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

ABSTRACT: We identified a novel germline mutation of the microphthalmia-associated transcription factor (MITF - E318K). This mutation was found to be present in numerous melanoma families, as well as the general population, where its association with melanoma has a significant effect. We determined the effect of the E318K mutation on global MITF target gene transcription. We developed a tetracycline-inducible system for expression of wild type MITF or the E318K variant in melanoma cell lines with constitutively low or undetectable levels of endogenous MITF (HT144 and C32). We examined whole-genome expression profiles in these cells following induction of either wild-type or E318K MITF for 48 hours. Analysis suggests that the MITF E318K mutant exhibits differential transcriptional activity against some, though not all, target genes. Expression profiling by array

ORGANISM(S): Homo sapiens

SUBMITTER: Yokoyama S

PROVIDER: S-ECPF-GEOD-31269 | biostudies-other | 2011 Dec

REPOSITORIES: biostudies-other

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

Project description:So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds. Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify 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 of odds (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.

| S-EPMC3266855 | biostudies-literature

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

Project description:We identified a novel germline mutation of the microphthalmia-associated transcription factor (MITF - E318K). This mutation was found to be present in numerous melanoma families, as well as the general population, where its association with melanoma has a significant effect. We determined the effect of the E318K mutation on global MITF target gene transcription. We developed a tetracycline-inducible system for expression of wild type MITF or the E318K variant in melanoma cell lines with constitutively low or undetectable levels of endogenous MITF (HT144 and C32). We examined whole-genome expression profiles in these cells following induction of either wild-type or E318K MITF for 48 hours. Analysis suggests that the MITF E318K mutant exhibits differential transcriptional activity against some, though not all, target genes. Expression profiling by array

2011-12-01 | E-GEOD-31269 | biostudies-arrayexpress

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

2011-12-01 | GSE31269 | GEO

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

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

| PRJNA76045 | ENA

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

Project description:<p>We conducted whole-genome sequencing of probands from several melanoma families, identifying one individual carrying a novel germline variant (c.G1075A, NM_000248.3; p.E318K, NP_000239.1; rs149617956) in the melanoma lineage-specific oncogene MITF. While the variant cosegregated with melanoma in some, but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a LOD score of 2.7 under a dominant model, suggesting E318K as a possible intermediate risk variant. Consistent with this, E318K was significantly associated with melanoma in a large Australian case-control sample, giving an odds ratio (OR) of 2.33, 95% CI 1.21-4.70 (case and control carrier frequency, 0.0165 and 0.0072, respectively; P=0.008). Likewise, it was similarly associated in an independent case-control sample from the United Kingdom (UK P=0.012; combined P=0.0003, OR 2.19, 95% CI 1.41-3.45). In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma (OR 2.95, 95% CI 1.23-6.92), multiple primary melanomas (OR 4.22, 95% CI 1.52-10.91), or both (OR 8.37, 95% CI 2.58-23.80). The variant allele was also associated with increased nevus count (combined P=0.002, OR 2.54, 95% CI 1.42-4.55) and non-blue eye color (combined P=0.008, OR 2.01, 95% CI 1.11-3.81). 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 highlights the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.</p>

| phs000419.v1.p1 | EGA

A Novel Recurrent Mutation in MITF Predisposes to Familial and Sporadic Melanoma

| phs000419 | dbGaP

A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma.

Project description:UNLABELLED:Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including the von Hippel-Lindau (VHL) tumor suppressor, which is also mutated in sporadic RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BRCA1-associated protein-1 (BAP1) gene is mutated in sporadic RCC. The BAP1 gene encodes a nuclear deubiquitinase and appears to be a classic two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade, clear-cell RCC (ccRCC) and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, the BAP1 gene was sequenced in 83 unrelated probands with unexplained familial RCC. Interestingly, a novel variant (c.41T>A; p.L14H) was uncovered that cosegregated with the RCC phenotype. The p.L14H variant targets a highly conserved residue in the catalytic domain, which is frequently targeted by missense mutations. The family with the novel BAP1 variant was characterized by early-onset ccRCC, occasionally of high Fuhrman grade, and lacked other features that typify VHL syndrome. These findings suggest that BAP1 is an early-onset familial RCC predisposing gene. IMPLICATIONS:BAP1 mutations may drive tumor development in a subset of patients with inherited renal cell cancer.

| S-EPMC4211292 | biostudies-literature

A conditional zebrafish MITF mutation reveals MITF levels are critical for melanoma promotion vs. regression in vivo.

Project description:The microphthalmia-associated transcription factor (MITF) is the "master melanocyte transcription factor" with a complex role in melanoma. MITF protein levels vary between and within clinical specimens, and amplifications and gain- and loss-of-function mutations have been identified in melanoma. How MITF functions in melanoma development and the effects of targeting MITF in vivo are unknown because MITF levels have not been directly tested in a genetic animal model. Here, we use a temperature-sensitive mitf zebrafish mutant to conditionally control endogenous MITF activity. We show that low levels of endogenous MITF activity are oncogenic with BRAF(V600E) to promote melanoma that reflects the pathology of the human disease. Remarkably, abrogating MITF activity in BRAF(V600E)mitf melanoma leads to dramatic tumor regression marked by melanophage infiltration and increased apoptosis. These studies are significant because they show that targeting MITF activity is a potent antitumor mechanism, but also show that caution is required because low levels of wild-type MITF activity are oncogenic.

| S-EPMC3898314 | biostudies-literature

A MITF germline mutation predisposes to melanoma and renal cell carcinoma

Project description:Study EGAS00000000048

| EGAS00000000048 | EGA

A recurrent PDGFRB mutation causes familial infantile myofibromatosis.

Project description:Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor ? (PDGFRB) in all 11 affected individuals with familial IM, although none of the five individuals with nonfamilial IM had mutations in this gene. We further identified a second heterozygous mutation in PDGFRB in two myofibromas from one of the affected familial cases, indicative of a potential second hit in this gene in the tumor. PDGFR-? promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-? as a cause of the dominant form of this disease. They provide a rationale for further investigations of this specific mutation and gene to assess the benefits of targeted therapies against PDGFR-? in aggressive life-threatening familial forms of the disease.

| S-EPMC3675240 | biostudies-literature

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