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Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA

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posted on 2020-06-30, 10:09 authored by MC Liu, GR Oxnard, EA Klein, C Swanton, MV Seiden, CCGA Consortium, Steven R Cummings, Farnaz Absalan, Gregory Alexander, Brian Allen, Hamed Amini, Alexander M Aravanis, Siddhartha Bagaria, Leila Bazargan, John F Beausang, Jennifer Berman, Craig Betts, Alexander Blocker, Joerg Bredno, Robert Calef, Gordon Cann, Jeremy Carter, Christopher Chang, Hemanshi Chawla, Xiaoji Chen, Tom C Chien, Daniel Civello, Konstantin Davydov, Vasiliki Demas, Mohini Desai, Zhao Dong, Saniya Fayzullina, Alexander P Fields, Darya Filippova, Peter Freese, Eric T Fung, Sante Gnerre, Samuel Gross, Meredith Halks-Miller, Megan P Hall, Anne-Renee Hartman, Chenlu Hou, Earl Hubbell, Nathan Hunkapiller, Karthik Jagadeesh, Arash Jamshidi, Roger Jiang, Byoungsok Jung, TaeHyung Kim, Richard D Klausner, Kathryn N Kurtzman, Mark Lee, Wendy Lin, Jafi Lipson, Hai Liu, Qinwen Liu, Margarita Lopatin, Tara Maddala, M Cyrus Maher, Collin Melton, Andrea Mich, Shivani Nautiyal, Jonathan Newman, Joshua Newman, Virgil Nicula, Cosmos Nicolaou, Ongjen Nikolic, Wenying Pan, Shilpen Patel, Sarah A Prins, Richard Rava, Neda Ronaghi, Onur Sakarya, Ravi Vijaya Satya, Jan Schellenberger, Eric Scott, Amy J Sehnert, Rita Shaknovich, Avinash Shanmugam, KC Shashidhar, Ling Shen, Archana Shenoy, Seyedmehdi Shojaee, Pranav Singh, Kristan K Steffen, Susan Tang, Jonathan M Toung, Anton Valouev, Oliver Venn, Richard T Williams, Tony Wu, Hui H Xu, Christopher Yakym, Xiao Yang, Jessica Yecies, Alexander S Yip, Jack Youngren, Jeanne Yue, Jingyang Zhang, Lily Zhang, Lori Quan Zhang, Nan Zhang, Christina Curtis, Donald A Berry
© 2020 The Authors Background: Early cancer detection could identify tumors at a time when outcomes are superior and treatment is less morbid. This prospective case-control sub-study (from NCT02889978 and NCT03085888) assessed the performance of targeted methylation analysis of circulating cell-free DNA (cfDNA) to detect and localize multiple cancer types across all stages at high specificity. Participants and methods: The 6689 participants [2482 cancer (>50 cancer types), 4207 non-cancer] were divided into training and validation sets. Plasma cfDNA underwent bisulfite sequencing targeting a panel of >100 000 informative methylation regions. A classifier was developed and validated for cancer detection and tissue of origin (TOO) localization. Results: Performance was consistent in training and validation sets. In validation, specificity was 99.3% [95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR)]. Stage I–III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for ∼63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types. Detection increased with increasing stage: in the pre-specified cancer types sensitivity was 39% (CI: 27% to 52%) in stage I, 69% (CI: 56% to 80%) in stage II, 83% (CI: 75% to 90%) in stage III, and 92% (CI: 86% to 96%) in stage IV. In all cancer types sensitivity was 18% (CI: 13% to 25%) in stage I, 43% (CI: 35% to 51%) in stage II, 81% (CI: 73% to 87%) in stage III, and 93% (CI: 87% to 96%) in stage IV. TOO was predicted in 96% of samples with cancer-like signal; of those, the TOO localization was accurate in 93%. Conclusions: cfDNA sequencing leveraging informative methylation patterns detected more than 50 cancer types across stages. Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies.


Crick (Grant ID: 10169, Grant title: Swanton FC001169)