Introduction Metastasis is a key hallmark of cancer and the principal cause of death of patients with colorectal cancer (CRC). The analysis of human CRC biospecimens is important to gain a greater understanding of the molecular drivers. Lymph node metastatic (LNM) tumour deposits are particularly interesting as the presence of lymphatic invasion is a histological feature of paramount importance, defining colorectal cancer stage and an important feature determining patient survival.
Method The novel technique of 3’ RNA sequencing was utilised to generate the GEP from 188 biospecimens from 69 patients with metastatic stage III CRC. Ribonucleic acid (RNA) was extracted from the primary tissue, lymph node metastatic tumour deposit (LNMTD) from each patient (n=69), and an area of normal Lymph node stroma adjacent (n=50), but separate to the LNM.
Results 69 patients were included in this analysis with a mean age of 69.2 years (sd 10.4) and 52.2% of patients were male. 218 genes were differentially expressed between the LNM and primary tumour at p<0.0001. The most significantly enriched gene in the LNMTD was CXCR4 (log2FC 1.69, p.adj=8.4×10-11). LNM demonstrated a more aggressive phenotype than the primary tumour with increase in KRAS and PI3K-AKT-MTOR signalling. Non-hierarchical clustering identified that LNM consists of two distinct subsets, LNMS1 and LNMS2. Patients with LNMS1 had very high mortality and high disease recurrence/death rates. Patients with LNMS2 in contrast had much better prognosis (Disease free survival, 1111 days vs 614 days, log rank p<0.001).
Conclusion A thorough understanding of the biological alterations involved in metastasis is important to improve and develop new therapies for patients with CRC. We have put together the largest cancer cohort of paired tumour-metastatic patients. LNM are more aggressive than the primary tumour and the KRAS signalling pathway is preferentially activated. The degree of activation of this pathway is in turn associated with higher risk of disease relapse/death and use and validation of these biomarkers, particularly LNMS classifications may help predict outcomes for stage III CRCs.
Disclosure of Interest None Declared
- COLORECTAL CANCER
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