A 13-gene colorectal cancer liquid biopsy with greater than 90 percent accuracy in diagnosis and assessment of disease status.

Abstract

18 Background: There are a paucity of blood-based biomarkers with clinical utility for colorectal cancer (CRC) We report the use of a 13-gene colon cancer circulating-free mRNA to diagnose CRC and identify disease burden and status Clinical utility of the assay was assessed in surgical and chemotherapy patients. Methods: Gene identification and validation: Publicly available colon cancer transcriptomes (TTs) (E-MTAB-57); gene expression in 3 CRC cell-lines (LOVO, LS-180 and COLO320DM) and validated in CRC tumors ( n=33). Tumor TT analysis: co-expression network generation and differential expression analysis compared with normal blood-based TT to identify candidate markers. Blood gene expression: CRC set (cancers: n=312, controls n=117) and a CRC artificial intelligence model constructed. Normalized gene expression algorithmically scored (0-100). Matched tumor/ blood samples were available in 33 patients. RECIST criteria Clinical score assessment: Score utility was assessed in surgical and treated cohorts: Surgical: n=37, follow>7 days. Treated chemotherapy: n=75; stable disease (SD): n=20, progressive disease (PD): n=55) The relationship to CEA and CA-19-9 were assessed. Statistics: Non-parametric (Mann-Whitney), Pearson-correlation, Fisher’s and AUROC analyses (Mean±SEM). Results: Transcriptomic analysis identified a13 genes blood signature for CRC. Expression levels were significantly elevated ( p<0.001, 20-100-fold) in cell lines and CRC tumors. The matched tissue/blood correlation r: 0.795 ( p=0.002). In CRC, levels were 54.4±1.5 ( p<0.0001) compared to controls (9.5±1.7); AUROC: 0.91±0.02, accuracy 90.5% (sensitivity 93.1%, specificity 81.2%). Surgical cohort: CRC assay accuracy 100% vs CEA (35%) or CA-19-9 (17%) (both p<0.0001). Resection (R0 – 92%) significantly decreased levels (47±2) at follow-up ( p=0.0055). Treated cohort: Levels were elevated in PD (63±4.1) vs SD (30±3.2, p<0.0001). Conclusions: The diagnostic accuracy of CRC blood-signature was 91%; significantly greater than CEA or CA-19 Surgical resection decreased levels. CRC score was elevated in progressive vs stable disease. A colorectal cancer liquid biopsy has probable clinical utility in management.