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Cited by 3,151Melanoma and MAPK PathwaysCutaneous Melanoma Detection and ManagementCancer Genomics and Diagnostics

Genomic classification of cutaneous melanoma

Open access
Akbani, Rehan, Akdemir, Kadir C., Aksoy, B. Arman, Albert, Monique, Ally, Adrian, Amin, Samirkumar B., Arachchi, Harindra, Arora, Arshi +344 more·2015·Cell
DOI 10.1016/j.cell.2015.05.044PMC PMC4580370
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Abstract

SUMMARY We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multidimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.

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  • The TCGA-SKCM cohort contains over 400 patients with both RNA sequencing and whole exome sequencing data, enabling differential gene expression analysis of human tumors based on the germline APOE genotype.

    “The Cancer Genome Atlas skin cutaneous melanoma (TCGA-SKCM) cohort contains over 400 patients with both RNA sequencing and whole exome sequencing data, enabling differential gene expression analysis of human tumors based on the germline APOE genotype (36) (Fig. 4A).”

    From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [36]

    The Results section, “Multi-dimensional Genomic Characterization of Cutaneous Melanoma” (page unavailable), reports both whole-exome sequencing and mRNA sequencing. But “Data Generation” says data from at least one platform were available for only 333 patients, so this paper does not support over 400 patients having both. It reports paired germline DNA sequencing but does not describe differential expression analysis by germline APOE genotype. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Multiple genome-wide sequencing studies have revealed a paucity of NER gene defects in sporadic malignant melanoma within the general population.

    “In view of this, it may be surprising that multiple genome-wide sequencing studies have revealed a paucity of NER gene defects in sporadic MM within the general population (2, 6, 7).”

    From A genome-wide screen reveals that Dyrk1A kinase promotes nucleotide excision repair by preventing aberrant overexpression of cyclin D1 and p21 (2023) · cites this paper as [6]

    The Results section (‘Identification of Significantly Mutated Genes’; page unavailable) describes whole-exome sequencing of melanomas and lists significantly mutated genes, but it does not assess the frequency of nucleotide excision repair (NER) gene defects. Searches for NER, nucleotide excision repair, and specific repair-gene names found no passage establishing the claimed paucity. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

  • NRAS mutations at codon 61 are common for NRAS-driven cancers such as skin cutaneous melanoma.

    “common for NRAS-driven cancers, such as skin cutaneous melanoma57,58”

    From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [57]

  • In TCGA-SKCM, three distinct melanoma immune classes (MICs) were identified, with significantly higher B cell expression in cluster C than in cluster A or cluster B (P < 0.0001).

    “we identified three distinct melanoma immune classes (MICs), with significantly higher expression of B cells in cluster C than in cluster A (P < 0.0001) or cluster B (P < 0.0001)”

    From B cells and tertiary lymphoid structures promote immunotherapy response (2020) · cites this paper as [42]

  • The melanoma immune classes had no clear association with known genomic subtypes of melanoma (BRAF, NRAS, NF1, or triple wild type) or with disease site (nodal or non-nodal).

    “Importantly, there was no clear association of MICs with known genomic subtypes of melanoma (BRAF, NRAS, NF1 or triple wild type)42 or disease site (nodal or non-nodal)”

    From B cells and tertiary lymphoid structures promote immunotherapy response (2020) · cites this paper as [42]

