TERT, BRAF, and NRAS Mutational Heterogeneity between Paired Primary and Metastatic Melanoma Tumors.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 0426720 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1523-1747 (Electronic) Linking ISSN: 0022202X NLM ISO Abbreviation: J Invest Dermatol Subsets: MEDLINE
    • Publication Information:
      Publication: 2016- : New York : Elsevier
      Original Publication: Baltimore, Williams & Wilkins.
    • Subject Terms:
      GTP Phosphohydrolases/*genetics ; Melanoma/*genetics ; Membrane Proteins/*genetics ; Neoplasms, Second Primary/*genetics ; Proto-Oncogene Proteins B-raf/*genetics ; Skin Neoplasms/*genetics ; Telomerase/*genetics; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; DNA Mutational Analysis ; Drug Resistance, Neoplasm/genetics ; Female ; Genetic Heterogeneity ; Humans ; Longitudinal Studies ; Male ; Melanoma/mortality ; Melanoma/secondary ; Middle Aged ; Mutation ; Neoplasms, Second Primary/drug therapy ; Neoplasms, Second Primary/mortality ; Neoplasms, Second Primary/pathology ; Prospective Studies ; Skin/pathology ; Skin Neoplasms/drug therapy ; Skin Neoplasms/mortality ; Skin Neoplasms/pathology
    • Abstract:
      Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequencies of intertumoral and intratumoral heterogeneity are controversial. We examined mutational heterogeneity within individual patients with melanoma using multiplatform analysis of commonly mutated driver and nonpassenger genes. We analyzed paired primary and metastatic tumors from 60 patients and multiple metastatic tumors from 39 patients whose primary tumors were unavailable (n = 271 tumors). We used a combination of multiplex SNaPshot assays, Sanger sequencing, mutation-specific PCR, or droplet digital PCR to determine the presence of BRAF V600 , NRAS Q61 , TERT -124C>T , and TERT -146C>T mutations. Mutations were detected in BRAF (39%), NRAS (21%), and/or TERT (78%). Thirteen patients had TERT mutant discordant tumors; seven of these had a single tumor with both TERT -124C>T and TERT -146C>T mutations present at different allele frequencies. Two patients had both BRAF and NRAS mutations; one had different tumors and the other had a single tumor with both mutations. One patient with a BRAF mutant primary lacked mutant BRAF in at least one of their metastases. Overall, we identified mutational heterogeneity in 18 of 99 patients (18%). These results suggest that some primary melanomas may be composed of subclones with differing mutational profiles. Such heterogeneity may be relevant to treatment responses and survival outcomes.
      (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
    • Comments:
      Comment in: J Invest Dermatol. 2020 Aug;140(8):1501-1503. (PMID: 32709275)
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    • Grant Information:
      P30 CA016087 United States CA NCI NIH HHS; P50 CA225450 United States CA NCI NIH HHS; U01 FD004203 United States FD FDA HHS; T32 AR064184 United States AR NIAMS NIH HHS; R21 CA198495 United States CA NCI NIH HHS; R21 CA154786 United States CA NCI NIH HHS
    • Accession Number:
      0 (Antineoplastic Agents)
      0 (Membrane Proteins)
      EC 2.7.11.1 (BRAF protein, human)
      EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
      EC 2.7.7.49 (TERT protein, human)
      EC 2.7.7.49 (Telomerase)
      EC 3.6.1.- (GTP Phosphohydrolases)
      EC 3.6.1.- (NRAS protein, human)
    • Publication Date:
      Date Created: 20200223 Date Completed: 20210308 Latest Revision: 20231103
    • Publication Date:
      20231215
    • Accession Number:
      PMC7387168
    • Accession Number:
      10.1016/j.jid.2020.01.027
    • Accession Number:
      32087194