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

Whitworth, James, Smith, Philip S., Martin, Jose-Ezequiel, West, Hannah, Luchetti, Andrea, Rodger, Faye, Clark, Graeme, Carss, Keren, Stephens, Jonathan, Stirrups, Kathleen, Penkett, Chris, Mapeta, Rutendo, Ashford, Sofie, Megy, Karyn, Shakeel, Hassan, Ahmed, Munaza, Adlard, Julian, Barwell, Julian, Brewer, Carole, Casey, Ruth T., Armstrong, Ruth, Cole, Trevor, Evans, Dafydd Gareth, Fostira, Florentia, Greenhalgh, Lynn, Hanson, Helen, Henderson, Alex, Hoffman, Jonathan, Izatt, Louise, Kumar, Ajith, Kwong, Ava, Lalloo, Fiona, Ong, Kai Ren, Paterson, Joan, Park, Soo-Mi, Chen-Shtoyerman, Rakefet, Searle, Claire, Side, Lucy, Skytte, Anne-Bine, Snape, Katie, Woodward, Emma R., Tischkowitz, Marc D., Maher, Eamonn R., Aitman, Timothy, Alachkar, Hana, Ali, Sonia, Allen, Louise, Allsup, David, Ambegaonkar, Gautum, Anderson, Julie, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Arumugakani, Gururaj, Ashford, Sofie, Astle, William, Attwood, Antony, Austin, Steve, Bacchelli, Chiara, Bakchoul, Tamam, Bariana, Tadbir K., Baxendale, Helen, Bennett, David, Bethune, Claire, Bibi, Shahnaz, Bitner-Glindzicz, Maria, Bleda, Marta, Boggard, Harm, Bolton-Maggs, Paula, Booth, Claire, Bradley, John R., Brady, Angie, Brown, Matthew, Browning, Michael, Bryson, Christine, Burns, Siobhan, Calleja, Paul, Canham, Natalie, Carmichael, Jenny, Carss, Keren, Caulfield, Mark, Chalmers, Elizabeth, Chandra, Anita, Chinnery, Patrick, Chitre, Manali, Church, Colin, Clement, Emma, Clements-Brod, Naomi, Clowes, Virginia, Coghlan, Gerry, Collins, Peter ORCID: https://orcid.org/0000-0002-6410-1324, Cookson, Victoria, Cooper, Nichola, Corris, Paul, Creaser-Myers, Amanda, DaCosta, Rosa, Daugherty, Louise, Davies, Sophie, Davis, John, De Vries, Minka, Deegan, Patrick, Deevi, Sri V.V., Deshpande, Charu, Devlin, Lisa, Dewhurst, Eleanor, Dixon, Peter, Doffinger, Rainer, Dormand, Natalie, Drewe, Elizabeth, Edgar, David, Egner, William, Erber, Wendy N., Erwood, Marie, Erwood, Marie, Everington, Tamara, Favier, Remi, Firth, Helen, Fletcher, Debra, Flinter, Frances, Frary, Amy, Freson, Kathleen, Furie, Bruce, Furnell, Abigail, Gale, Daniel, Gardham, Alice, Gattens, Michael, Ghali, Neeti, Ghataorhe, Pavandeep K., Ghurye, Rohit, Gibbs, Simon, Gilmour, Kimberley, Gissen, Paul, Goddard, Sarah, Gomez, Keith, Gordins, Pavel, Graf, Stefan, Gräf, Stefan, Greene, Daniel, Greenhalgh, Alan, Greinacher, Andreas, Grigoriadou, Sofia, Grozeva, Detelina ORCID: https://orcid.org/0000-0003-3239-8415, Hackett, Scott, Hadinnapola, Charaka, Hague, Rosie, Haimel, Matthias, Halmagyi, Csaba, Hammerton, Tracey, Hart, Daniel, Hayman, Grant, Heemskerk, Johan W.M., Henderson, Robert, Hensiek, Anke, Henskens, Yvonne, Herwadkar, Archana, Holden, Simon, Holder, Muriel, Holder, Susan, Hu, Fengyuan, Huis in?t Veld, Anna, Huissoon, Aarnoud, Humbert, Marc, Hurst, Jane, James, Roger, Jolles, Stephen, Josifova, Dragana, Kazmi, Rashid, Keeling, David, Kelleher, Peter, Kelly, Anne M., Kennedy, Fiona, Kiely, David, Kingston, Nathalie, Koziell, Ania, Krishnakumar, Deepa, Kuijpers, Taco W., Kuijpers, Taco, Kumararatne, Dinakantha, Kurian, Manju, Laffan, Michael A., Lambert, Michele P., Allen, Hana