Mutations in BRIP1 confer high risk of ovarian cancer
Using a combination of whole-genome sequencing, haplotype sharing and the genealogies of the Icelandic population, Thorunn Rafnar, Kari Stefansson and colleagues identified a rare coding mutation in the gene of a BRCA1-interacting factor, BRIP1 , that confers a high relative risk of ovarian cancer....
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| Published in | Nature genetics Vol. 43; no. 11; pp. 1104 - 1107 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Nature Publishing Group US
01.11.2011
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1061-4036 1546-1718 1546-1718 |
| DOI | 10.1038/ng.955 |
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| Abstract | Using a combination of whole-genome sequencing, haplotype sharing and the genealogies of the Icelandic population, Thorunn Rafnar, Kari Stefansson and colleagues identified a rare coding mutation in the gene of a BRCA1-interacting factor,
BRIP1
, that confers a high relative risk of ovarian cancer.
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. |
|---|---|
| AbstractList | Using a combination of whole-genome sequencing, haplotype sharing and the genealogies of the Icelandic population, Thorunn Rafnar, Kari Stefansson and colleagues identified a rare coding mutation in the gene of a BRCA1-interacting factor, BRIP1, that confers a high relative risk of ovarian cancer. 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^sup -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. [PUBLICATION 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.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. 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. 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 x 10 super(-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. Using a combination of whole-genome sequencing, haplotype sharing and the genealogies of the Icelandic population, Thorunn Rafnar, Kari Stefansson and colleagues identified a rare coding mutation in the gene of a BRCA1-interacting factor, BRIP1 , that confers a high relative risk of ovarian cancer. 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. |
| Audience | Academic |
| Author | Masson, Gisli Mayordomo, Jose I Stacey, Simon N Aaltonen, Lauri A García-Prats, Maria D Salvarsdottir, Anna Massuger, Leon F A G Olafsdottir, Kristrun Thorsteinsdottir, Unnur Aavikko, Mervi Lundin, Pär Panadero, Angeles Mayordomo, Carlos Rafnar, Thorunn Helgadottir, Hafdis T Gudbjartsson, Daniel F van Altena, Anne M Benediktsdottir, Kristrun R Orlygsdottir, Gudbjorg Bjornsson, Johannes Kong, Augustine Saemundsson, Hafsteinn Magnusson, Olafur T le Roux, Louise de Juan, Ana Jonasdottir, Adalbjorg Stefansson, Kari Gulcher, Jeffrey Sulem, Patrick Ortega, Eugenia Jonasson, Jon G Olafsson, Karl Johannsdottir, Hrefna Staff, Synnöve Gylfason, Arnaldur Tryggvadottir, Laufey Aben, Katja K H Jonasdottir, Aslaug Sigurdsson, Asgeir Kujala, Paula M Gudmundsson, Julius Kiemeney, Lambertus A Besenbacher, Soren Ramon-Cajal, Jose M Rivera, Fernando |
| Author_xml | – sequence: 1 givenname: Thorunn surname: Rafnar fullname: Rafnar, Thorunn email: thorunn.rafnar@decode.is organization: deCODE genetics – sequence: 2 givenname: Daniel F surname: Gudbjartsson fullname: Gudbjartsson, Daniel F organization: deCODE genetics – sequence: 3 givenname: Patrick surname: Sulem fullname: Sulem, Patrick organization: deCODE genetics – sequence: 4 givenname: Aslaug surname: Jonasdottir fullname: Jonasdottir, Aslaug organization: deCODE genetics – sequence: 5 givenname: Asgeir surname: Sigurdsson fullname: Sigurdsson, Asgeir organization: deCODE genetics – sequence: 6 givenname: Adalbjorg surname: Jonasdottir fullname: Jonasdottir, Adalbjorg organization: deCODE genetics – sequence: 7 givenname: Soren surname: Besenbacher fullname: Besenbacher, Soren organization: deCODE genetics – sequence: 8 givenname: Pär surname: Lundin fullname: Lundin, Pär organization: deCODE genetics – sequence: 9 givenname: Simon N surname: Stacey fullname: Stacey, Simon N organization: deCODE genetics – sequence: 10 givenname: Julius surname: Gudmundsson fullname: Gudmundsson, Julius organization: deCODE genetics – sequence: 11 givenname: Olafur T surname: Magnusson fullname: Magnusson, Olafur T organization: deCODE genetics – sequence: 12 givenname: Louise surname: le Roux fullname: le Roux, Louise organization: deCODE genetics – sequence: 13 givenname: Gudbjorg surname: Orlygsdottir fullname: Orlygsdottir, Gudbjorg organization: deCODE genetics – sequence: 14 givenname: Hafdis T surname: Helgadottir fullname: Helgadottir, Hafdis T organization: deCODE genetics – sequence: 15 givenname: Hrefna surname: Johannsdottir fullname: Johannsdottir, Hrefna organization: deCODE genetics – sequence: 16 givenname: Arnaldur surname: Gylfason fullname: Gylfason, Arnaldur organization: deCODE genetics – sequence: 17 givenname: Laufey surname: Tryggvadottir fullname: Tryggvadottir, Laufey organization: Icelandic Cancer Registry, Faculty of Medicine, University of Iceland – sequence: 18 givenname: Jon G surname: Jonasson fullname: Jonasson, Jon G organization: Icelandic Cancer Registry, Faculty of Medicine, University of Iceland – sequence: 19 givenname: Ana surname: de Juan fullname: de Juan, Ana organization: Division of Medical Oncology, Marques de Valdecilla University Hospital – sequence: 20 givenname: Eugenia surname: Ortega fullname: Ortega, Eugenia organization: Division of Medical Oncology, Arnau de Vilanova University Hospital – sequence: 21 givenname: Jose M surname: Ramon-Cajal fullname: Ramon-Cajal, Jose M organization: Division