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Akbani, R., Akdemir, K. C., Aksoy, B. A., Albert, M., Ally, A., Amin, S. B., Arachchi, H., Arora, A., Auman, J. T., Ayala, B., Baboud, J., Balasundaram, M., Balu, S., Barnabas, N., Bartlett, J., Bartlett, P., Bastian, B. C., Baylin, S. B., Behera, M., Belyaev, D., Benz, C., Bernard, B., Beroukhim, R., Bir, N., Black, A. D., Bodenheimer, T., Boice, L., Boland, G. M., Bono, R., Bootwalla, M. S., Bosenberg, M., Bowen, J., Bowlby, R., Bristow, C. A., Brockway-Lunardi, L., Brooks, D., Brzezinski, J., Bshara, W., Buda, E., Burns, W. R., Butterfield, Y. S. N., Button, M., Calderone, T., Cappellini, G. A., Carter, C., Carter, S. L., Cherney, L., Cherniack, A. D., Chevalier, A., Chin, L., Cho, J., Cho, R. J., Choi, Y.-L., Chu, A., Chudamani, S., Cibulskis, K., Ciriello, G., Clarke, A., Coons, S., Cope, L., Crain, D., Curley, E., Danilova, L., D’Atri, S., Davidsen, T., Davies, M. A., Delman, K. A., Demchok, J. A., Deng, Q. A., Deribe, Y. L., Dhalla, N., Dhir, R., DiCara, D., Dinikin, M., Dubina, M., Ebrom, J. S., Egea, S., Eley, G., Engel, J., Eschbacher, J. M., Fedosenko, K. V., Felau, I., Fennell, T., Ferguson, M. L., Fisher, S., Flaherty, K. T., Frazer, S., Frick, J., Fulidou, V., Gabriel, S. B., Gao, J., Gardner, J., Garraway, L. A., Gastier-Foster, J. M., Gaudioso, C., Gehlenborg, N., Genovese, G., Gerken, M., Gershenwald, J. E., Getz, G., Gomez-Fernandez, C., Gribbin, T., Grimsby, J., Gross, B., Guin, R., Gutschner, T., Hadjipanayis, A., Halaban, R., Hanf, B., Haussler, D., Haydu, L. E., Hayes, D. N., Hayward, N. K., Heiman, D. I., Herbert, L., Herman, J. G., Hersey, P., Hoadley, K. A., Hodis, E., Holt, R. A., Hoon, D. S., Hoppough, S., Hoyle, A. P., Huang, F. W., Huang, M., Huang, S., Hutter, C. M., Ibbs, M., Iype, L., Jacobsen, A., Jakrot, V., Janning, A., Jeck, W. R., Jefferys, S. R., Jensen, M. A., Jones, C. D., Jones, S. J. M., Ju, Z., Kakavand, H., Kang, H., Kefford, R. F., Khuri, F. R., Kim, J., Kirkwood, J. M., Klode, J., Korkut, A., Korski, K., Krauthammer, M., Kucherlapati, R., Kwong, L. N., Kycler, W., Ladanyi, M., Lai, P. H., Laird, P. W., Lander, E., Lawrence, M. S., Lazar, A. J., Łaźniak, R., Lee, D., Lee, J. E., Lee, J., Lee, K., Lee, S., Lee, W., Leporowska, E., Leraas, K. M., Li, H. I., Lichtenberg, T. M., Lichtenstein, L., Lin, P., Ling, S., Liu, J., Liu, O., Liu, W., Long, G. V., Lu, Y., Ma, S., Ma, Y., Mackiewicz, A., Mahadeshwar, H. S., Malke, J., Mallery, D., Manikhas, G. M., Mann, G. J., Marra, M. A., Matejka, B., Mayo, M., Mehrabi, S., Meng, S., Meyerson, M., Mieczkowski, P. A., Miller, J. P., Miller, M. L., Mills, G. B., Moiseenko, F., Moore, R. A., Morris, S., Morrison, C., Morton, D., Moschos, S., Mose, L. E., Muller, F. L., Mungall, A. J., Murawa, D., Murawa, P., Murray, B. A., Nezi, L., Ng, S., Nicholson, D., Noble, M. S., Osunkoya, A., Owonikoko, T. K., Ozenberger, B. A., Pagani, E., Paklina, O. V., Pantazi, A., Parfenov, M., Parfitt, J., Park, P. J., Park, W.