389/fonc.2018.00584
- Journal volume & issue
-
Vol. 8
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.
Keywords
- The Cancer Genome Atlas Project
- cutaneous melanoma
- next generation sequencing
- RNA sequencing
- prognostic significance
- UV signature
