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DOI 10.1038/gim.2016.147

Медицинская библиотека · Genetics in medicine : official journal of the American College of Medical Genetics · 2016

Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.

Muranen Taru A, Greco Dario, Blomqvist Carl, Aittomäki Kristiina, Khan Sofia, Hogervorst Frans, Verhoef Senno, Pharoah Paul D P, Dunning Alison M, Shah Mitul, Luben Robert, Bojesen Stig E, Nordestgaard Børge G, Schoemaker Minouk, Swerdlow Anthony, García-Closas Montserrat, Figueroa Jonine, Dörk Thilo, Bogdanova Natalia V, Hall Per, Li Jingmei, Khusnutdinova Elza, Bermisheva Marina, Kristensen Vessela, Borresen-Dale Anne-Lise, NBCS Investigators, Peto Julian, Dos Santos Silva Isabel, Couch Fergus J, Olson Janet E, Hillemans Peter, Park-Simon Tjoung-Won, Brauch Hiltrud, Hamann Ute, Burwinkel Barbara, Marme Frederik, Meindl Alfons, Schmutzler Rita K, Cox Angela, Cross Simon S, Sawyer Elinor J, Tomlinson Ian, Lambrechts Diether, Moisse Matthieu, Lindblom Annika, Margolin Sara, Hollestelle Antoinette, Martens John W M, Fasching Peter A, Beckmann Matthias W, Andrulis Irene L, Knight Julia A, kConFab/AOCS Investigators, Anton-Culver Hoda, Ziogas Argyrios, Giles Graham G, Milne Roger L, Brenner Hermann, Arndt Volker, Mannermaa Arto, Kosma Veli-Matti, Chang-Claude Jenny, Rudolph Anja, Devilee Peter, Seynaeve Caroline, Hopper John L, Southey Melissa C, John Esther M, Whittemore Alice S, Bolla Manjeet K, Wang Qin, Michailidou Kyriaki, Dennis Joe, Easton Douglas F, Schmidt Marjanka K, Nevanlinna Heli

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Аннотация

PURPOSE: CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).

METHODS

Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.

RESULTS

The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.

CONCLUSION

Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.

Для цитирования: Muranen Taru A, Greco Dario, Blomqvist Carl, Aittomäki Kristiina, Khan Sofia, Hogervorst Frans, Verhoef Senno, Pharoah Paul D P, Dunning Alison M, Shah Mitul, Luben Robert, Bojesen Stig E, Nordestgaard Børge G, Schoemaker Minouk, Swerdlow Anthony, García-Closas Montserrat, Figueroa Jonine, Dörk Thilo, Bogdanova Natalia V, Hall Per, Li Jingmei, Khusnutdinova Elza, Bermisheva Marina, Kristensen Vessela, Borresen-Dale Anne-Lise, NBCS Investigators, Peto Julian, Dos Santos Silva Isabel, Couch Fergus J, Olson Janet E, Hillemans Peter, Park-Simon Tjoung-Won, Brauch Hiltrud, Hamann Ute, Burwinkel Barbara, Marme Frederik, Meindl Alfons, Schmutzler Rita K, Cox Angela, Cross Simon S, Sawyer Elinor J, Tomlinson Ian, Lambrechts Diether, Moisse Matthieu, Lindblom Annika, Margolin Sara, Hollestelle Antoinette, Martens John W M, Fasching Peter A, Beckmann Matthias W, Andrulis Irene L, Knight Julia A, kConFab/AOCS Investigators, Anton-Culver Hoda, Ziogas Argyrios, Giles Graham G, Milne Roger L, Brenner Hermann, Arndt Volker, Mannermaa Arto, Kosma Veli-Matti, Chang-Claude Jenny, Rudolph Anja, Devilee Peter, Seynaeve Caroline, Hopper John L, Southey Melissa C, John Esther M, Whittemore Alice S, Bolla Manjeet K, Wang Qin, Michailidou Kyriaki, Dennis Joe, Easton Douglas F, Schmidt Marjanka K, Nevanlinna Heli. Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.. Genetics in medicine : official journal of the American College of Medical Genetics. 2016. DOI: 10.1038/gim.2016.147.

Предметные рубрики MeSH

Breast NeoplasmsCheckpoint Kinase 2FemaleGenes, ModifierGenetic Predisposition to DiseaseHumansOdds RatioPenetranceSequence Deletion
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