A primary melanoma and its asynchronous metastasis highlight the role of BRAF, CDKN2A, and TERT

Abstract

Background Alterations in pathways including BRAF, CDKN2A, and TERT contribute to the development of melanoma, but the sequence in which the genetic alterations occur and their prognostic significance remain unclear. To clarify the role of these pathways, we analyzed a primary melanoma and its metastasis. Methods Immunohistochemistry for BRAF-V600E, Sanger sequencing of BRAF and the TERT promoter, fluorescence in-situ hybridization, and telomere analyses were performed on a primary melanoma and its asynchronous cerebellar metastasis. Using the log-rank test and Cox-proportional model, the cancer genome atlas (TCGA) cohort of melanomas was analyzed for the effect of BRAF mutation and CDKN2A loss on survival. Results The primary melanoma expressed mutant BRAF-V600E and possessed a homozygous deletion of CDKN2A. In addition to these early defects, the metastatic lesion also possessed evidence of aneuploidy and an activating mutation of the TERT promoter. In the TCGA melanoma cohort, there was a non-significant trend towards poor prognosis in early stage cutaneous melanoma patients with concomitant BRAF mutation and CDKN2A loss. Conclusion BRAF mutation and CDKN2A loss occurred early and TERT promoter mutation later in a case of lethal metastatic melanoma. The effects of these pathways on survival warrant further investigation in early stage cutaneous melanoma patients.

Presence of TERT Promoter Mutations is a Secondary Event and Associates with Elongated Telomere Length in Myxoid Liposarcomas

“…Chiba et al have indeed shown that TERT promoter mutations are sufficient to overcome the proliferative barrier imposed by critical telomere shortening without additional tumor-selected mutations [ 40 ]. In addition, some studies suggest TERT promoter mutations are among the earliest genetic events in bladder cancer [ 41 ], thyroid carcinoma [ 42 ], cutaneous melanoma [ 14 , 43 , 44 ], basal cell and squamous cell carcinoma [ 45 ] and oligodendroglioma [ 46 ]. In contrast, other studies implicate that the occurrence of TERT mutations is more likely a secondary genetic event following the activation of an oncogenic signaling pathway, such as MAPK signaling in melanoma [ 14 ] or Wnt signaling in hepatocellular carcinoma [ 47 ].…”

Cancer-Specific Telomerase Reverse Transcriptase (TERT) Promoter Mutations: Biological and Clinical Implications

“…The identified hotspot mutations, which cause a cytidine-to-thymidine (C>T) dipyrimidine transition at chromosome 5 1,295,228 and 1,295,250 (−124 and −146 bp from the ATG), are thus named −124C>T and −146C>T, respectively [ 5 ] ( Figure 1 ). During last three years, the TERT promoter mutations have been widely investigated and identified in various types of human cancer with different frequencies [ 5 , 6 , 7 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ,…”

Contemporary and potential future molecular diagnosis of melanoma

“…The CDKN2A gene encode for p16, a crucial gatekeeper at the G1-S checkpoint. The prognostic role of CDKN2A locus deletion is controversial; its association with increased risk of relapse and with poorer prognosis has been reported in some studies [45][46], but this alteration did not significantly affect survival in 273 samples from the TGCA dataset [47].…”