ID
45221
Descrizione
Principal Investigator: Kevin M. Brown, PhD, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA MeSH: Melanoma https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000419 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.
collegamento
Keywords
versioni (2)
- 31/07/22 31/07/22 - Simon Heim
- 12/10/22 12/10/22 - Adrian Schulz
Titolare del copyright
Kevin M. Brown, PhD, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Caricato su
12 ottobre 2022
DOI
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Licenza
Creative Commons BY 4.0
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dbGaP phs000419 A Novel Recurrent Mutation in MITF Predisposes to Familial and Sporadic Melanoma
Eligibility Criteria
- StudyEvent: SEV1
- Eligibility Criteria
- Subject ID, consent group, and affection status of patients with melanoma and involved in the project "A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma."
- Sample ID and subject ID of patients with melanoma and involved in the project "A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma."
- Subject ID, age, sex, and race of patients with melanoma and involved in the project "A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma."
- Sample ID, analyte type, body site where from samples were collected, histological type of samples, and tumor status of samples obtained from of patients with melanoma and involved in the project "A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma."
Similar models
Eligibility Criteria
- StudyEvent: SEV1
- Eligibility Criteria
- Subject ID, consent group, and affection status of patients with melanoma and involved in the project "A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma."
- Sample ID and subject ID of patients with melanoma and involved in the project "A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma."
- Subject ID, age, sex, and race of patients with melanoma and involved in the project "A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma."
- Sample ID, analyte type, body site where from samples were collected, histological type of samples, and tumor status of samples obtained from of patients with melanoma and involved in the project "A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma."
C1512693 (UMLS CUI [1,2])
C4699042 (UMLS CUI [1,3])
C2736925 (UMLS CUI [1,4])
C1517194 (UMLS CUI [1,5])
C1519210 (UMLS CUI [1,6])
C0522476 (UMLS CUI [1,7])
C0025202 (UMLS CUI [1,8])