Comprehensive cancer-predisposition gene testing in an adult multiple primary tumor series shows a broad range of deleterious variants and atypical tumor phenotypes

Abstract

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 (χ2 = 43.642; p ≤ 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.

Metadata

Item Type:	Article
Authors/Creators:	Whitworth, J Smith, PS Martin, J-E West, H Luchetti, A Rodger, F Clark, G Carss, K Stephens, J Stirrups, K Penkett, C Mapeta, R Ashford, S Megy, K Shakeel, H Ahmed, M Adlard, J Barwell, J Brewer, C Casey, RT Armstrong, R Cole, T Evans, DG Fostira, F Greenhalgh, L Hanson, H Henderson, A Hoffman, J Izatt, L Kumar, A Kwong, A Lalloo, F Ong, KR Paterson, J Park, S-M Chen-Shtoyerman, R Searle, C Side, L Skytte, A-B Snape, K Woodward, ER Tischkowitz, MD Maher, ER Aitman, T Alachkar, H Ali, S Allen, L Allsup, D Ambegaonkar, G Anderson, J Antrobus, R Armstrong, R Arno, G Arumugakani, G Ashford, S Astle, W Attwood, A Austin, S Bacchelli, C Bakchoul, T Bariana, TK Baxendale, H Bennett, D Bethune, C Bibi, S Bitner-Glindzicz, M Bleda, M Boggard, H Bolton-Maggs, P Booth, C Bradley, JR Brady, A Brown, M Browning, M Bryson, C Burns, S Calleja, P Canham, N Carmichael, J Carss, K Caulfield, M Chalmers, E Chandra, A Chinnery, P Chitre, M Church, C Clement, E Clements-Brod, N Clowes, V Coghlan, G Collins, P Cookson, V Cooper, N Corris, P Creaser-Myers, A DaCosta, R Daugherty, L Davies, S Davis, J De Vries, M Deegan, P Deevi, SVV Deshpande, C Devlin, L Dewhurst, E Dixon, P Doffinger, R Dormand, N Drewe, E Edgar, D Egner, W Erber, WN Erwood, M Erwood, M Everington, T Favier, R Firth, H Fletcher, D Flinter, F Frary, A Freson, K Furie, B Furnell, A Gale, D Gardham, A Gattens, M Ghali, N Ghataorhe, PK Ghurye, R Gibbs, S Gilmour, K Gissen, P Goddard, S Gomez, K Gordins, P Graf, S Gräf, S Greene, D Greenhalgh, A Greinacher, A Grigoriadou, S Grozeva, D Hackett, S Hadinnapola, C Hague, R Haimel, M Halmagyi, C Hammerton, T Hart, D Hayman, G Heemskerk, JWM Henderson, R Hensiek, A Henskens, Y Herwadkar, A Holden, S Holder, M Holder, S Hu, F Huis in’t Veld, A Huissoon, A Humbert, M Hurst, J James, R Jolles, S Josifova, D Kazmi, R Keeling, D Kelleher, P Kelly, AM Kennedy, F Kiely, D https://orcid.org/0000-0003-0184-6502 Kingston, N Koziell, A Krishnakumar, D Kuijpers, TW Kuijpers, T Kumararatne, D Kurian, M Laffan, MA Lambert, MP Allen, HL Lango-Allen, H Lawrie, A Lear, S Lees, M Lentaigne, C Liesner, R Linger, R Longhurst, H Lorenzo, L Louka, E Machado, R Ross, RM MacLaren, R Maher, E Maimaris, J Mangles, S Manson, A Mapeta, R Markus, HS Martin, J Masati, L Mathias, M Matser, V Maw, A McDermott, E McJannet, C Meacham, S Meehan, S Megy, K Mehta, S Michaelides, M Millar, CM Moledina, S Moore, A Morrell, N Mumford, A Murng, S Murphy, E Nejentsev, S Noorani, S Nurden, P Oksenhendler, E Othman, S Ouwehand, WH Ouwehand, WH Papadia, S Park, S-M Parker, A Pasi, J Patch, C Paterson, J Payne, J Peacock, A Peerlinck, K Penkett, CJ Pepke-Zaba, J Perry, D Perry, DJ Pollock, V Polwarth, G Ponsford, M Qasim, W Quinti, I Rankin, S Rankin, J Raymond, FL Rayner-Matthews, P Rehnstrom, K Reid, E Rhodes, CJ Richards, M Richardson, S Richter, A Roberts, I Rondina, M Rosser, E Roughley, C Roy, N Rue-Albrecht, K Samarghitean, C Sanchis-Juan, A Sandford, R Santra, S Sargur, R Savic, S Schotte, G Schulman, S Schulze, H Scott, R Scully, M Seneviratne, S Sewell, C Shamardina, O Shipley, D Simeoni, I Sivapalaratnam, S Smith, KGC Sohal, A Southgate, L Staines, S Staples, E Stark, H Stauss, H Stein, P Stephens, J Stirrups, K Stock, S Suntharalingam, J Talks, K Tan, Y Thachil, J Thaventhiran, J Thomas, E Thomas, M Thompson, D Thrasher, A Tischkowitz, M Titterton, C Toh, C-H Toshner, M Treacy, C Trembath, R Tuna, S Turek, W Turro, E Van Geet, C Veltman, M Vogt, J von Ziegenweldt, J Vonk Noordegraaf, A Wakeling, E Wanjiku, I Warner, TQ Wassmer, E Watkins, H Watt, C Webster, N Welch, S Westbury, S Wharton, J Whitehorn, D Wilkins, M Willcocks, L Williamson, C Woods, G Woods, G Wort, J Yeatman, N Yong, P Young, T Yu, P
Copyright, Publisher and Additional Information:	© 2018 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords:	cancer-predisposition syndromes; inherited cancer genetics; genetic testing; whole genome sequencing
Dates:	Accepted: 25 April 2018 Published (online): 14 June 2018 Published: 5 July 2018
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	18 Feb 2020 09:13
Last Modified:	19 Feb 2020 15:08
Status:	Published
Publisher:	Elsevier
Refereed:	Yes
Identification Number:	10.1016/j.ajhg.2018.04.013
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:157277

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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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