Introduction Patients with colorectal cancers that have pathological extramural vascular invasion (EMVI+) are known to have a poorer prognosis than those with EMVI – tumours. EMVI status influences the need for neoadjuvant radiotherapy and adjuvant chemotherapy. There is a growing body of evidence to suggest that DNA hypermethylation in specific gene promoter regions (CpG islands) is an important pathway in colorectal cancer tumourigenesis. Previous work by our group has suggested a link between these two processes. The purpose of this work is therefore to explore the relationship between CpG island methylator phenotype (CIMP) grade and EMVI in rectal cancer.
Method In this study tissue blocks were obtained from 30 consecutive patients with known EMVI+ve tumours and 43 patients with EMVI-ve tumours who did not receive neoadjuvant chemoradiotherapy. Following targeted DNA extraction, CIMP status was determined by methylation specific PCR (MSP) using a two panel approach. MSP is accomplished by performing bisulfite conversion of genomic DNA (Imprint DNA Modification Kit, Sigma Aldrich, USA). This is followed by a PCR reaction with primers for the methylated and unmethylated promoter regions of 8 DNA mismatch repair genes (hMLH, SOCS1, MINT1, ADAMSTS, HAND1, THBD, NEUROG and IGFBP3). The sample is then identified as CIMP-High, Intermediate or Low.
Results DNA samples from 73 patients were analysed (30 EMVI+ve and 43 EMVI-ve) comprising 55 males and 18 females with median age 70 (range 45–84 years). As expected, the postoperative histopathological tumour (T) and nodal (N) status was more advanced in the EMVI+ tumours (p = 0.007 and <0.001 respectively). A greater proportion of EMVI+ tumours had the CIMP-high and CIMP-intermediate epigenotype compared to EMVI- tumours, which demonstrated mostly the CIMP-low epigenotype (p = 0.002). Of the 8 genes in the CIMP panel, two (IGFBP3 and ADAMSTS) had significantly greater methylation in the EMVI+ve group (p < 0.001 and 0.004 respectively).
Conclusion These early results have demonstrated that there is a clear relationship between extramural vascular invasion and CIMP status in rectal cancer. The finding warrants further exploration given the drive to utilise methylation biomarker panels to inform treatment decisions in rectal cancer. Further research is underway to explore the molecular mechanisms responsible for this pathway.
Disclosure of interest None Declared.
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