Methylated Septin9 (mSEPT9): A Promising Blood-Based Biomarker for the Detection and Screening of Early-Onset Colorectal Cancer

Early-onset colorectal cancer (EOCRC), defined as a diagnosis under age 50, is an emerging public health burden. As many of these individuals fall outside of screening guidelines, the development of a minimally invasive, accurate screening modality for this population is warranted. We evaluated the FDA-approved blood-based biomarker methylated Septin9 (mSEPT9) test as screening tool for EOCRC. EOCRC plasma, healthy plasma, and serum-free conditioned media from cancer cell lines were collected. Cell-free DNA (cfDNA) was isolated and bisulfite converted for use in the assay. mSEPT9 and ACTB measured using Epi proColon V2.0. EOCRC plasma was collected at Massachusetts General Hospital (2005-2019) and controls were collected at the NIH and by ZenBio Inc. (prior to 2019). Twenty-seven EOCRC cases, 48 healthy controls <50 years old, and 39 healthy controls >50 years old were included in this study. mSEPT9 was detected more fre-quently in EOCRC cases (88.9%) compared with healthy controls age <50 (4.2%) and >50 (15.4%), respectively (P < 0.001). The sensitivity, specificity, positive predictive value, and negative predictive values of the mSEPT9 assay to detect EOCRC was 90.8% (95% CI, 84.7%-96.9%), 88.9% (95% CI, 77.0%-100.0%), 96.3% (95% CI, 92.3%-100.0%), and 75.0% (95% CI, 60.0%-90.0%), respectively, compared with all healthy controls. mSEPT9 cfDNA level was an independent predictor of survival (P = 0.02). mSEPT9 is a sensitive and specific biomarker for EOCRC detection. These results suggest that mSEPT9 may be useful in the detection of EOCRC, providing a minimally invasive method for screening in this growing population of patients with colorectal cancer.Significance: mSEPT9 may be a novel biomarker for the detection of early-onset colorectal cancer, as it demonstrated high sensitivity and specificity in our study.