Dataset Information

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

ABSTRACT:

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.

PROVIDER: phs000419 | dbGaP |

SECONDARY ACCESSION(S): PRJNA76045PRJNA76047

REPOSITORIES: dbGaP

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Dataset's files

Source:

			Action	DRS
	GapExchange_phs000419.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs000419.MelanomaPredisposition_Seq.v1.p1.MULTI.pdf	Pdf
	manifest_phs000419.MelanomaPredisposition_Seq.v1.p1.c1.CRO.pdf	Pdf
	datadict_v2.xsl	Other

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

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