J E Higgs1, E F Harkness2, N L Bowers1, E Howard1, A J Wallace1, F Lalloo1, W G Newman1, D G Evans3. 1. Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, University of Manchester and Central Manchester Foundation Trust, Manchester, UK. 2. Centre for Imaging Sciences, Institute for Population Health, University of Manchester, Manchester, UK. 3. Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, University of Manchester and Central Manchester Foundation Trust, Manchester, UK Genesis Breast Cancer Prevention Centre and Nightingale Breast Screening Centre, University Hospital of South Manchester, Manchester, UK.
Abstract
BACKGROUND: Despite classification of the BRCA2c.9976A>T, p.(Lys3326Ter) variant as a polymorphism, it has been associated with increased risks of pancreatic, lung, oesophageal and breast cancer. METHODS: We have noticed multiple co-occurrences of the BRCA2 c.9976A>T variant with the pathogenic BRCA2c.6275_6276delTT frameshift mutation p.(Leu2092ProfsTer7) and using a cohort study have assessed if this might account for these tumour risk associations. RESULTS: We identified 52 families with BRCA2c.6275_6276delTT, all of which occur in cis with the BRCA2c.9976A>T variant allele as demonstrated by co-segregation in all family members tested. Of 3245 breast/ovarian cancer samples sequenced for BRCA2, only 43/3245 (1.3%) carried BRCA2 c.9976A>T alone, after excluding individuals with BRCA2c.6275_6276delTT (n=22) or other BRCA1 (n=3) or BRCA2 (n=2) pathogenic mutations. The resultant frequency (1.3%) after removal of co-occurring mutations is lower than the 1.7% and 1.67% frequencies from two control populations for BRCA2 c.9976A>T, but similar to the 1.39% seen in the Exome Aggregation Consortium database. We did not identify increased frequencies of oesophageal, pancreatic or lung cancer in families with just BRCA2 c.9976A>T using person-years at risk analysis. CONCLUSIONS: It is likely that the previous associations of increased cancer risks due to BRCA2c.9976A>T represent reporting bias and are contributed to because the variant is in LD with BRCA2c.6275_6276delTT. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
BACKGROUND: Despite classification of the BRCA2c.9976A>T, p.(Lys3326Ter) variant as a polymorphism, it has been associated with increased risks of pancreatic, lung, oesophageal and breast cancer. METHODS: We have noticed multiple co-occurrences of the BRCA2 c.9976A>T variant with the pathogenic BRCA2c.6275_6276delTT frameshift mutation p.(Leu2092ProfsTer7) and using a cohort study have assessed if this might account for these tumour risk associations. RESULTS: We identified 52 families with BRCA2c.6275_6276delTT, all of which occur in cis with the BRCA2c.9976A>T variant allele as demonstrated by co-segregation in all family members tested. Of 3245 breast/ovarian cancer samples sequenced for BRCA2, only 43/3245 (1.3%) carried BRCA2 c.9976A>T alone, after excluding individuals with BRCA2c.6275_6276delTT (n=22) or other BRCA1 (n=3) or BRCA2 (n=2) pathogenic mutations. The resultant frequency (1.3%) after removal of co-occurring mutations is lower than the 1.7% and 1.67% frequencies from two control populations for BRCA2 c.9976A>T, but similar to the 1.39% seen in the Exome Aggregation Consortium database. We did not identify increased frequencies of oesophageal, pancreatic or lung cancer in families with just BRCA2 c.9976A>T using person-years at risk analysis. CONCLUSIONS: It is likely that the previous associations of increased cancer risks due to BRCA2c.9976A>T represent reporting bias and are contributed to because the variant is in LD with BRCA2c.6275_6276delTT. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Kathryn B Garber; Lisa M Vincent; John J Alexander; Lora J H Bean; Sherri Bale; Madhuri Hegde Journal: Am J Hum Genet Date: 2016-10-27 Impact factor: 11.025