Lango, Lango-Allen, Hana, Lawrie, Allan, Lear, Sara, Lees, Melissa, Lentaigne, Claire, Liesner, Ri, Linger, Rachel, Longhurst, Hilary, Lorenzo, Lorena, Louka, Eleni, Machado, Rajiv, Ross, Rob Mackenzie, MacLaren, Robert, Maher, Eamonn, Maimaris, Jesmeen, Mangles, Sarah, Manson, Ania, Mapeta, Rutendo, Markus, Hugh S., Martin, Jennifer, Masati, Larahmie, Mathias, Mary, Matser, Vera, Maw, Anna, McDermott, Elizabeth, McJannet, Coleen, Meacham, Stuart, Meehan, Sharon, Megy, Karyn, Mehta, Sarju, Michaelides, Michel, Millar, Carolyn M., Moledina, Shahin, Moore, Anthony, Morrell, Nicholas, Mumford, Andrew, Murng, Sai, Murphy, Elaine, Nejentsev, Sergey, Noorani, Sadia, Nurden, Paquita, Oksenhendler, Eric, Othman, Shokri, Ouwehand, Willem H., Ouwehand, Willem H., Papadia, Sofia, Park, Soo-Mi, Parker, Alasdair, Pasi, John, Patch, Chris, Paterson, Joan, Payne, Jeanette, Peacock, Andrew, Peerlinck, Kathelijne, Penkett, Christopher J., Pepke-Zaba, Joanna, Perry, David, Perry, David J., Pollock, Val, Polwarth, Gary, Ponsford, Mark, Qasim, Waseem, Quinti, Isabella, Rankin, Stuart, Rankin, Julia, Raymond, F. Lucy, Rayner-Matthews, Paula, Rehnstrom, Karola, Reid, Evan, Rhodes, Christopher J., Richards, Michael, Richardson, Sylvia, Richter, Alex, Roberts, Irene, Rondina, Matthew, Rosser, Elisabeth, Roughley, Catherine, Roy, Noémi, Rue-Albrecht, Kevin, Samarghitean, Crina, Sanchis-Juan, Alba, Sandford, Richard, Santra, Saikat, Sargur, Ravishankar, Savic, Sinisa, Schotte, Gwen, Schulman, Sol, Schulze, Harald, Scott, Richard, Scully, Marie, Seneviratne, Suranjith, Sewell, Carrock, Shamardina, Olga, Shipley, Debbie, Simeoni, Ilenia, Sivapalaratnam, Suthesh, Smith, Kenneth G.C., Sohal, Aman, Southgate, Laura, Staines, Simon, Staples, Emily, Stark, Hannah, Stauss, Hans, Stein, Penelope, Stephens, Jonathan, Stirrups, Kathleen, Stock, Sophie, Suntharalingam, Jay, Talks, Kate, Tan, Yvonne, Thachil, Jecko, Thaventhiran, James, Thomas, Ellen, Thomas, Moira, Thompson, Dorothy, Thrasher, Adrian, Tischkowitz, Marc, Titterton, Catherine, Toh, Cheng-Hock, Toshner, Mark, Treacy, Carmen, Trembath, Richard, Tuna, Salih, Turek, Wojciech, Turro, Ernest, Van Geet, Chris, Veltman, Marijke, Vogt, Julie, von Ziegenweldt, Julie, Vonk Noordegraaf, Anton, Wakeling, Emma, Wanjiku, Ivy, Warner, Timothy Q., Wassmer, Evangeline, Watkins, Hugh, Watt, Christopher, Webster, ndrew, Welch, Steve, Westbury, Sarah, Wharton, John, Whitehorn, Deborah, Wilkins, Martin, Willcocks, Lisa, Williamson, Catherine, Woods, Geoffrey, Woods, Geoff, Wort, John, Yeatman, Nigel, Yong, Patrick, Young, Tim and Yu, Ping 2018. Comprehensive cancer-predisposition gene testing in an adult multiple primary tumor series shows a broad range of deleterious variants and atypical tumor phenotypes. American Journal of Human Genetics 103 (1) , pp. 3-18. 10.1016/j.ajhg.2018.04.013

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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

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Cell Press
ISSN:	0002-9297
Date of First Compliant Deposit:	30 November 2018
Date of Acceptance:	25 April 2018
Last Modified:	06 May 2023 02:16
URI:	https://orca.cardiff.ac.uk/id/eprint/117273

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