of Gynecology, San Jorge General Hospital – sequence: 22 givenname: Maria D surname: García-Prats fullname: García-Prats, Maria D organization: Division of Pathology, San Jorge General Hospital – sequence: 23 givenname: Carlos surname: Mayordomo fullname: Mayordomo, Carlos organization: School of Medicine, University of Zaragoza – sequence: 24 givenname: Angeles surname: Panadero fullname: Panadero, Angeles organization: Division of Medical Oncology, Ciudad de Coria Hospital – sequence: 25 givenname: Fernando surname: Rivera fullname: Rivera, Fernando organization: Division of Medical Oncology, Marques de Valdecilla University Hospital – sequence: 26 givenname: Katja K H surname: Aben fullname: Aben, Katja K H organization: Comprehensive Cancer Center The Netherlands, Department of Epidemiology, Biostatistics and Health Technology Assesment, Radboud University Nijmegen Medical Centre – sequence: 27 givenname: Anne M surname: van Altena fullname: van Altena, Anne M organization: Department of Gynaecology, Radboud University Nijmegen Medical Centre – sequence: 28 givenname: Leon F A G surname: Massuger fullname: Massuger, Leon F A G organization: Department of Gynaecology, Radboud University Nijmegen Medical Centre – sequence: 29 givenname: Mervi surname: Aavikko fullname: Aavikko, Mervi organization: Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki – sequence: 30 givenname: Paula M surname: Kujala fullname: Kujala, Paula M organization: Department of Pathology, Centre for Laboratory Medicine, University of Tampere and Tampere University Hospital – sequence: 31 givenname: Synnöve surname: Staff fullname: Staff, Synnöve organization: Laboratory of Cancer Biology, Institute of Biomedical Technology, University of Tampere, Department of Obstetrics and Gynecology, Tampere University Hospital – sequence: 32 givenname: Lauri A surname: Aaltonen fullname: Aaltonen, Lauri A organization: Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki – sequence: 33 givenname: Kristrun surname: Olafsdottir fullname: Olafsdottir, Kristrun organization: Department of Pathology, Landspitali University Hospital – sequence: 34 givenname: Johannes surname: Bjornsson fullname: Bjornsson, Johannes organization: Department of Pathology, Landspitali University Hospital – sequence: 35 givenname: Augustine surname: Kong fullname: Kong, Augustine organization: deCODE genetics – sequence: 36 givenname: Anna surname: Salvarsdottir fullname: Salvarsdottir, Anna organization: Department of Obstetrics and Gynecology, Landspitali University Hospital – sequence: 37 givenname: Hafsteinn surname: Saemundsson fullname: Saemundsson, Hafsteinn organization: Department of Obstetrics and Gynecology, Landspitali University Hospital – sequence: 38 givenname: Karl surname: Olafsson fullname: Olafsson, Karl organization: Department of Obstetrics and Gynecology, Landspitali University Hospital – sequence: 39 givenname: Kristrun R surname: Benediktsdottir fullname: Benediktsdottir, Kristrun R organization: Faculty of Medicine, University of Iceland, Department of Pathology, Landspitali University Hospital – sequence: 40 givenname: Jeffrey surname: Gulcher fullname: Gulcher, Jeffrey organization: deCODE genetics – sequence: 41 givenname: Gisli surname: Masson fullname: Masson, Gisli organization: deCODE genetics – sequence: 42 givenname: Lambertus A surname: Kiemeney fullname: Kiemeney, Lambertus A organization: Comprehensive Cancer Center The Netherlands, Department of Epidemiology, Biostatistics and Health Technology Assesment, Radboud University Nijmegen Medical Centre, Department of Urology, Radboud University Nijmegen Medical Centre – sequence: 43 givenname: Jose I surname: Mayordomo fullname: Mayordomo, Jose I organization: Division of Medical Oncology, University Hospital – sequence: 44 givenname: Unnur surname: Thorsteinsdottir fullname: Thorsteinsdottir, Unnur organization: deCODE genetics, Faculty of Medicine, University of Iceland – sequence: 45 givenname: Kari surname: Stefansson fullname: Stefansson, Kari email: kstefans@decode.is organization: deCODE genetics, Faculty of Medicine, University of Iceland |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24750149$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/21964575$$D View this record in MEDLINE/PubMed |
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| Snippet | Using a combination of whole-genome sequencing, haplotype sharing and the genealogies of the Icelandic population, Thorunn Rafnar, Kari Stefansson and... Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries. Sixteen million sequence variants, identified through... |
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| SubjectTerms | 631/208/737 631/67/581 692/699/67/1517/1709 Agriculture Animal Genetics and Genomics Biological and medical sciences Biomedical and Life Sciences Biomedicine Breast cancer Cancer prevention Cancer Research Developed countries DNA-Binding Proteins - genetics Fanconi Anemia Complementation Group Proteins Female Female genital diseases Fundamental and applied biological sciences. Psychology Gene Function Genes Genetic aspects Genetics Genetics of eukaryotes. Biological and molecular evolution Genomes Genomics Gynecology. Andrology. Obstetrics Health aspects Health risks Human Human Genetics Humans letter Medical schools Medical sciences Mutation Ovarian cancer Ovarian Neoplasms - genetics Polymorphism, Single Nucleotide Population genetics, reproduction patterns Risk factors RNA Helicases - genetics Tumors |
| Title | Mutations in BRIP1 confer high risk of ovarian cancer |
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