Prevalence ofMITFp.E318K in Patients With Melanoma Independent of the Presence ofCDKN2ACausative Mutations

Abstract

The main high-penetrance melanoma susceptibility gene is CDKN2A, encoding p16INK4A and p14ARF. The gene MITF variant p.E318K also predisposes to melanoma and renal cell carcinoma. To date, the prevalence of MITF p.E318K and its clinical and phenotypical implications has not been previously assessed in a single cohort of Spanish patients with melanoma or in p16INK4A mutation carriers. OBJECTIVES To evaluate the prevalence of MITF p.E318K in Spanish patients with melanoma and assess the association with clinical and phenotypic features. DESIGN, SETTING, AND PARTICIPANTS A hospital-based, case-control study was conducted at the Melanoma Unit of Hospital Clinic of Barcelona, with MITF p.E318K genotyped in all patients using TaqMan probes. We included 531 patients: 271 patients with multiple primary melanoma (MPM) without mutations affecting p16INK4A (wild-type p16INK4A); 191 probands from melanoma-prone families with a single melanoma diagnosis and without mutations affecting p16INK4A, and 69 probands from different families carrying CDKN2A mutations affecting p16INK4A. A population-based series of 499 age-and sex-matched cancer-free individuals from the Spanish National Bank of DNA were included as controls.

Genetic susceptibility to cutaneous melanoma in southern Switzerland: role ofCDKN2A,MC1RandMITF

“…The MITF p.E318K variant was identified in three additional cases (two families and one patient). The occurrence (7%) of this variant among families is higher than reported previously for other populations . Also, contrary to what has been reported, no kidney cancer was detected in these three families.…”

“…4,6,14 Recently, some studies have implicated the BRCA1-associated protein 1 gene (BAP1) and the microphthalmia-associated transcription factor gene (MITF) as high-and intermediate-penetrance melanoma predisposition genes, respectively. [16][17][18][19] Germline BAP1 mutations are associated with a novel cancer syndrome characterized by an increased risk of malignant mesothelioma, atypical melanocytic tumours (melanocytic BAP1-mutated atypical intradermal tumours), uveal and cutaneous melanoma and other neoplasms. 17 The MITF mutation p.E318K is associated with both familial and sporadic melanoma susceptibility and/or renal cell carcinoma risk, an increased naevus count and nonblue eye colour.…”

“…17 The MITF mutation p.E318K is associated with both familial and sporadic melanoma susceptibility and/or renal cell carcinoma risk, an increased naevus count and nonblue eye colour. 6,16,18,19 In spite of these important and recent studies on new genes implicated in melanoma susceptibility, genetic counselling is still only broadly recommended for high-risk melanoma gene (CDKN2A and CDK4) mutation carriers, and it should be performed in genetic referral units and/or as a part of a research investigation programme. 1 The incidence of CM in southern Switzerland is considered moderate to high with around 20-25 cases per 100 000 habitants.…”

“…Germline BAP1 mutations are associated with a novel cancer syndrome characterized by an increased risk of malignant mesothelioma, atypical melanocytic tumours (melanocytic BAP1‐mutated atypical intradermal tumours), uveal and cutaneous melanoma and other neoplasms . The MITF mutation p.E318K is associated with both familial and sporadic melanoma susceptibility and/or renal cell carcinoma risk, an increased naevus count and nonblue eye colour …”

IRF4 rs12203592 functional variant and melanoma survival

“…IRF4 activates the melanogenesis pathway by the regulation of TYR expression, together with MITF. This could be one explanation of why these genes are both implicated in nevi count . It has been suggested that IRF4 expression enables suppressive regulatory T cells (Treg) to suppress effector T cells .…”