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 frequently 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.