Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes

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From: American Journal of Human Genetics(Vol. 103, Issue 1)
Publisher: Elsevier B.V.
Document Type: Report
Length: 1,366 words

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Keywords cancer-predisposition syndromes; inherited cancer genetics; genetic testing; whole-genome sequencing Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population ([chi].sup.2 = 43.642; p [less than or equal to] 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals. Author Affiliation: (1) University of Cambridge Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK (2) NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK (3) Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK (4) Department of Clinical Genetics, Princess Anne Hospital, Southampton SO16 5YA, UK (5) North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London WC1N 3JH, UK (6) Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds LS7 4SA, UK (7) Department of Clinical Genetics, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester LE1 5WW, UK (8) Peninsula Clinical Genetics, Royal Devon & Exeter Hospital, Exeter EX1 2ED, UK (9) East Anglian Medical Genetics Service, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK (10) West Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham B15 2TG, UK (11) Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, University of Manchester, Manchester Academic Health Science Centre, St. Mary's Hospital, Manchester M13 9WL, UK (12) Molecular Diagnostics Laboratory, National Centre of Scientific Research "Demokritos," Athens, Greece (13) Department of Clinical Genetics, Liverpool Women's Hospital, Liverpool L8 7SS, UK (14) Department of Clinical Genetics, St. George's Hospital, London SW17 0QT, UK (15) Northern Genetics Service, Newcastle upon Tyne Hospitals, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK (16) Department of Clinical Genetics, Guy's and St. Thomas' Hospital, London SE1 9RT, UK (17) Division of Breast Surgery, University of Hong Kong, Pokfulam, Hong Kong (18) Hong Kong Hereditary Breast Cancer Family Registry, Shau Kei Wan, Hong Kong (19) Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong (20) Clinical Genetics Institute, Kaplan Medical Center, Rehovot 76100, Israel (21) Hebrew University and Hadassah Medical Center, Jerusalem, Israel (22) Department of Clinical Genetics, Nottingham University Hospitals, City Hospital, Nottingham NG5 1PB, UK (23) Department of Clinical Genetics, Aarhus University Hospital, Aarhus 8200, Denmark * Corresponding author Article History: Received 6 December 2017; Accepted 25 April 2018 (miscellaneous) Published: June 14, 2018 Byline: James Whitworth (1), Philip S. Smith (1), Jose-Ezequiel Martin (1), Hannah West (1), Andrea Luchetti (1), Faye Rodger (1), Graeme Clark (1), Keren Carss (2,3), Jonathan Stephens (2,3), Kathleen Stirrups (2,3), Chris Penkett (2,3), Rutendo Mapeta (2,3), Sofie Ashford (2), Karyn Megy (2,3), Hassan Shakeel (1), Munaza Ahmed (4,5), Julian Adlard (6), Julian Barwell (7), Carole Brewer (8), Ruth T. Casey (1), Ruth Armstrong (1,2,9), Trevor Cole (10), Dafydd Gareth Evans (11), Florentia Fostira (12), Lynn Greenhalgh (13), Helen Hanson (14), Alex Henderson (15), Jonathan Hoffman (10), Louise Izatt (16), Ajith Kumar (5), Ava Kwong (17,18,19), Fiona Lalloo (11), Kai Ren Ong (10), Joan Paterson (9), Soo-Mi Park (1,2,9), Rakefet Chen-Shtoyerman (20,21), Claire Searle (22), Lucy Side (4,5), Anne-Bine Skytte (23), Katie Snape (14), Emma R. Woodward (11), Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Ruth Armstrong, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Maria Bitner-Glindzicz, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Jenny Carmichael, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Victoria Cookson, Nichola Cooper, Paul Corris, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Eleanor Dewhurst, Peter Dixon, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Graf, Stefan Graf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Detelina Grozeva, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Anna Huis in't Veld, Aarnoud Huissoon, Marc Humbert, Jane Hurst, Roger James, Stephen Jolles, Dragana Josifova, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Taco Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Hana Lango-Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Eleni Louka, Rajiv Machado, Rob Mackenzie Ross, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Sarju Mehta, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Shokri Othman, Willem H. Ouwehand, Willem H. Ouwehand, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Joan Paterson, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David Perry, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, F. Lucy Raymond, Paula Rayner-Matthews, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Elisabeth Rosser, Catherine Roughley, Noemi Roy, Kevin Rue-Albrecht, Crina Samarghitean, Alba Sanchis-Juan, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Gwen Schotte, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth G.C. Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hannah Stark, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Emma Wakeling, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Christopher Watt, ndrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, Geoff Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu

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Gale Document Number: GALE|A545538931