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Allele-informed copy number evaluation of plasma DNA samples from metastatic prostate cancer patients: the PCF_SELECT consortium assay

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posted on 22.06.2022, 09:39 authored by Francesco Orlando, Alessandro Romanel, Blanca Trujillo, Michael Sigouros, Daniel Wetterskog, Orsetta Quaini, Gianmarco Leone, Jenny Z Xiang, Anna Wingate, Scott Tagawa, Anuradha Jayaram, Mark Linch, Charles Swanton, Mariam Jamal-Hanjani, Chris Abbosh, Simone Zaccaria, Sonya Hessey, Kai-Keen Shiu, John Bridgewater, Daniel Hochhauser, Martin Forster, Siow-Ming Lee, Tanya Ahmad, Dionysis Papadatos-Pastos, Sam Janes, Peter Van Loo, Katey Enfield, Nicholas McGranahan, Ariana Huebner, Sergio Quezada, Stephan Beck, Peter Parker, Tariq Enver, Robert E Hynds, Krijn Dijkstra, David R Pearce, Mary Falzon, Ian Proctor, Ron Sinclair, Chi-wah Lok, Zoe Rhodes, David Moore, Teresa Marafioti, Miriam Mitchison, Peter Ellery, Monica Sivakumar, Sebastian Brandner, Andrew Rowan, Crispin Hiley, Selvaraju Veeriah, Heather Shaw, Gert Attard, Cristina Naceur-Lombardelli, Antonia Toncheva, Paulina Prymas, Tom Watkins, Chris Bailey, Carlos Martinez Ruiz, Kevin Litchfield, Maise Al-Bakir, Nnenna Kanu, Sophie Ward, Emilia Lim, James Reading, Benny Chain, Blanca Trujillo Alba, Melek Akay, Adrienne Flanagan, Dhruva Biswas, Oriol Pich, Michelle Dietzen, Clare Puttick, Emma Colliver, Alistair Magness, Mihaela Angelova, James Black, Olivia Lucas, William Hill, Wing-Kin Liu, Alexander Frankell, Neil Magno, Foteini Athanasopoulou, Gareth Wilson, Rachel Rosenthal, Roberto Salgado, Claudia Lee, Kristiana Grigoriadis, Othman Al-Sawaf, Takahiro Karasaki, Abigail Bunkum, Imran Noorani, Sarah Benafif, Vittorio Barbe, Supreet Bola, Osvaldas Vainauskas, Mahedi Hasan, Stefano Lise, GianMarco Leone, Constantine Alifrangis, Ursula McGovern, Kerstin Thol, Samuel Gamble, Seng Kuong Ung, Teerapon Sahwangarrom, Claudia Peinador Marin, Sophia Wong, Piotr Pawlik, Faye Gishen, Adrian Tookman, Paddy Stone, Caroline Stirling, Samra Turajlic, James Larkin, Lisa Pickering, Andrew Furness, Kate Young, Will Drake, Kim Edmonds, Nikki Hunter, Mary Mangwende, Karla Pearce, Lauren Grostate, Lewis Au, Lavinia Spain, Scott Shepherd, Haixi Yan, Ben Shum, Zayd Tippu, Brian Hanley, Charlotte Spencer, Max Emmerich, Camille Gerard, Andreas Michael Schmitt, Lyra Del Rosario, Eleanor Carlyle, Charlotte Lewis, Lucy Holt, Analyn Lucanas, Molly O'Flaherty, Steve Hazell, Hardeep Mudhar, Christina Messiou, Arash Latifoltojar, Annika Fendler, Fiona Byrne, Husayn Pallinkonda, Irene Lobon, Alex Coulton, Anne Laure Cattin, Daqi Deng, Geoffrey Hugang Feng, Andew Rowan, Nadia Yousaf, Sanjay Popat, Olivia Curtis, Charlotte Milner-Watts, Gordon Stamp, Emma Nye, Aida Murra, Justine Korteweg, Denise Kelly, Lauren Terry, Jennifer Biano, Kema Peat, Kayleigh Kelly, Peter Hill, Debra Josephs, Sheeba Irshad, Ashish Chandra, James Spicer, Ula Mahadeva, Anna Green, Ruby Stewart, Lara-Rose Iredale, Tina Mackay, Ben Deakin, Debra Enting, Sarah Rudman, Sharmistha Ghosh, Lena Karapagniotou, Elias Pintus, Andrew Tutt, Sarah Howlett, Vasiliki Michalarea, James Brenton, Carlos Caldas, Rebecca Fitzgerald, Merche Jimenez-Linan, Elena Provenzano, Alison Cluroe, Anna Paterson, Sarah Aitken, Kieren Allinson, Grant Stewart, Ultan McDermott, Emma Beddowes, Tim Maughan, Olaf Ansorge, Peter Campbell, Patricia Roxburgh, Sioban Fraser, Andrew Kidd, Kevin Blyth, John Le Quesne, Matthew Krebs, Fiona Blackhall, Yvonne Summers, Pedro Oliveira, Ana Ortega-Franco, Caroline Dive, Fabio Gomes, Mat Carter, Jo Dransfield, Anne Thomas, Dean Fennell, Jacqui Shaw, Babu Naidu, Shobhit Baijal, Bruce Tanchel, Gerald Langman, Andrew Robinson, Martin Collard, Peter Cockcroft, Charlotte Ferris, Hollie Bancroft, Amy Kerr, Gary Middleton, Joanne Webb, Salma Kadiri, Peter Colloby, Bernard Olisemeke, Rodelaine Wilson, Ian Tomlinson, Iain McNeish, Sanjay Jogai, Samantha Holden, Tania Fernandes, Blanche Hampton, Mairead McKenzie, Allan Hackshaw, Abby Sharp, Kitty Chan, Laura Farrelly, Hayley Bridger, Rachel Leslie, PEACE Consortium, Mark A Rubin, Alexander W Wyatt, Himisha Beltran, Gerhardt Attard, Francesca Demichelis
Sequencing of cell-free DNA (cfDNA) in cancer patients’ plasma offers a minimally-invasive solution to detect tumor cell genomic alterations to aid real-time clinical decision-making. The reliability of copy number detection decreases at lower cfDNA tumor fractions, limiting utility at earlier stages of the disease. To test a novel strategy for detection of allelic imbalance, we developed a prostate cancer bespoke assay, PCF_SELECT, that includes an innovative sequencing panel covering ∼25 000 high minor allele frequency SNPs and tailored analytical solutions to enable allele-informed evaluation. First, we assessed it on plasma samples from 50 advanced prostate cancer patients. We then confirmed improved detection of genomic alterations in samples with <10% tumor fractions when compared against an independent assay. Finally, we applied PCF_SELECT to serial plasma samples intensively collected from three patients previously characterized as harboring alterations involving DNA repair genes and consequently offered PARP inhibition. We identified more extensive pan-genome allelic imbalance than previously recognized in prostate cancer. We confirmed high sensitivity detection of BRCA2 allelic imbalance with decreasing tumor fractions resultant from treatment and identified complex ATM genomic states that may be incongruent with protein losses. Overall, we present a framework for sensitive detection of allele-specific copy number changes in cfDNA.

Funding

Crick (Grant ID: CC2041, Grant title: Swanton CC2041)

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