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Evaluation of cell-free DNA approaches for multi-cancer early detection.

In Cancer cell ; h5-index 124.0

In the Circulating Cell-free Genome Atlas (NCT02889978) substudy 1, we evaluate several approaches for a circulating cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test by defining clinical limit of detection (LOD) based on circulating tumor allele fraction (cTAF), enabling performance comparisons. Among 10 machine-learning classifiers trained on the same samples and independently validated, when evaluated at 98% specificity, those using whole-genome (WG) methylation, single nucleotide variants with paired white blood cell background removal, and combined scores from classifiers evaluated in this study show the highest cancer signal detection sensitivities. Compared with clinical stage and tumor type, cTAF is a more significant predictor of classifier performance and may more closely reflect tumor biology. Clinical LODs mirror relative sensitivities for all approaches. The WG methylation feature best predicts cancer signal origin. WG methylation is the most promising technology for MCED and informs development of a targeted methylation MCED test.

Jamshidi Arash, Liu Minetta C, Klein Eric A, Venn Oliver, Hubbell Earl, Beausang John F, Gross Samuel, Melton Collin, Fields Alexander P, Liu Qinwen, Zhang Nan, Fung Eric T, Kurtzman Kathryn N, Amini Hamed, Betts Craig, Civello Daniel, Freese Peter, Calef Robert, Davydov Konstantin, Fayzullina Saniya, Hou Chenlu, Jiang Roger, Jung Byoungsok, Tang Susan, Demas Vasiliki, Newman Joshua, Sakarya Onur, Scott Eric, Shenoy Archana, Shojaee Seyedmehdi, Steffen Kristan K, Nicula Virgil, Chien Tom C, Bagaria Siddhartha, Hunkapiller Nathan, Desai Mohini, Dong Zhao, Richards Donald A, Yeatman Timothy J, Cohn Allen L, Thiel David D, Berry Donald A, Tummala Mohan K, McIntyre Kristi, Sekeres Mikkael A, Bryce Alan, Aravanis Alexander M, Seiden Michael V, Swanton Charles

2022-Nov-15

CCGA, MCED, cancer screening, cfDNA, multi-cancer early detection, single nucleotide variants, somatic copy number alterations, whole-genome bisulfite sequencing, whole-genome methylation