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Pathway Alterations in Stage II/III Primary Melanoma.
Kostrzewa, Caroline E; Luo, Li; Arora, Arshi; Seshan, Venkatraman E; Ernstoff, Marc S; Edmiston, Sharon N; Conway, Kathleen; Gorlov, Ivan; Busam, Klaus; Orlow, Irene; Hernando-Monge, Eva; Thomas, Nancy E; Berwick, Marianne; Begg, Colin B; Shen, Ronglai.
Affiliation
  • Kostrzewa CE; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
  • Luo L; Department of Internal Medicine and the UNM Comprehensive Cancer Center, Albuquerque, NM.
  • Arora A; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
  • Seshan VE; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
  • Ernstoff MS; ImmunoOncology Branch, National Cancer Institute, Rockville, MD.
  • Edmiston SN; Department of Dermatology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC.
  • Conway K; Department of Dermatology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC.
  • Gorlov I; Department of Epidemiology, University of North Carolina, Chapel Hill, NC.
  • Busam K; Epidemiology and Population Science, Baylor Medical Center, Houston, TX.
  • Orlow I; Department of Pathology and Laboratory Science, Memorial Sloan Kettering Cancer Center, New York, NY.
  • Hernando-Monge E; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
  • Thomas NE; Langone Cancer Center, New York University, New York, NY.
  • Berwick M; Department of Dermatology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC.
  • Begg CB; Department of Internal Medicine and the UNM Comprehensive Cancer Center, Albuquerque, NM.
  • Shen R; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
JCO Precis Oncol ; 7: e2200439, 2023 03.
Article in En | MEDLINE | ID: mdl-36926987
ABSTRACT

PURPOSE:

Genomic classification of melanoma has thus far focused on the mutational status of BRAF, NRAS, and NF1. The clinical utility of this classification remains limited, and the landscape of alterations in other oncogenic signaling pathways is underexplored.

METHODS:

Using primary samples from the InterMEL study, a retrospective cohort of cases with specimens collected from an international consortium with participating institutions throughout the United States and Australia, with oversampling of cases who ultimately died of melanoma, we examined mutual exclusivity and co-occurrence of genomic alterations in 495 stage II/III primary melanomas across 11 cancer pathways. Somatic mutation and copy number alterations were analyzed from next-generation sequencing using a clinical sequencing panel.

RESULTS:

Mutations in the RTK-RAS pathway were observed in 81% of cases. Other frequently occurring pathways were TP53 (31%), Cell Cycle (30%), and PI3K (18%). These frequencies are generally lower than was observed in The Cancer Genome Atlas, where the specimens analyzed were predominantly obtained from metastases. Overall, 81% of the cases had at least one targetable mutation. The RTK-RAS pathway was the only pathway that demonstrated strong and statistically significant mutual exclusivity. However, this strong mutual exclusivity signal was evident only for the three common genes in the pathway (BRAF, NRAS, and NF1). Analysis of co-occurrence of different pathways exhibited no positive significant trends. However, interestingly, a high frequency of cases with none of these pathways represented was observed, 8.4% of cases versus 4.0% expected (P < .001). A higher frequency of RTK-RAS singletons (with no other pathway alteration) was observed compared with The Cancer Genome Atlas. Clonality analyses suggest strongly that both the cell cycle and RTK-RAS pathways represent early events in melanogenesis.

CONCLUSION:

Our results confirm the dominance of mutations in the RTK-RAS pathway. The presence of many mutations in several well-known, actionable pathways suggests potential avenues for targeted therapy in these early-stage cases.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Skin Neoplasms / Melanoma Type of study: Observational_studies Limits: Humans Language: En Journal: JCO Precis Oncol Year: 2023 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Skin Neoplasms / Melanoma Type of study: Observational_studies Limits: Humans Language: En Journal: JCO Precis Oncol Year: 2023 Document type: Article