Phenotypic Characterization of Nevus and Tumor Patterns in MITF E318K Mutation Carrier Melanoma Patients

Sturm, Richard A.; Fox, Carly; McClenahan, Phil; Jagirdar, Kasturee; Ibarrola‐Villava, Maider; Banan, Parastoo; Abbott, Nicola C. D.; Ribas, Gloría; Gabrielli, Brian; Duffy, David L.; Soyer, H. Peter

doi:10.1038/jid.2013.272

Cited by 74 publications

(111 citation statements)

References 42 publications

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“…The low frequency detected might hint to technical problems or contaminated material, but positive and negative controls showed the expected results. Moreover, this mutation frequency was comparable to those of the general populations of France (frequency = 0.3%), Australia (frequency = 0.72%), Poland (0.09%), and the UK (frequency = 0.85%) [8,14,15]. Furthermore, Guo et al [16] performed exome sequencing on 10 clear-cell RCC and screened >1,000 genes (including MITF) in an additional 88 clear-cell RCC cases, but could not detect an MITF mutation.…”

Section: Discussionsupporting

confidence: 64%

The Microphthalmia-Associated Transcription Factor p.E318K Mutation Does Not Play a Major Role in Sporadic Renal Cell Tumors from Caucasian Patients

Stoehr¹,

Walter²,

Denzinger³

et al. 2016

Pathobiology

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Objective: The transcription factor MITF (microphthalmia-associated transcription factor) is known to induce expression of hypoxia-inducible factor (HIF1-α), which is involved in renal carcinogenesis. The MITF p.E318K mutation leads to deficient SUMOylation of MITF, resulting in enhanced activation of its target genes. A case-control study on melanoma patients who coincidentally were affected by renal cell carcinoma (RCC) has revealed an elevated risk for mutation carriers to be affected by one or both of these malignancies, suggesting a possible role for MITF p.E318K in renal carcinogenesis. The same study described an MITF mutation frequency of 1.5% in a small cohort of sporadic RCC, but comprehensive data on sporadic renal cell tumors are missing. We therefore tested a large cohort of sporadic renal tumors for MITF p.E318K mutation status. Methods: Genomic DNA was extracted from 426 formalin-fixed, paraffin-embedded sporadic renal tumors that had been graded according to the 2004 WHO classification of renal tumors and staged according to the 2002 TNM classification. The tumor cohort was enriched with papillary and chromophobe RCC, and also contained benign oncocytomas. DNA was tested for MITF p.E318K by pyrosequencing. Results: Of 403 analyzable tumors, 402 renal tumors were wild-type ones, and only 1 case showed the MITF p.E318K mutation. This tumor was a clear-cell RCC (pT3b N0 M0 G3 according to the TNM classification 2002). The affected patient was male, 61 years old, and had no known coexisting malignancies. Conclusion: The MITF p.E318K mutation does not appear to play a major role in sporadic RCC carcinogenesis, but is possibly restricted to a rare subpopulation of inherited RCC.

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Section: Discussionsupporting

confidence: 64%

The Microphthalmia-Associated Transcription Factor p.E318K Mutation Does Not Play a Major Role in Sporadic Renal Cell Tumors from Caucasian Patients

Stoehr¹,

Walter²,

Denzinger³

et al. 2016

Pathobiology

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Section: Hereditary Geneticssupporting

confidence: 93%

“…Unfortunately, the family members were not available to investigate the presence of this variant. This result is in agreement with the reported association of MITF E318K with multiple primary melanomas in two recent works [13,16] corroborating the relation between the presence of E318K variant and the development of multiple primary melanomas.It is important to document the prevalence of these rare mutations in different ethnic groups to further substantiate their role in melanomagenesis. Our data points to a low frequency of TERT and MITF mutations in the genetic etiology of Brazilian melanoma-prone patients, at least based on this small cohort.…”

supporting

confidence: 93%

“…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].…”

Section: Short Communicationmentioning

confidence: 99%

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

Dt¹,

Aguiar²,

Essd³

et al. 2014

Hereditary Genet

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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...

