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PMID |
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TITLE |
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A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. |
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ABSTRACT |
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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. |
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DATE PUBLISHED |
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HISTORY |
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PUBSTATUS |
PUBSTATUSDATE |
received |
2011/03/17 |
accepted |
2011/10/13 |
entrez |
2011/11/15 06:00 |
pubmed |
2011/11/15 06:00 |
medline |
2012/02/24 06:00 |
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AUTHORS |
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NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
Yokoyama S |
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Yokoyama |
Satoru |
S |
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Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Massachusetts 02114, USA. |
Woods SL |
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Woods |
Susan L |
SL |
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Boyle GM |
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Boyle |
Glen M |
GM |
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Aoude LG |
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Aoude |
Lauren G |
LG |
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MacGregor S |
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MacGregor |
Stuart |
S |
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Zismann V |
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Zismann |
Victoria |
V |
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Gartside M |
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Gartside |
Michael |
M |
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Cust AE |
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Cust |
Anne E |
AE |
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Haq R |
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Haq |
Rizwan |
R |
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Harland M |
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Harland |
Mark |
M |
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Taylor JC |
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Taylor |
John C |
JC |
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Duffy DL |
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Duffy |
David L |
DL |
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Holohan K |
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Holohan |
Kelly |
K |
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Dutton-Regester K |
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Dutton-Regester |
Ken |
K |
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Palmer JM |
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Palmer |
Jane M |
JM |
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Bonazzi V |
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Bonazzi |
Vanessa |
V |
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Stark MS |
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Stark |
Mitchell S |
MS |
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Symmons J |
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Symmons |
Judith |
J |
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Law MH |
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Law |
Matthew H |
MH |
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Schmidt C |
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Schmidt |
Christopher |
C |
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Lanagan C |
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Lanagan |
Cathy |
C |
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O'Connor L |
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O'Connor |
Linda |
L |
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Holland EA |
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Holland |
Elizabeth A |
EA |
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Schmid H |
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Schmid |
Helen |
H |
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Maskiell JA |
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Maskiell |
Judith A |
JA |
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Jetann J |
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Jetann |
Jodie |
J |
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Ferguson M |
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Ferguson |
Megan |
M |
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Jenkins MA |
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Jenkins |
Mark A |
MA |
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Kefford RF |
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Kefford |
Richard F |
RF |
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Giles GG |
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Giles |
Graham G |
GG |
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Armstrong BK |
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Armstrong |
Bruce K |
BK |
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Aitken JF |
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Aitken |
Joanne F |
JF |
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Hopper JL |
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Hopper |
John L |
JL |
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Whiteman DC |
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Whiteman |
David C |
DC |
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Pharoah PD |
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Pharoah |
Paul D |
PD |
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Easton DF |
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Easton |
Douglas F |
DF |
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Dunning AM |
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Dunning |
Alison M |
AM |
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Newton-Bishop JA |
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Newton-Bishop |
Julia A |
JA |
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Montgomery GW |
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Montgomery |
Grant W |
GW |
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Martin NG |
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Martin |
Nicholas G |
NG |
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Mann GJ |
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Mann |
Graham J |
GJ |
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Bishop DT |
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Bishop |
D Timothy |
DT |
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Tsao H |
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Tsao |
Hensin |
H |
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Trent JM |
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Trent |
Jeffrey M |
JM |
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Fisher DE |
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Fisher |
David E |
DE |
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Hayward NK |
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Hayward |
Nicholas K |
NK |
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Brown KM |
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Brown |
Kevin M |
KM |
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INVESTIGATORS |
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JOURNAL |
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VOLUME: 480 |
ISSUE: 7375 |
TITLE: Nature |
ISOABBREVIATION: Nature |
YEAR: 2011 |
MONTH: Nov |
DAY: 13 |
MEDLINEDATE: |
SEASON: |
CITEDMEDIUM: Internet |
ISSN: 1476-4687 |
ISSNTYPE: Electronic |
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MEDLINE JOURNAL |
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MEDLINETA: Nature |
COUNTRY: England |
ISSNLINKING: 0028-0836 |
NLMUNIQUEID: 0410462 |
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PUBLICATION TYPE |
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PUBLICATIONTYPE TEXT |
Journal Article |
Research Support, N.I.H., Extramural |
Research Support, Non-U.S. Gov't |
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COMMENTS AND CORRECTIONS |
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REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
CommentIn |
Nat Rev Cancer. 2012 Jan;12(1):1 |
22158021 |
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CommentIn |
Pigment Cell Melanoma Res. 2011 Dec;24(6):1079-80 |
22216437 |
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GRANTS |
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GRANTID |
AGENCY |
COUNTRY |
R01 CA083115 |
NCI NIH HHS |
United States |
P50CA9368 |
NCI NIH HHS |
United States |
11022 |
Cancer Research UK |
United Kingdom |
R01 CA83115 |
NCI NIH HHS |
United States |
C588/A10589 |
Cancer Research UK |
United Kingdom |
R01 AR043369 |
NIAMS NIH HHS |
United States |
AR043369-14 |
NIAMS NIH HHS |
United States |
R01 CA088363 |
NCI NIH HHS |
United States |
K24CA149202 |
NCI NIH HHS |
United States |
R01 CA-83115-01A2 |
NCI NIH HHS |
United States |
C490/A11021 |
Cancer Research UK |
United Kingdom |
R01 CA088363-09 |
NCI NIH HHS |
United States |
C8216/A6129 |
Cancer Research UK |
United Kingdom |
P50 CA093683 |
NCI NIH HHS |
United States |
C8197/A10123 |
Cancer Research UK |
United Kingdom |
K24 CA149202 |
NCI NIH HHS |
United States |
CA88363 |
NCI NIH HHS |
United States |
C588/A4994 |
Cancer Research UK |
United Kingdom |
10118 |
Cancer Research UK |
United Kingdom |
10589 |
Cancer Research UK |
United Kingdom |
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GENERAL NOTE |
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KEYWORDS |
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MESH HEADINGS |
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DESCRIPTORNAME |
QUALIFIERNAME |
Adult |
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Aged |
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Aged, 80 and over |
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Female |
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Gene Expression Regulation, Neoplastic |
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Genetic Predisposition to Disease |
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Humans |
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Male |
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Melanoma |
genetics |
Microphthalmia-Associated Transcription Factor |
genetics |
Middle Aged |
genetics |
Mutation |
genetics |
Sumoylation |
genetics |
Young Adult |
genetics |
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SUPPLEMENTARY MESH |
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GENE SYMBOLS |
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CHEMICALS |
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REGISTRYNUMBER |
NAMEOFSUBSTANCE |
0 |
MITF protein, human |
0 |
Microphthalmia-Associated Transcription Factor |
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OTHER ID's |
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