-Y., Parker, J. S., Passarelli, F., Penny, R., Perou, C. M., Pihl, T. D., Potapova, O., Prieto, V. G., Protopopov, A., Quinn, M. J., Radenbaugh, A., Rai, K., Ramalingam, S. S., Raman, A. T., Ramirez, N. C., Ramirez, R., Rao, U., Rathmell, W. K., Ren, X., Reynolds, S. M., Roach, J., Robertson, A. G., Ross, M. I., Roszik, J., Russo, G., Saksena, G., Saller, C., Samuels, Y., Sander, C., Sander, C., Sandusky, G., Santoso, N., Saul, M., Saw, R. P., Schadendorf, D., Schein, J. E., Schultz, N., Schumacher, S. E., Schwallier, C., Scolyer, R. A., Seidman, J., Sekhar, P. C., Sekhon, H. S., Senbabaoglu, Y., Seth, S., Shannon, K. F., Sharpe, S., Sharpless, N. E., Shaw, K. R. M., Shelton, C., Shelton, T., Shen, R., Sheth, M., Shi, Y., Shiau, C. J., Shmulevich, I., Sica, G. L., Simons, J. V., Sinha, R., Sipahimalani, P., Sofia, H. J., Soloway, M. G., Song, X., Sougnez, C., Spillane, A. J., Spychała, A., Stretch, J. R., Stuart, J., Suchorska, W. M., Sucker, A., Sumer, S. O., Sun, Y., Synott, M., Tabak, B., Tabler, T. R., Tam, A., Tan, D., Tang, J., Tarnuzzer, R., Tarvin, K., Tatka, H., Taylor, B. S., Teresiak, M., Thiessen, N., Thompson, J. F., Thorne, L., Thorsson, V., Trent, J. M., Triche, T. J., Tsai, K. Y., Tsou, P., Van Den Berg, D. J., Van Allen, E. M., Veluvolu, U., Verhaak, R. G., Voet, D., Voronina, O., Walter, V., Walton, J. S., Wan, Y., Wang, Y., Wang, Z., Waring, S., Watson, I. R., Weinhold, N., Weinstein, J. N., Weisenberger, D. J., White, P., Wilkerson, M. D., Wilmott, J. S., Wise, L., Wiznerowicz, M., Woodman, S. E., Wu, C.-J., Wu, C.-C., Wu, J., Wu, Y., Xi, R., Xu, A. W., Yang, D., Yang, L., Yang, L., Zack, T. I., Zenklusen, J. C., Zhang, H., Zhang, J., Zhang, W., Zhao, X., Zhu, J., Zhu, K., Zimmer, L., Zmuda, E., & Zou, L.
Affiliations
National Institutes of Health (US)
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2015-06
Volume
161
Issue
7
Pages
1681-1696
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2015.05.044
PMC
PMC4580370
OpenAlex
W1950829641
Semantic Scholar
2505fe509225f7d26acc3f4106ecee083bdcfb3d
Cited by
3,151
References
71
Citations by year
2026: 151 · 2025: 218 · 2024: 266 · 2023: 307 · 2022: 332 · 2021: 323 · 2020: 366 · 2019: 341 · 2018: 293 · 2017: 292 · 2016: 213 · 2015: 44 · 2014: 2 · 2012: 2
FWCI
121.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Bayer
  • Cancer Research UK (21141)
  • National Institutes of Health (UL1TR000005, CA- 016672)
  • Foundation Medicine
  • National Human Genome Research Institute (U54HG003067, U54HG003079, U54HG003273)
  • National Cancer Institute (U24CA143882, U24CA143843, U24CA143840, U24CA143858, U24CA144025, U24CA143866, U24CA143883, U24CA143845, U24CA180951, U24CA143867, U24CA143848, U24CA143799, U24CA143835, R01CA163896, P30CA008748, P30CA016672, P50CA121974)
  • National Institute of General Medical Sciences (T32GM007753)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
cutaneous melanoma, genomic classification, melanoma subtypes, BRAF mutation, RAS mutations, NF1 mutation, KIT mutations, focal amplification, structural rearrangement, tumor immune microenvironment, lymphocyte infiltration, patient survival, metastatic melanoma
MeSH terms
Humans, Melanoma, Mutation, Skin Neoplasms, United States, Databases, Genetic, National Cancer Institute (U.S.)

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