Comparative Genomics Provides Etiologic and Biological Insight into Melanoma Subtypes

Abstract

Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation, uveal melanoma occurs in the eyes, mucosal melanoma in internal mucous membranes, and acral melanoma on the palms, soles and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNAseq for subsets of tumors. Uveal melanoma is genomically distinct from other melanoma subtypes, harboring the lowest tumor mutation burden and with significantly mutated genes in the G-protein signaling pathway. Most cutaneous, acral and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16 and telomere pathways. However, the mechanism by which these pathways are activated or inactivated varies between melanoma subtypes. Additionally, we identify potential novel germline predisposition genes for some of the less common melanoma subtypes.

Camrelizumab Plus Apatinib and Temozolomide as First-Line Treatment in Patients With Advanced Acral Melanoma

“…It predominates and accounts for approximately 40% of melanoma cases in Asian populations . In contrast to cutaneous melanoma, AM presents with more aggressive biological behavior, with distinct genetic profiles characterized by a lower tumor mutation burden (TMB) . Immunotherapy (pembrolizumab, nivolumab, nivolumab plus ipilimumab, and nivolumab plus relatlimab) as a standard first-line therapy for advanced cutaneous melanoma yields modest efficacy in advanced AM .…”

“…Immunotherapy (pembrolizumab, nivolumab, nivolumab plus ipilimumab, and nivolumab plus relatlimab) as a standard first-line therapy for advanced cutaneous melanoma yields modest efficacy in advanced AM . Despite the favorable efficacy of treatment with BRAF inhibitors combined with MEK inhibitors in patients with BRAF V600 -mutant advanced melanoma, infrequent variants of BRAF (10%-22%) and NRAS (9%-28%) in AM limited the use of this combination . KIT variants are primarily found in mucosal and acral melanomas, but also with a low frequency (10%-20%) .…”

“…1,2 In contrast to cutaneous melanoma, AM presents with more aggressive biological behavior, with distinct genetic profiles characterized by a lower tumor mutation burden (TMB). [3][4][5] Immunotherapy (pembrolizumab, nivolumab, nivolumab plus ipilimumab, and nivolumab plus relatlimab) as a standard first-line therapy for advanced cutaneous melanoma 6 yields modest efficacy in advanced AM. [7][8][9][10][11] Despite the favorable efficacy of treatment with BRAF inhibitors combined with MEK inhibitors in patients with BRAF V600 -mutant advanced melanoma, 12,13 infrequent variants of BRAF (10%-22%) and NRAS (9%-28%) in AM limited the use of this combination.…”

“…[7][8][9][10][11] Despite the favorable efficacy of treatment with BRAF inhibitors combined with MEK inhibitors in patients with BRAF V600 -mutant advanced melanoma, 12,13 infrequent variants of BRAF (10%-22%) and NRAS (9%-28%) in AM limited the use of this combination. [3][4][5]14,15 KIT variants are primarily found in mucosal and acral melanomas, but also with a low frequency (10%-20%). [3][4][5]14,15 In addition, KIT inhibitors only brought limited activity for patients with KIT-mutant advanced melanoma.…”

“…[3][4][5]14,15 KIT variants are primarily found in mucosal and acral melanomas, but also with a low frequency (10%-20%). [3][4][5]14,15 In addition, KIT inhibitors only brought limited activity for patients with KIT-mutant advanced melanoma. 16 More effective first-line treatments are needed for advanced AM.…”