OBJECTIVE: Germline mutations in the BRCA1 gene are associated with an increased risk of breast and ovarian cancer, but there is controversy about the true magnitude of these risks. Observed differences can arise from several sources, both genetic and methodological. To examine the efficiency and bias associated with different methods of risk calculation, we analyzed a single mutation in a large pedigree with known ascertainment. METHODS: Age-specific penetrance of breast and ovarian cancer was estimated using the Kaplan-Meier method and two likelihood-based approaches [maximum likelihood estimation, maximization of the logarithm of the odds (LOD) score]. Excess risk of other cancers due to the BRCA1 mutation was assessed. RESULTS: The estimated risk of breast and ovarian cancer at age 70 was 0.80 using the Kaplan-Meier approach and 0.55 using the maximum likelihood method. Both likelihood-based methods yielded similar results for the combined breast/ovarian phenotype, but using the maximum LOD score method lower estimates were obtained if only cancer at one site was considered. In the examined family, a high risk of ovarian cancer was found which might be an effect of the central location of the mutation within BRCA1. The risk of cancer at other sites than breast and ovaries was significantly elevated, but it was not possible to identify a single cancer site that could be said to be associated with the BRCA1 mutation. CONCLUSION: Estimating the penetrance of a specific mutation using different approaches, we found that both the choice of study population and statistical method affect the magnitude of the estimates.
OBJECTIVE: Germline mutations in the BRCA1 gene are associated with an increased risk of breast and ovarian cancer, but there is controversy about the true magnitude of these risks. Observed differences can arise from several sources, both genetic and methodological. To examine the efficiency and bias associated with different methods of risk calculation, we analyzed a single mutation in a large pedigree with known ascertainment. METHODS: Age-specific penetrance of breast and ovarian cancer was estimated using the Kaplan-Meier method and two likelihood-based approaches [maximum likelihood estimation, maximization of the logarithm of the odds (LOD) score]. Excess risk of other cancers due to the BRCA1 mutation was assessed. RESULTS: The estimated risk of breast and ovarian cancer at age 70 was 0.80 using the Kaplan-Meier approach and 0.55 using the maximum likelihood method. Both likelihood-based methods yielded similar results for the combined breast/ovarian phenotype, but using the maximum LOD score method lower estimates were obtained if only cancer at one site was considered. In the examined family, a high risk of ovarian cancer was found which might be an effect of the central location of the mutation within BRCA1. The risk of cancer at other sites than breast and ovaries was significantly elevated, but it was not possible to identify a single cancer site that could be said to be associated with the BRCA1 mutation. CONCLUSION: Estimating the penetrance of a specific mutation using different approaches, we found that both the choice of study population and statistical method affect the magnitude of the estimates.
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Authors: R Chen-Shtoyerman; A Figer; H H Fidder; P Rath; L Yeremin; S Bar Meir; E Friedman; L Theodor Journal: Br J Cancer Date: 2001-02 Impact factor: 7.640
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Authors: Yuan C Ding; Lesley McGuffog; Sue Healey; Eitan Friedman; Yael Laitman; Shani- Paluch-Shimon; Bella Kaufman; Annelie Liljegren; Annika Lindblom; Håkan Olsson; Ulf Kristoffersson; Marie Stenmark-Askmalm; Beatrice Melin; Susan M Domchek; Katherine L Nathanson; Timothy R Rebbeck; Anna Jakubowska; Jan Lubinski; Katarzyna Jaworska; Katarzyna Durda; Jacek Gronwald; Tomasz Huzarski; Cezary Cybulski; Tomasz Byrski; Ana Osorio; Teresa Ramóny Cajal; Alexandra V Stavropoulou; Javier Benítez; Ute Hamann; Matti Rookus; Cora M Aalfs; Judith L de Lange; Hanne E J Meijers-Heijboer; Jan C Oosterwijk; Christi J van Asperen; Encarna B Gómez García; Nicoline Hoogerbrugge; Agnes Jager; Rob B van der Luijt; Douglas F Easton; Susan Peock; Debra Frost; Steve D Ellis; Radka Platte; Elena Fineberg; D Gareth Evans; Fiona Lalloo; Louise Izatt; Ros Eeles; Julian Adlard; Rosemarie Davidson; Diana Eccles; Trevor Cole; Jackie Cook; Carole Brewer; Marc Tischkowitz; Andrew K Godwin; Harsh Pathak; Dominique Stoppa-Lyonnet; Olga M Sinilnikova; Sylvie Mazoyer; Laure Barjhoux; Mélanie Léoné; Marion Gauthier-Villars; Virginie Caux-Moncoutier; Antoine de Pauw; Agnès Hardouin; Pascaline Berthet; Hélène Dreyfus; Sandra Fert Ferrer; Marie-Agnès Collonge-Rame; Johanna Sokolowska; Saundra Buys; Mary Daly; Alex Miron; Mary Beth Terry; Wendy Chung; Esther M John; Melissa Southey; David Goldgar; Christian F Singer; Muy-Kheng Maria Tea; Daphne Gschwantler-Kaulich; Anneliese Fink-Retter; Thomas V O Hansen; Bent Ejlertsen; Oskar T Johannsson; Kenneth Offit; Kara Sarrel; Mia M Gaudet; Joseph Vijai; Mark Robson; Marion R Piedmonte; Lesley Andrews; David Cohn; Leslie R DeMars; Paul DiSilvestro; Gustavo Rodriguez; Amanda Ewart Toland; Marco Montagna; Simona Agata; Evgeny Imyanitov; Claudine Isaacs; Ramunas Janavicius; Conxi Lazaro; Ignacio Blanco; Susan J Ramus; Lara Sucheston; Beth Y Karlan; Jenny Gross; Patricia A Ganz; Mary S Beattie; Rita K Schmutzler; Barbara Wappenschmidt; Alfons Meindl; Norbert Arnold; Dieter Niederacher; Sabine Preisler-Adams; Dorotehea Gadzicki; Raymonda Varon-Mateeva; Helmut Deissler; Andrea Gehrig; Christian Sutter; Karin Kast; Heli Nevanlinna; Kristiina Aittomäki; Jacques Simard; Amanda B Spurdle; Jonathan Beesley; Xiaoqing Chen; Gail E Tomlinson; Jeffrey Weitzel; Judy E Garber; Olufunmilayo I Olopade; Wendy S Rubinstein; Nadine Tung; Joanne L Blum; Steven A Narod; Sean Brummel; Daniel L Gillen; Noralane Lindor; Zachary Fredericksen; Vernon S Pankratz; Fergus J Couch; Paolo Radice; Paolo Peterlongo; Mark H Greene; Jennifer T Loud; Phuong L Mai; Irene L Andrulis; Gord Glendon; Hilmi Ozcelik; Anne-Marie Gerdes; Mads Thomassen; Uffe Birk Jensen; Anne-Bine Skytte; Maria A Caligo; Andrew Lee; Georgia Chenevix-Trench; Antonis C Antoniou; Susan L Neuhausen Journal: Cancer Epidemiol Biomarkers Prev Date: 2012-06-22 Impact factor: 4.254