Low Frequency of Germline TERT and MITF Mutations in Brazilian Melanoma- Prone Patients

Abstract

Recent studies have reported rare germline mutations affecting the MITF gene, and the promoter of the TERT gene in melanoma families. Here we looked at the prevalence of these rare penetrant mutations in a series of 48 patients (either familial melanoma or multiple melanomas), all of them negative for CDKN2A and CDK4 mutations. A single mutation was detected in a multiple melanoma patient, who was a heterozygous carrier of the E318K MITF variant. However, this variant was also detected in 1 out of 125 controls. This preliminary data points to a low frequency of MITF and TERT mutations in this Brazilian group of melanoma-prone patients.Keywords: TERT; MITF; CDKN2A; Melanoma predisposition; Germline mutation Short CommunicationCutaneous melanoma is a rare and aggressive form of cancer, responsible for the majority of deaths caused by skin malignancies [1]. Approximately 10% of the melanoma cases occur in a familial context due to the segregation of germline mutations [2]. The major known gene of melanoma predisposition is CDKN2A, which mutations segregate with up to 40% of familial melanoma [3]. The identification of melanoma susceptibility genes is relevant for proper genetic counseling of individuals at high-risk and also to provide mechanistic insights on melanomagenesis.Recent works [4][5][6] have identified two distinct genes exhibiting germline activating mutations in melanoma-prone individuals. One of these alterations is a highly penetrant T>G mutation in the promoter of the TERT gene at -57 bp from the start site, which encodes one subunit of the telomerase. This mutation creates a new anchoring site for the Ets transcription factor family, thus shifting the expression level of TERT [4]. Somatic mutations in the promoter region of TERT were also disclosed in tumors, such as cutaneous and conjunctival melanomas [4,7,8]. However, until now, there are no other reports of TERT germline mutations in familial melanoma.The second variant consists of a G>A transition in the exon 10 of MITF (rs149617956; E318K), a known melanoma gene expressed in melanocytes, responsible for the activation of genes involved in development and survival [9]. The E318K mutation affects the SUM Oylation of the MITF protein, therefore increasing its transcriptional activity. This E318K variant was found at higher frequency in melanoma families than in general population, representing an intermediate risk variant. However, E318K frequency seems to vary according to the population [10,11], and it has not been investigated among Brazilians. The E318K alteration has been associated with development of multiple primary melanomas, as well as concomitant occurrence of melanoma and renal carcinoma [10,12,13]. Additionally, MITF amplifications and other mutations have already been reported in melanoma samples [9].The aim of this study was to evaluate the contribution of germline MITF and TERT on the burden of cutaneous melanoma in patients negative for CDKN2A mutations. This study was approved by the Ethics Committee of the AC Camargo C...

Characterization of Potential Melanoma Predisposition Genes in High-Risk Brazilian Patients

“…Besides CDKN2A, other genes potentially associated with familial melanoma have also been investigated in Brazilian melanoma-prone families, such as CDK4, MITF, and TERT promoter variants [24,25,27]. No pathogenic variant in CDK4 was identified so far [21,24,25].…”

“…No pathogenic variant in CDK4 was identified so far [21,24,25]. Both TERT promoter mutation at −57 bp from the start site and the MITF p.E318K variant, which are, respectively, high-and moderate-penetrance variants, were also assessed in 48 unrelated probands negative for CDKN2A GPV, detecting only one patient with the MITF GPV p.E318K [27].…”