TY - JOUR
T1 - Mutations in BRIP1 confer high risk of ovarian cancer
AU - Rafnar, Thorunn
AU - Gudbjartsson, Daniel F.
AU - Sulem, Patrick
AU - Jonasdottir, Aslaug
AU - Sigurdsson, Asgeir
AU - Jonasdottir, Adalbjorg
AU - Besenbacher, Soren
AU - Lundin, Pär
AU - Stacey, Simon N.
AU - Gudmundsson, Julius
AU - Magnusson, Olafur T.
AU - Le Roux, Louise
AU - Orlygsdottir, Gudbjorg
AU - Helgadottir, Hafdis T.
AU - Johannsdottir, Hrefna
AU - Gylfason, Arnaldur
AU - Tryggvadottir, Laufey
AU - Jonasson, Jon G.
AU - De Juan, Ana
AU - Ortega, Eugenia
AU - Ramon-Cajal, Jose M.
AU - García-Prats, Maria D.
AU - Mayordomo, Carlos
AU - Panadero, Angeles
AU - Rivera, Fernando
AU - Aben, Katja K.H.
AU - Van Altena, Anne M.
AU - Massuger, Leon F.A.G.
AU - Aavikko, Mervi
AU - Kujala, Paula M.
AU - Staff, Synnöve
AU - Aaltonen, Lauri A.
AU - Olafsdottir, Kristrun
AU - Bjornsson, Johannes
AU - Kong, Augustine
AU - Salvarsdottir, Anna
AU - Saemundsson, Hafsteinn
AU - Olafsson, Karl
AU - Benediktsdottir, Kristrun R.
AU - Gulcher, Jeffrey
AU - Masson, Gisli
AU - Kiemeney, Lambertus A.
AU - Mayordomo, Jose I.
AU - Thorsteinsdottir, Unnur
AU - Stefansson, Kari
N1 - Funding Information: This work was partly funded by the European Commission 7th Framework Programme FP7-MC-IAPP (grant agreement no. 218071 CancerGene).
PY - 2011/11
Y1 - 2011/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/80054973810
U2 - 10.1038/ng.955
DO - 10.1038/ng.955
M3 - Article
C2 - 21964575
SN - 1061-4036
VL - 43
SP - 1104
EP - 1107
JO - Nature Genetics
JF - Nature Genetics
IS - 11
ER -
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