|
|
| PMID |
|
|
| 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 |
|
|
| HISTORY |
|
| 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 |
|
| 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: Nov |
| DAY: 13 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1476-4687 |
| ISSNTYPE: Electronic |
|
| 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 |
| CommentIn |
Nat Rev Cancer. 2012 Jan;12(1):1 |
22158021 |
|
| CommentIn |
Pigment Cell Melanoma Res. 2011 Dec;24(6):1079-80 |
22216437 |
|
|
| GRANTS |
|
| 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 |
|
| 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 |
|
|
|
