An exosome-based liquid biopsy signature for pre-operative identification of lymph node metastasis in patients with pathological high-risk T1 colorectal cancer

• Published in: Molecular cancer 2023-01, Vol.22 (1), p.2-2, Article 2
• Main Authors: Miyazaki, Katsuki, Wada, Yuma, Okuno, Keisuke, Murano, Tatsuro, Morine, Yuji, Ikemoto, Tetsuya, Saito, Yu, Ikematsu, Hiroaki, Kinugasa, Yusuke, Shimada, Mitsuo, Goel, Ajay
• Format: Article
• Language: English
• Subjects: Biomarkers, Tumor - genetics; Cancer patients; Care and treatment; Cell-free miRNA; Colorectal cancer; Colorectal Neoplasms - diagnosis; Colorectal Neoplasms - genetics; Colorectal Neoplasms - surgery; Correspondence; Exosomal miRNA; Exosomes - genetics; Exosomes - pathology; Genetic transcription; Health aspects; Humans; Liquid Biopsy; Lymph node metastasis; Lymphatic Metastasis; Metastasis; MicroRNA; MicroRNAs; Risk factors; T1 CRC
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-022-01685-8

According to current guidelines, more than 70% of patients with invasive submucosal colorectal cancer (T1 CRC) undergo a radical operation with lymph node dissection, even though only ~ 10% have lymph node metastasis (LNM). Hence, there is imperative to develop biomarkers that can help robustly identify LNM-positive patients to prevent such overtreatments. Given the emerging interest in exosomal cargo as a source for biomarker development in cancer, we examined the potential of exosomal miRNAs as LNM prediction biomarkers in T1 CRC. We analyzed 200 patients with high-risk T1 CRC from two independent cohorts, including a training (n = 58) and a validation cohort (n = 142). Cell-free and exosomal RNAs from pre-operative serum were extracted, followed by quantitative reverse-transcription polymerase chain reactions for a panel of miRNAs. A panel of four miRNAs (miR-181b, miR-193b, miR-195, and miR-411) exhibited robust ability for detecting LNM in the exosomal vs. cell-free component. We subsequently established a cell-free and exosomal combination signature, successfully validated in two independent clinical cohorts (AUC, 0.84; 95% CI 0.70-0.98). Finally, we developed a risk-stratification model by including key pathological features, which reduced the false positive rates for LNM by 76% without missing any true LNM-positive patients. Our novel exosomal miRNA-based liquid biopsy signature robustly identifies T1 CRC patients at risk of LNM in a preoperative setting. This could be clinically transformative in reducing the significant overtreatment burden of this malignancy.