A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma

Abstract

So far, two familial melanoma genes have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases1, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds2. To identify other familial melanoma genes, here we conducted whole-genome sequencing of probands from several melanoma families, identifying one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log odds ratio (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case–control sample. Likewise, it was similarly associated in an independent case–control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.

Melanoma Epidemiology and Prevention

“…More recently, MITF, the microphthalmia-associated transcription factor, was identified as a medium-penetrance melanoma susceptibility gene through a candidate gene approach in individuals affected with melanoma and renal cell carcinoma [21] and whole-genome sequencing of melanoma-prone families [249]. MITF regulates several other genes whose functions in melanocytes range from development, differentiation, survival, cell cycle regulation, and pigment production [249].…”

“…MITF regulates several other genes whose functions in melanocytes range from development, differentiation, survival, cell cycle regulation, and pigment production [249]. The MITF E318K variant allele is relatively uncommon in the population (about 1 % prevalence) but is associated with a 2-3-fold increased risk of melanoma, which is higher for those with multiple primary melanomas [249]. The presence of the E318K variant allele is associated with a higher nevus count and non-blue eye color.…”

MITF : une clé génétique du mélanome et du carcinome rénal ?

“…Identification d'une mutation germinale faux sens dans le gène MITF Récemment, nous avons identifié par séquençage une mutation germinale fauxsens dans le gène MITF (microphthalmiaassociated transcription factor) qui est associée à un risque accru de mélanome chez les porteurs [3,4]. MITF code pour un facteur de transcription de la superfamille MYC, de type hélice-boucle-hélice, qui comporte des répétitions de leucines.…”

“…Cette mutation augmente au moins d'un facteur deux (étude australienne sur 3 920 sujets) à cinq (étude française sur 2 262 sujets) le risque de développer un méla-nome. De plus, cette mutation ségrège dans certaines familles dans lesquelles surviennent des cas multiples de méla-nome, mais pas dans toutes [3,4]. Ces observations indiquent que ce variant de MITF est rarement retrouvé dans la population générale et qu'il appartient à la classe des variants génétiques conférant un risque intermédiaire de développer la maladie (Figure 1).…”

“…De plus, plusieurs facteurs tels que p53, pRb, BRCA1 (breast cancer), dont les activités sont dérégulées au cours de la progression tumorale, sont des cibles de la sumoylation [12]. Nos résultats récents apportent un nouvel éclairage sur le rôle essentiel de la sumoylation dans le cancer [3,4]. En effet, la mutation E318K de MITF abolit un site de conjugaison aux protéines SUMO et altère drastiquement la sumoylation de la protéine.…”