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“…Individuals with familial atypical multiple mole and melanoma syndrome (FAMMM; OMIM #606719) or dysplastic naevus syndrome (DNS; OMIM #155600) present an almost guaranteed lifetime risk of CM. As described before, phenotypic naevi differences in count and density are in part genetically determined, and genetic variants predisposing to naevi are postulated to be low-tomedium penetrance susceptibility genes for CM (141)(142)(143)(144). Additionally, several studies have focused on analysing the impact of genes involved in UV-induced DNA photoproduct repair (145,146).…”

Section: Cutaneous Melanomamentioning

confidence: 99%

The genetic basis of sunlight sensitivity and melanoma-risk pigmentation phenotypes: The role of sex-specific genetic effects, 3' untranslated regions and melanoma susceptibility genes

Fuster¹

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AGRADECIMIENTOSAntes de presentar este trabajo, es momento de agradecer el respaldo de todas aquellas personas que han hecho posible que hoy sea una finisher de esta carrera de larga distancia que es hacer una tesis doctoral.Mis primeras líneas de agradecimiento son para mi director, Conrado Martínez-Cadenas, y co-directora de tesis, Gloria Ribas; quienes con su dedicación, experiencia y profesionalidad me han guiado de manera excepcional durante las diferentes fases de este trabajo, tanto en el proceso puramente experimental como en el análisis, interpretación y presentación de los datos. A Conrado, gracias por darme la oportunidad de realizar la tesis en su grupo de investigación, además de por su apoyo personal, confianza, cercanía y dedicación. Gracias por mover cielo y tierra porque esto fuera posible. A Gloria, gracias por abrirme las puertas de su laboratorio y, sobre todo, por sus excepcionales consejos que, no sólo me han ayudado a desarrollar esta tesis, sino que también han permitido la publicación de los resultados obtenidos.Gracias a Maider Ibarrola-Villava y Maria Peña-Chilet, miembros del grupo de investigación del Departamento de Oncología del INCLIVA, por acompañarme en este largo camino, por su valiosa aportación y su gran compañerismo.Gracias a Zalfa Abdel-Malek por acogerme en su laboratorio y darme la oportunidad de participar en un ambicioso proyecto que ha enriquecido sustancialmente mi carrera investigadora. Gracias por su exigencia y crítica constructiva, pero también por su cariño durante mi estancia. Mención especial a Vicky Sope y Renny Starner por su incalculable ayuda, paciencia y amistad. Gracias de corazón por dejarme empapar de vuestra profesionalidad.Gracias a todo el personal de la Unidad Predepartamental de Medicina de la Universitat Jaume I de Castellón, por el buen humor y compañerismo demostrado. Mención especial para mis compañeros de batalla en el laboratorio. Gracias por esas largas conversaciones y hacerme sentir afortunada por compartir mi trabajo diario con vosotros. Gracias por todo lo compartido.Gracias también a todas esas personas anónimas que voluntariamente han donado una muestra, y al personal médico de los diferentes hospitales encargados de recoger dichas muestras, ya que sin su contribución este trabajo no habría existido.Finalmente, es necesario expresar mi mayor gratitud a todas esas personas que indirectamente también han sido partícipes de este trabajo. A mi familia, por creer en mí.A mi padre, por enseñarme el valor del esfuerzo, el trabajo duro y la disciplina. A mi madre, por enseñarme a tener paciencia. A mi hermana, por ser mi mejor amiga y consejera, especialmente en la estadística y el uso del R. A Manoli, porque todo lo vivido juntas es lo que me ha hecho ser lo que soy. A mi grupo de entrenamiento, por ayudarme a evadirme de todo en los momentos que más lo necesitaba. A Iván, por estar siempre a mi lado. Por no dejarme caer. Por saber cómo hacer que confiara en mi misma. Por hacerme ver que soy una privilegiada hasta en los momentos menos buenos...

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Phenotypic Characterization of Nevus and Tumor Patterns in MITF E318K Mutation Carrier Melanoma Patients

Cited by 74 publications

References 42 publications

The Microphthalmia-Associated Transcription Factor p.E318K Mutation Does Not Play a Major Role in Sporadic Renal Cell Tumors from Caucasian Patients

The Microphthalmia-Associated Transcription Factor p.E318K Mutation Does Not Play a Major Role in Sporadic Renal Cell Tumors from Caucasian Patients

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

The genetic basis of sunlight sensitivity and melanoma-risk pigmentation phenotypes: The role of sex-specific genetic effects, 3' untranslated regions and melanoma susceptibility genes

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