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. 2023 Jan 6;22(1):2.
doi: 10.1186/s12943-022-01685-8.

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

Katsuki Miyazaki  1   2 , Yuma Wada  1   2 , Keisuke Okuno  1   3 , Tatsuro Murano  4 , Yuji Morine  2 , Tetsuya Ikemoto  2 , Yu Saito  2 , Hiroaki Ikematsu  4 , Yusuke Kinugasa  3 , Mitsuo Shimada  2 , Ajay Goel  5   6
Affiliations

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

Katsuki Miyazaki et al. Mol Cancer. .

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Cell-free miRNA; Exosomal miRNA; Liquid biopsy; Lymph node metastasis; T1 CRC.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Training of exosomal miRNAs and cell-free miRNAs in predicting lymph node metastasis from high-risk T1 CRC patients. A A receiver operating characteristic (ROC) curve analysis to evaluate the performance of cell-free miRNAs panel. B ROC curve analysis to evaluate the performance of the exosomal miRNAs panel. C Correlation of 4 miRNAs’ expression between exosomal component and total serum. D ROC curve analysis to evaluate the performance of exosomal and cell-free miRNAs combination panel. E Waterfall plot for modified risk score distribution in a training cohort. Cf-: cell-free, exo: exosomal, LNN: lymph node metastasis negative, LNP: lymph node metastasis positive, AUC: area under the curve
Fig. 2
Fig. 2
Performance evaluation of novel combination panel and risk-stratification model in predicting lymph node metastasis from high-risk T1 CRC patients. A A receiver operating characteristic curve analysis to compare the performance of the combination panel, key pathological features, and risk-stratification model in a validation cohort. B Decision curve plotting net benefit (detection of lymph node metastasis) against threshold probability. C Decision curve plotting net benefit untreated (avoidance of unnecessary operation) against threshold probability. D Comparison of overtreatment frequency between current guidelines and our risk-stratification model. NPV: negative predictive value, PPV: positive predictive value, LNN: lymph node metastasis negative, LNP: lymph node metastasis positive, AUC: area under the curve
See this image and copyright information in PMC

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