Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
22080950
TITLE
A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.
ABSTRACT
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.
DATE PUBLISHED
2011 Dec 1
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2011/03/17
accepted 2011/10/13
aheadofprint 2011/11/13
entrez 2011/11/15 06:00
pubmed 2011/11/15 06:00
medline 2012/02/24 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Yokoyama S Yokoyama Satoru S Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Massachusetts 02114, USA.
Woods SL Woods Susan L SL
Boyle GM Boyle Glen M GM
Aoude LG Aoude Lauren G LG
MacGregor S MacGregor Stuart S
Zismann V Zismann Victoria V
Gartside M Gartside Michael M
Cust AE Cust Anne E AE
Haq R Haq Rizwan R
Harland M Harland Mark M
Taylor JC Taylor John C JC
Duffy DL Duffy David L DL
Holohan K Holohan Kelly K
Dutton-Regester K Dutton-Regester Ken K
Palmer JM Palmer Jane M JM
Bonazzi V Bonazzi Vanessa V
Stark MS Stark Mitchell S MS
Symmons J Symmons Judith J
Law MH Law Matthew H MH
Schmidt C Schmidt Christopher C
Lanagan C Lanagan Cathy C
O'Connor L O'Connor Linda L
Holland EA Holland Elizabeth A EA
Schmid H Schmid Helen H
Maskiell JA Maskiell Judith A JA
Jetann J Jetann Jodie J
Ferguson M Ferguson Megan M
Jenkins MA Jenkins Mark A MA
Kefford RF Kefford Richard F RF
Giles GG Giles Graham G GG
Armstrong BK Armstrong Bruce K BK
Aitken JF Aitken Joanne F JF
Hopper JL Hopper John L JL
Whiteman DC Whiteman David C DC
Pharoah PD Pharoah Paul D PD
Easton DF Easton Douglas F DF
Dunning AM Dunning Alison M AM
Newton-Bishop JA Newton-Bishop Julia A JA
Montgomery GW Montgomery Grant W GW
Martin NG Martin Nicholas G NG
Mann GJ Mann Graham J GJ
Bishop DT Bishop D Timothy DT
Tsao H Tsao Hensin H
Trent JM Trent Jeffrey M JM
Fisher DE Fisher David E DE
Hayward NK Hayward Nicholas K NK
Brown KM Brown Kevin M KM
INVESTIGATORS
JOURNAL
VOLUME: 480
ISSUE: 7375
TITLE: Nature
ISOABBREVIATION: Nature
YEAR: 2011
MONTH: Dec
DAY: 1
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN:
ISSNTYPE:
MEDLINE JOURNAL
MEDLINETA: Nature
COUNTRY: England
ISSNLINKING: 0028-0836
NLMUNIQUEID: 0410462
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
AR043369-14 NIAMS NIH HHS United States
C490/A11021 Cancer Research UK United Kingdom
C588/A10589 Cancer Research UK United Kingdom
C588/A4994 Cancer Research UK United Kingdom
C8197/A10123 Cancer Research UK United Kingdom
C8216/A6129 Cancer Research UK United Kingdom
CA88363 NCI NIH HHS United States
K24CA149202 NCI NIH HHS United States
P50CA9368 NCI NIH HHS United States
R01 CA-83115-01A2 NCI NIH HHS United States
R01 CA088363 NCI NIH HHS United States
R01 CA088363-09 NCI NIH HHS United States
R01 CA83115 NCI NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adult
Aged
Aged, 80 and over
Female
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Humans
Male
Melanoma genetics
Microphthalmia-Associated Transcription Factor genetics
Middle Aged genetics
Mutation genetics
Sumoylation genetics
Young Adult genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 MITF protein, human
0 Microphthalmia-Associated Transcription Factor
OTHER ID's
OTHERID SOURCE
NIHMS349919 NLM
PMC3266855 NLM