Authors: Huong D Meeks; Honglin Song; Kyriaki Michailidou; Manjeet K Bolla; Joe Dennis; Qin Wang; Daniel Barrowdale; Debra Frost; Lesley McGuffog; Steve Ellis; Bingjian Feng; Saundra S Buys; John L Hopper; Melissa C Southey; Andrea Tesoriero; Paul A James; Fiona Bruinsma; Ian G Campbell; Annegien Broeks; Marjanka K Schmidt; Frans B L Hogervorst; Matthias W Beckman; Peter A Fasching; Olivia Fletcher; Nichola Johnson; Elinor J Sawyer; Elio Riboli; Susana Banerjee; Usha Menon; Ian Tomlinson; Barbara Burwinkel; Ute Hamann; Frederik Marme; Anja Rudolph; Ramunas Janavicius; Laima Tihomirova; Nadine Tung; Judy Garber; Daniel Cramer; Kathryn L Terry; Elizabeth M Poole; Shelley S Tworoger; Cecilia M Dorfling; Elizabeth J van Rensburg; Andrew K Godwin; Pascal Guénel; Thérèse Truong; Dominique Stoppa-Lyonnet; Francesca Damiola; Sylvie Mazoyer; Olga M Sinilnikova; Claudine Isaacs; Christine Maugard; Stig E Bojesen; Henrik Flyger; Anne-Marie Gerdes; Thomas V O Hansen; Allen Jensen; Susanne K Kjaer; Claus Hogdall; Estrid Hogdall; Inge Sokilde Pedersen; Mads Thomassen; Javier Benitez; Anna González-Neira; Ana Osorio; Miguel de la Hoya; Pedro Perez Segura; Orland Diez; Conxi Lazaro; Joan Brunet; Hoda Anton-Culver; Lee Eunjung; Esther M John; Susan L Neuhausen; Yuan Chun Ding; Danielle Castillo; Jeffrey N Weitzel; Patricia A Ganz; Robert L Nussbaum; Salina B Chan; Beth Y Karlan; Jenny Lester; Anna Wu; Simon Gayther; Susan J Ramus; Weiva Sieh; Alice S Whittermore; Alvaro N A Monteiro; Catherine M Phelan; Mary Beth Terry; Marion Piedmonte; Kenneth Offit; Mark Robson; Douglas Levine; Kirsten B Moysich; Rikki Cannioto; Sara H Olson; Mary B Daly; Katherine L Nathanson; Susan M Domchek; Karen H Lu; Dong Liang; Michelle A T Hildebrant; Roberta Ness; Francesmary Modugno; Leigh Pearce; Marc T Goodman; Pamela J Thompson; Hermann Brenner; Katja Butterbach; Alfons Meindl; Eric Hahnen; Barbara Wappenschmidt; Hiltrud Brauch; Thomas Brüning; Carl Blomqvist; Sofia Khan; Heli Nevanlinna; Liisa M Pelttari; Kristiina Aittomäki; Ralf Butzow; Natalia V Bogdanova; Thilo Dörk; Annika Lindblom; Sara Margolin; Johanna Rantala; Veli-Matti Kosma; Arto Mannermaa; Diether Lambrechts; Patrick Neven; Kathleen B M Claes; Tom Van Maerken; Jenny Chang-Claude; Dieter Flesch-Janys; Florian Heitz; Raymonda Varon-Mateeva; Paolo Peterlongo; Paolo Radice; Alessandra Viel; Monica Barile; Bernard Peissel; Siranoush Manoukian; Marco Montagna; Cristina Oliani; Ana Peixoto; Manuel R Teixeira; Anita Collavoli; Emily Hallberg; Janet E Olson; Ellen L Goode; Steven N Hart; Hermela Shimelis; Julie M Cunningham; Graham G Giles; Roger L Milne; Sue Healey; Kathy Tucker; Christopher A Haiman; Brian E Henderson; Mark S Goldberg; Marc Tischkowitz; Jacques Simard; Penny Soucy; Diana M Eccles; Nhu Le; Anne-Lise Borresen-Dale; Vessela Kristensen; Helga B Salvesen; Line Bjorge; Elisa V Bandera; Harvey Risch; Wei Zheng; Alicia Beeghly-Fadiel; Hui Cai; Katri Pylkäs; Robert A E M Tollenaar; Ans M W van der Ouweland; Irene L Andrulis; Julia A Knight; Steven Narod; Peter Devilee; Robert Winqvist; Jonine Figueroa; Mark H Greene; Phuong L Mai; Jennifer T Loud; Montserrat García-Closas; Minouk J Schoemaker; Kamila Czene; Hatef Darabi; Iain McNeish; Nadeem Siddiquil; Rosalind Glasspool; Ava Kwong; Sue K Park; Soo Hwang Teo; Sook-Yee Yoon; Keitaro Matsuo; Satoyo Hosono; Yin Ling Woo; Yu-Tang Gao; Lenka Foretova; Christian F Singer; Christine Rappaport-Feurhauser; Eitan Friedman; Yael Laitman; Gad Rennert; Evgeny N Imyanitov; Peter J Hulick; Olufunmilayo I Olopade; Leigha Senter; Edith Olah; Jennifer A Doherty; Joellen Schildkraut; Linetta B Koppert; Lambertus A Kiemeney; Leon F A G Massuger; Linda S Cook; Tanja Pejovic; Jingmei Li; Ake Borg; Anna Öfverholm; Mary Anne Rossing; Nicolas Wentzensen; Karin Henriksson; Angela Cox; Simon S Cross; Barbara J Pasini; Mitul Shah; Maria Kabisch; Diana Torres; Anna Jakubowska; Jan Lubinski; Jacek Gronwald; Bjarni A Agnarsson; Jolanta Kupryjanczyk; Joanna Moes-Sosnowska; Florentia Fostira; Irene Konstantopoulou; Susan Slager; Michael Jones; Antonis C Antoniou; Andrew Berchuck; Anthony Swerdlow; Georgia Chenevix-Trench; Alison M Dunning; Paul D P Pharoah; Per Hall; Douglas F Easton; Fergus J Couch; Amanda B Spurdle; David E Goldgar Journal: J Natl Cancer Inst Date: 2015-11-19 Impact factor: 13.506
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