LIN28 promotes tumorigenesis in colorectal cancer but is not associated with metastatic spread

AbstractMetastatic spread is the most important life-threatening feature of colorectal cancer and is supposed to be mainly driven by alterations in different carcinogenic pathways. The present study compared mutation and expression profiles of distinctive biomarkers in colorectal cancer patients with different clinical metastatic patterns. As for a case-control study, patients were matched according to T category, grading and primary tumour site. Overall, 246 patients with either exclusive lung metastasis (N = 82), exclusive liver metastasis (N = 82) or non-metastatic colorectal cancer (N = 82) were identified. Paraffin-embedded specimens were examined for mutations in the RAS and RAF genes and for the expression of β-catenin and CD133. Clinical endpoints were presence or absence of distant metastasis, formation of metastasis in lungs versus the liver and survival. MAPK pathway mutations in either the KRAS, NRAS or BRAF gene were associated with the development of lung metastasis (63.4%) compared to the control group (47.6%; p = 0.04). MAPK pathway alterations plus high β-catenin expression were associated with metastasis to the lungs but not to the liver (28.0% vs. 13.4%; p = 0.02). High CD133 expression correlated with the development of liver metastasis compared to the control group (30.5% vs. 14.6%; p = 0.02). This data indicates that different patterns of distant spread are associated with specific biomarker alterations and may represent different molecular subtypes of colorectal cancer. However, underlying mechanisms of metastasis formation in different anatomic sites remains unclear. Since knowledge of the anticipated site of distant spread would substantially impact clinical management, further research is needed to identify solid biomarkers for different metastatic patterns.

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O48: MYOFERLIN: A NOVEL PREDICTIVE BIOMARKER AND THERAPEUTIC TARGET IN ADVANCED COLORECTAL CANCER

British Journal of Surgery ◽

10.1093/bjs/znab117.048 ◽

2021 ◽

Vol 108 (Supplement_1) ◽

Author(s):

H Fowler ◽

P Sutton ◽

D Bowden ◽

J Parsons ◽

D Vimalachandran

Keyword(s):

Colorectal Cancer ◽

Rectal Cancer ◽

Wound Healing ◽

Lymph Node ◽

Lymph Nodes ◽

Clinical Outcomes ◽

Therapeutic Target ◽

Predictive Value ◽

Predictive Biomarker ◽

Metastatic Spread

Abstract Introduction Myoferlin is a protein involved in cell proliferation, migration and angiogenesis, which are essential in tumour metastasis. Its expression correlates with a poorer prognosis in various epithelial cancers, but has yet to be associated with survival in colorectal cancer. We aim to investigate myoferlin's role in cell migration, and the development of metastases in our patients with rectal cancer. Method Tissue Microarrays (TMAs) of matched tumour and lymph node samples from 111 patients with rectal cancer were stained for myoferlin. Expression profiles were examined and correlated with clinical outcomes. Wound healing assays were used to assess the rate of migration in immortalised colorectal cells (HCT116, HT29) following myoferlin knockdown with siRNA. Result Our TMAs demonstrated that high myoferlin expression in rectal tumour samples was associated with metastatic spread to local lymph nodes (p<0.05). Positive lymph nodes had significantly higher levels of myoferlin than non-involved lymph nodes (p<0.001). The positive predictive value (PPV) of a highly expressing lymph node containing metastatic spread was 100%, negative predictive value (NPV) 88.41%, 95% CI [80.81, 93.24]. Wound healing assays demonstrated a decreased ability of cells to migrate following myoferlin knockdown with siRNA, compared to controls (p<0.05). Conclusion Our results demonstrate that high myoferlin expression is associated with metastatic spread to local lymph nodes, and increased migration and proliferation of cells. It is a predictor of poor clinical outcomes, and therefore warrants further investigation as a potential therapeutic target in both locally advanced and metastatic rectal cancer. Take-home message We have demonstrated that the protein myoferlin is associated with metastatic spread of rectal cancer to local lymph nodes. Therefore it is a potential predictive biomarker and therapeutic target in advanced rectal cancer.

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