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Ovarian and breast cancer risks associated with pathogenic variants in RAD51C and RAD51D.
Journal of the National Cancer Institute ( IF 10.211 ) Pub Date : 2020-02-28 , DOI: 10.1093/jnci/djaa030
Xin Yang,Honglin Song,Goska Leslie,Christoph Engel,Eric Hahnen,Bernd Auber,Judit Horváth,Karin Kast,Dieter Niederacher,Clare Turnbull,Richard Houlston,Helen Hanson,Chey Loveday,Jill S Dolinsky,Holly LaDuca,Susan J Ramus,Usha Menon,Adam N Rosenthal,Ian Jacobs,Simon A Gayther,Ed Dicks,Heli Nevanlinna,Kristiina Aittomäki,Liisa M Pelttari,Hans Ehrencrona,Åke Borg,Anders Kvist,Barbara Rivera,Thomas V O Hansen,Malene Djursby,Andrew Lee,Joe Dennis,David D Bowtell,Nadia Traficante,Orland Diez,Judith Balmaña,Stephen B Gruber,Georgia Chenevix-Trench,,Allan Jensen,Susanne K Kjær,Estrid Høgdall,Laurent Castéra,Judy Garber,Ramunas Janavicius,Ana Osorio,Lisa Golmard,Ana Vega,Fergus J Couch,Mark Robson,Jacek Gronwald,Susan M Domchek,Julie O Culver,Miguel de la Hoya,Douglas F Easton,William D Foulkes,Marc Tischkowitz,Alfons Meindl,Rita K Schmutzler,Paul D P Pharoah,Antonis C Antoniou

BACKGROUND The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS We analysed data from 6178 families, 125 with pathogenic variants in RAD51C; and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families, while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C RR = 7.55, 95%CI:5.60-10.19, p = 5 × 10-40; RAD51D RR = 7.60, 95%CI:5.61-10.30, p = 5 × 10-39) and BC (RAD51C RR = 1.99, 95%CI:1.39-2.85, p = 1.55 × 10-4; RAD51D RR = 1.83, 95%CI:1.24-2.72, p = 0.002). For both RAD51C and RAD51D, there was a suggestion that the TOC RRs increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 were 11% (95%CI:6-21%) for RAD51C and 13% (95%CI:7-23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 were 21% (95%CI:15-29%) for RAD51C and 20% (95%CI:14-28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C/D pathogenic variant carriers varied by cancer family history, and could be as high as 32-36% for TOC, for carriers with two first degree relatives diagnosed with TOC; or 44-46% for BC, for carriers with two first degree relatives diagnosed with BC. CONCLUSIONS These estimates will facilitate the genetic counselling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.
更新日期:2020-02-28

 

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