Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer.

Authors:
Hermela Shimelis Romy L S Mesman Catharina Von Nicolai Asa Ehlen Lucia Guidugli Charlotte Martin Fabienne M G R Calléja Huong Meeks Emily Hallberg Jamie Hinton Jenna Lilyquist Chunling Hu Cora M Aalfs Kristiina Aittomäki Irene Andrulis Hoda Anton-Culver Volker Arndt Matthias W Beckmann Javier Benitez Natalia V Bogdanova Stig E Bojesen Manjeet K Bolla Anne-Lise Borresen-Dale Hiltrud Brauch Paul Brennan Hermann Brenner Annegien Broeks Barbara Brouwers Thomas Brüning Barbara Burwinkel Jenny Chang-Claude Georgia Chenevix-Trench Ching-Yu Cheng Ji-Yeob Choi J Margriet Collée Angela Cox Simon S Cross Kamila Czene Hatef Darabi Joe Dennis Thilo Dörk Isabel Dos-Santos-Silva Alison M Dunning Peter A Fasching Jonine Figueroa Henrik Flyger Montserrat García-Closas Graham G Giles Gord Glendon Pascal Guénel Christopher A Haiman Per Hall Ute Hamann Mikael Hartman Frans B Hogervorst Antoinette Hollestelle John L Hopper Hidemi Ito Anna Jakubowska Daehee Kang Veli-Matti Kosma Vessela Kristensen Kah-Nyin Lai Diether Lambrechts Loic Le Marchand Jingmei Li Annika Lindblom Artitaya Lophatananon Jan Lubinski Eva Machackova Arto Mannermaa Sara Margolin Frederik Marme Keitaro Matsuo Hui Miao Kyriaki Michailidou Roger L Milne Kenneth Muir Susan L Neuhausen Heli Nevanlinna Janet E Olson Curtis Olswold Jan J C Oosterwijk Ana Osorio Paolo Peterlongo Julian Peto Paul D P Pharoah Katri Pylkäs Paolo Radice Muhammad Usman Rashid Valerie Rhenius Anja Rudolph Suleeporn Sangrajrang Elinor J Sawyer Marjanka K Schmidt Minouk J Schoemaker Caroline Seynaeve Mitul Shah Chen-Yang Shen Martha Shrubsole Xiao-Ou Shu Susan Slager Melissa C Southey Daniel O Stram Anthony Swerdlow Soo H Teo Ian Tomlinson Diana Torres Thérèse Truong Christi J van Asperen Lizet E van der Kolk Qin Wang Robert Winqvist Anna H Wu Jyh-Cherng Yu Wei Zheng Ying Zheng Jennifer Leary Logan Walker Lenka Foretova Florentia Fostira Kathleen B M Claes Liliana Varesco Setareh Moghadasi Douglas F Easton Amanda Spurdle Peter Devilee Harry Vrieling Alvaro N A Monteiro David E Goldgar Aura Carreira Maaike P G Vreeswijk Fergus J Couch

Cancer Res 2017 06 10;77(11):2789-2799. Epub 2017 Mar 10.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Breast cancer risks conferred by many germline missense variants in the and genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. .

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Source
http://dx.doi.org/10.1158/0008-5472.CAN-16-2568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508554PMC
June 2017
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