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PMID: 21964575 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Mutations in BRIP1 confer high risk of ovarian cancer.

Nature genetics ·Vol. 43 ·No. 11 ·2011-10-02 ·Pages 1104-7

Rafnar T, Gudbjartsson DF, Sulem P, Jonasdottir A, Sigurdsson A, Jonasdottir A, Besenbacher S, Lundin P, Stacey SN, Gudmundsson J, Magnusson OT, le Roux L, Orlygsdottir G, Helgadottir HT, Johannsdottir H, Gylfason A, Tryggvadottir L, Jonasson JG, de Juan A, Ortega E, Ramon-Cajal JM, García-Prats MD, Mayordomo C, Panadero A, Rivera F, Aben KK, van Altena AM, Massuger LF, Aavikko M, Kujala PM, Staff S, Aaltonen LA, Olafsdottir K, Bjornsson J, Kong A, Salvarsdottir A, Saemundsson H, Olafsson K, Benediktsdottir KR, Gulcher J, Masson G, Kiemeney LA, Mayordomo JI, Thorsteinsdottir U, Stefansson K

Abstract

Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries. Sixteen million sequence variants, identified through whole-genome sequencing of 457 Icelanders, were imputed to 41,675 Icelanders genotyped using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer (N of affected individuals = 656). We discovered a rare (0.41% allelic frequency) frameshift mutation, c.2040_2041insTT, in the BRIP1 (FANCJ) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, P = 2.8 × 10(-14)). The mutation was also associated with increased risk of cancer in general and reduced lifespan by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1, c.1702_1703del, was seen in 2 out of 144 subjects with ovarian cancer and 1 out of 1,780 control subjects (P = 0.016). This allele was also associated with breast cancer (seen in 6/927 cases; P = 0.0079). Ovarian tumors from heterozygous carriers of the Icelandic mutation show loss of the wild-type allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer.

MeSH Terms
DNA-Binding Proteins/genetics Fanconi Anemia Complementation Group Proteins Female Humans Mutation Ovarian Neoplasms/genetics Polymorphism, Single Nucleotide RNA Helicases/genetics
Chemicals
DNA-Binding Proteins Fanconi Anemia Complementation Group Proteins BRIP1 protein, human RNA Helicases
Authors & Affiliations
45 authors, click to expand affiliations / ORCID
Rafnar Thorunn
deCODE genetics, Reykjavik, Iceland. [email protected]
Gudbjartsson Daniel F
Sulem Patrick
Jonasdottir Aslaug
Sigurdsson Asgeir
Jonasdottir Adalbjorg
Besenbacher Soren
Lundin Pär
Stacey Simon N
Gudmundsson Julius
Magnusson Olafur T
le Roux Louise
Orlygsdottir Gudbjorg
Helgadottir Hafdis T
Johannsdottir Hrefna
Gylfason Arnaldur
Tryggvadottir Laufey
Jonasson Jon G
de Juan Ana
Ortega Eugenia
Ramon-Cajal Jose M
García-Prats Maria D
Mayordomo Carlos
Panadero Angeles
Rivera Fernando
Aben Katja K H
van Altena Anne M
Massuger Leon F A G
Aavikko Mervi
Kujala Paula M
Staff Synnöve
Aaltonen Lauri A
Olafsdottir Kristrun
Bjornsson Johannes
Kong Augustine
Salvarsdottir Anna
Saemundsson Hafsteinn
Olafsson Karl
Benediktsdottir Kristrun R
Gulcher Jeffrey
Masson Gisli
Kiemeney Lambertus A
Mayordomo Jose I
Thorsteinsdottir Unnur
Stefansson Kari
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.955
Email
[email protected]
Published
2011-10-02
Epub
2011-00-02
Pages
1104-7
Language
English
Region
United States
NLM ID
9216904
Subset
IM
Databases
RefSeq
NM_032043
External Links
PubMed source DOI: 10.1038/ng.955 View journal details
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