The :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Authors:
Gisella Figlioli Massimo Bogliolo Irene Catucci Laura Caleca Sandra Viz Lasheras Roser Pujol Johanna I Kiiski Taru A Muranen Daniel R Barnes Joe Dennis Kyriaki Michailidou Manjeet K Bolla Goska Leslie Cora M Aalfs Muriel A Adank Julian Adlard Simona Agata Karen Cadoo Bjarni A Agnarsson Thomas Ahearn Kristiina Aittomäki Christine B Ambrosone Lesley Andrews Hoda Anton-Culver Natalia N Antonenkova Volker Arndt Norbert Arnold Kristan J Aronson Banu K Arun Ella Asseryanis Bernd Auber Päivi Auvinen Jacopo Azzollini Judith Balmaña Rosa B Barkardottir Daniel Barrowdale Julian Barwell Laura E Beane Freeman Charles Joly Beauparlant Matthias W Beckmann Sabine Behrens Javier Benitez Raanan Berger Marina Bermisheva Amie M Blanco Carl Blomqvist Natalia V Bogdanova Anders Bojesen Stig E Bojesen Bernardo Bonanni Ake Borg Angela F Brady Hiltrud Brauch Hermann Brenner Thomas Brüning Barbara Burwinkel Saundra S Buys Trinidad Caldés Almuth Caliebe Maria A Caligo Daniele Campa Ian G Campbell Federico Canzian Jose E Castelao Jenny Chang-Claude Stephen J Chanock Kathleen B M Claes Christine L Clarke Anita Collavoli Thomas A Conner David G Cox Cezary Cybulski Kamila Czene Mary B Daly Miguel de la Hoya Peter Devilee Orland Diez Yuan Chun Ding Gillian S Dite Nina Ditsch Susan M Domchek Cecilia M Dorfling Isabel Dos-Santos-Silva Katarzyna Durda Miriam Dwek Diana M Eccles Arif B Ekici A Heather Eliassen Carolina Ellberg Mikael Eriksson D Gareth Evans Peter A Fasching Jonine Figueroa Henrik Flyger William D Foulkes Tara M Friebel Eitan Friedman Marike Gabrielson Pragna Gaddam Manuela Gago-Dominguez Chi Gao Susan M Gapstur Judy Garber Montserrat García-Closas José A García-Sáenz Mia M Gaudet Simon A Gayther Graham G Giles Gord Glendon Andrew K Godwin Mark S Goldberg David E Goldgar Pascal Guénel Angelica M Gutierrez-Barrera Lothar Haeberle Christopher A Haiman Niclas Håkansson Per Hall Ute Hamann Patricia A Harrington Alexander Hein Jane Heyworth Peter Hillemanns Antoinette Hollestelle John L Hopper H Dean Hosgood Anthony Howell Chunling Hu Peter J Hulick David J Hunter Evgeny N Imyanitov Claudine Isaacs Milena Jakimovska Anna Jakubowska Paul James Ramunas Janavicius Wolfgang Janni Esther M John Michael E Jones Audrey Jung Rudolf Kaaks Beth Y Karlan Elza Khusnutdinova Cari M Kitahara Irene Konstantopoulou Stella Koutros Peter Kraft Diether Lambrechts Conxi Lazaro Loic Le Marchand Jenny Lester Fabienne Lesueur Jenna Lilyquist Jennifer T Loud Karen H Lu Robert N Luben Jan Lubinski Arto Mannermaa Mehdi Manoochehri Siranoush Manoukian Sara Margolin John W M Martens Tabea Maurer Dimitrios Mavroudis Noura Mebirouk Alfons Meindl Usha Menon Austin Miller Marco Montagna Katherine L Nathanson Susan L Neuhausen William G Newman Tu Nguyen-Dumont Finn Cilius Nielsen Sarah Nielsen Liene Nikitina-Zake Kenneth Offit Edith Olah Olufunmilayo I Olopade Andrew F Olshan Janet E Olson Håkan Olsson Ana Osorio Laura Ottini Bernard Peissel Ana Peixoto Julian Peto Dijana Plaseska-Karanfilska Timea Pocza Nadege Presneau Miquel Angel Pujana Kevin Punie Brigitte Rack Johanna Rantala Muhammad U Rashid Rohini Rau-Murthy Gad Rennert Flavio Lejbkowicz Valerie Rhenius Atocha Romero Matti A Rookus Eric A Ross Maria Rossing Vilius Rudaitis Matthias Ruebner Emmanouil Saloustros Kristin Sanden Marta Santamariña Maren T Scheuner Rita K Schmutzler Michael Schneider Christopher Scott Leigha Senter Mitul Shah Priyanka Sharma Xiao-Ou Shu Jacques Simard Christian F Singer Christof Sohn Penny Soucy Melissa C Southey John J Spinelli Linda Steele Dominique Stoppa-Lyonnet William J Tapper Manuel R Teixeira Mary Beth Terry Mads Thomassen Jennifer Thompson Darcy L Thull Marc Tischkowitz Rob A E M Tollenaar Diana Torres Melissa A Troester Thérèse Truong Nadine Tung Michael Untch Celine M Vachon Elizabeth J van Rensburg Elke M van Veen Ana Vega Alessandra Viel Barbara Wappenschmidt Jeffrey N Weitzel Camilla Wendt Greet Wieme Alicja Wolk Xiaohong R Yang Wei Zheng Argyrios Ziogas Kristin K Zorn Alison M Dunning Michael Lush Qin Wang Lesley McGuffog Michael T Parsons Paul D P Pharoah Florentia Fostira Amanda E Toland Irene L Andrulis Susan J Ramus Anthony J Swerdlow Mark H Greene Wendy K Chung Roger L Milne Georgia Chenevix-Trench Thilo Dörk Marjanka K Schmidt Douglas F Easton Paolo Radice Eric Hahnen Antonis C Antoniou Fergus J Couch Heli Nevanlinna Jordi Surrallés Paolo Peterlongo

NPJ Breast Cancer 2019 1;5:38. Epub 2019 Nov 1.

IFOM - the FIRC Institute for Molecular Oncology, Genome Diagnostics Program, Milan, Italy.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes , , , , and are associated with breast cancer risk. , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of or . These three variants were also studied functionally by measuring survival and chromosome fragility in patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44,  = 0.034 and OR = 3.79;  = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for :p.Arg658* and found that also :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96;  = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat -associated tumors.

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Source
http://dx.doi.org/10.1038/s41523-019-0127-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825205PMC
November 2019
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