Analytical validation of a multi-cancer early detection test with cancer signal origin using a cell-free DNA-based targeted methylation assay

被引：8

作者：

Alexander, Gregory E. ^{[1
]}

Lin, Wendy ^{[1
,2
]}

Ortega, Fabian E. ^{[1
,3
]}

Ramaiah, Madhuvanthi ^{[1
,4
]}

Jung, Byoungsok ^{[1
]}

Ji, Lijuan ^{[1
]}

Revenkova, Ekaterina ^{[1
]}

Shah, Payal ^{[1
,5
]}

Croisetiere, Christian ^{[1
]}

Berman, Jennifer R. ^{[1
]}

Eubank, Lane ^{[1
]}

Naik, Gunjan ^{[1
,6
]}

Brooks, Jacqueline ^{[1
]}

Mich, Andrea ^{[1
]}

Shojaee, Seyedmehdi ^{[1
]}

Ronaghi, Neda ^{[1
]}

Chawla, Hemanshi ^{[1
]}

Hou, Xinyi ^{[1
]}

Liu, Qinwen ^{[1
]}

Yakym, Christopher-James A. V. ^{[1
]}

Moradi, Patriss Wais ^{[1
]}

Halks-Miller, Meredith ^{[1
,7
]}

Aravanis, Alexander M. ^{[1
,8
]}

Parpart-Li, Sonya ^{[1
]}

Hunkapiller, Nathan ^{[1
]}

机构：

[1] GRAIL LLC, Menlo Pk, CA 94025 USA

[2] Genentech Inc, South San Francisco, CA USA

[3] Olema Oncol, San Francisco, CA USA

[4] PrognomiQ Inc, San Mateo, CA USA

[5] Roche Diagnost, Santa Clara, CA USA

[6] Cepheid, Sunnyvale, CA USA

[7] Delfi Diagnost, Palo Alto, CA USA

[8] Illumina Inc, San Diego, CA USA

来源：

PLOS ONE | 2023年 / 18卷 / 04期

关键词：

CIRCULATING TUMOR DNA; LIQUID BIOPSY; PERSPECTIVE;

D O I：

10.1371/journal.pone.0283001

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The analytical validation is reported for a targeted methylation-based cell-free DNA multi-cancer early detection test designed to detect cancer and predict the cancer signal origin (tissue of origin). A machine-learning classifier was used to analyze the methylation patterns of >10(5) genomic targets covering >1 million methylation sites. Analytical sensitivity (limit of detection [95% probability]) was characterized with respect to tumor content by expected variant allele frequency and was determined to be 0.07%-0.17% across five tumor cases and 0.51% for the lymphoid neoplasm case. Test specificity was 99.3% (95% confidence interval, 98.6-99.7%). In the reproducibility and repeatability study, results were consistent in 31/34 (91.2%) pairs with cancer and 17/17 (100%) pairs without cancer; between runs, results were concordant for 129/133 (97.0%) cancer and 37/37 (100%) non-cancer sample pairs. Across 3- to 100-ng input levels of cell-free DNA, cancer was detected in 157/182 (86.3%) cancer samples but not in any of the 62 non-cancer samples. In input titration tests, cancer signal origin was correctly predicted in all tumor samples detected as cancer. No cross-contamination events were observed. No potential interferent (hemoglobin, bilirubin, triglycerides, genomic DNA) affected performance. The results of this analytical validation study support continued clinical development of a targeted methylation cell-free DNA multi-cancer early detection test.

引用

页数：23

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