Olivia Beaudoux1,2, Jean-Baptiste Oudart3,4,5, Laurence Riffaud6, Laetitia Visseaux6, Aude Marchal7, Anne-Sophie Lebre8,9, Florent Grange10,6,9. 1. CHU Reims, Service de Pathologie, Reims, France. obeaudoux@chu-reims.fr. 2. Université de Reims Champagne-Ardenne, EA 7509: Immune Dysregulation and Tissue Remodelling in Cancer, Autoimmune and Inflammatory Diseases, Reims, France. obeaudoux@chu-reims.fr. 3. Université de Reims Champagne-Ardenne, SFR CAP-Santé (FED 4231), Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France. 4. CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire - MEDyC, Reims, France. 5. CHU Reims, Pôle de Biologie, Service de Biochimie - Pharmacologie - Toxicologie, Reims, France. 6. CHU Reims, Service d'Oncodermatologie, Reims, France. 7. CHU Reims, Service de Pathologie, Reims, France. 8. CHU Reims, Pôle de Biologie, Service de Génétique, Reims, France. 9. Université de Reims Champagne-Ardenne, Reims, France. 10. Université de Reims Champagne-Ardenne, EA 7509: Immune Dysregulation and Tissue Remodelling in Cancer, Autoimmune and Inflammatory Diseases, Reims, France.
Abstract
BACKGROUND: Primary mucosal melanomas (PMMs) are rare and clinically heterogeneous, including head and neck (HNMs), vulvovaginal (VVMs), conjunctival (CjMs), anorectal (ARMs) and penile (PMs) melanomas. While the prognosis of advanced cutaneous melanoma has noticeably improved using treatments with immune checkpoint inhibitors (ICIs) and molecules targeting BRAF and MEK, few advances have been made for PMMs because of their poorer response to ICIs and their different genetic profile. This prompted us to conduct a systematic review of molecular studies of PMMs to clarify their pathogenesis and potential therapeutic targets. METHODS: All articles that examined gene mutations in PMMs were identified from the databases and selected based on predefined inclusion criteria. Mutation rate was calculated for all PMMs and each location group by relating the number of mutations identified to the total number of samples analysed. RESULTS: Among 1,581 studies identified, 88 were selected. Overall, the frequency of KIT, BRAF and NRAS mutation was 13.5%, 12.9% and 12.1%, respectively. KIT mutation ranged from 6.4% for CjMs to 16.6% for ARMs, BRAF mutation from 8.6% for ARMs to 31.1% for CjMs, and NRAS mutation from 6.2% for ARMs to 18.5% for CjMs. Among 101 other genes analysed, 33 had mutation rates over 10%, including TTN, TSC1, POM121, NF1, MTOR and SF3B1. CONCLUSION: In addition to BRAF, NRAS and KIT genes commonly studied, our systematic review identified significantly mutated genes that have already been associated (e.g., TSC1, mTOR, POLE or ATRX) or could be associated with (future) targeted therapies. PROSPERO ID: CRD42020185552.
BACKGROUND: Primary mucosal melanomas (PMMs) are rare and clinically heterogeneous, including head and neck (HNMs), vulvovaginal (VVMs), conjunctival (CjMs), anorectal (ARMs) and penile (PMs) melanomas. While the prognosis of advanced cutaneous melanoma has noticeably improved using treatments with immune checkpoint inhibitors (ICIs) and molecules targeting BRAF and MEK, few advances have been made for PMMs because of their poorer response to ICIs and their different genetic profile. This prompted us to conduct a systematic review of molecular studies of PMMs to clarify their pathogenesis and potential therapeutic targets. METHODS: All articles that examined gene mutations in PMMs were identified from the databases and selected based on predefined inclusion criteria. Mutation rate was calculated for all PMMs and each location group by relating the number of mutations identified to the total number of samples analysed. RESULTS: Among 1,581 studies identified, 88 were selected. Overall, the frequency of KIT, BRAF and NRAS mutation was 13.5%, 12.9% and 12.1%, respectively. KIT mutation ranged from 6.4% for CjMs to 16.6% for ARMs, BRAF mutation from 8.6% for ARMs to 31.1% for CjMs, and NRAS mutation from 6.2% for ARMs to 18.5% for CjMs. Among 101 other genes analysed, 33 had mutation rates over 10%, including TTN, TSC1, POM121, NF1, MTOR and SF3B1. CONCLUSION: In addition to BRAF, NRAS and KIT genes commonly studied, our systematic review identified significantly mutated genes that have already been associated (e.g., TSC1, mTOR, POLE or ATRX) or could be associated with (future) targeted therapies. PROSPERO ID: CRD42020185552.
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