Effects of Somatic Methylation in Colonic Polyps on Risk of Developing Metachronous Advanced Colorectal Lesions

Abstract

The utility of molecular markers for predicting the risk of metachronous advanced colorectal lesions (MACLs) remains poorly investigated. We examined the relationship between somatic hypermethylation in polyps at baseline and the risk of developing MACL. This retrospective cohort study included 281 consecutive patients with colonic polyps who were enrolled between 2007 and 2009 and followed-up until 2014. MACLs were defined as adenomas of ≥10 mm, high-grade dysplasia, or with a villous component; and serrated lesions of ≥10 mm or with dysplasia. In total, 595 polyps were removed at baseline colonoscopy and analyzed for pathological characteristics and CpG island methylator phenotype (CIMP) using the MS-MLPA (Methylation-Specific -- Multiplex Ligation-dependent Probe Amplification) technique. Forty-five patients (16.0%) showed at least one CIMP+ polyp. MACL risk was higher in patients with CIMP+ polyps (odds ratio (OR), 4.50; 95% CI, 1.78–11.4; p = 0.002). Patients with CIMP+ polyps also exhibited shorter time to MACL development (33.8 months vs. 50.1 months; p < 0.001), even with adjustment for polyp size and number (OR, 2.40; 95% CI, 1.33–4.34). Adding CIMP analysis improved the sensitivity (57.0% to 70.9%), negative predictive value (71.1% to 77.3%), and overall accuracy (49.8% to 52.0%) for MACL risk estimation. These results highlight that CIMP may be a useful marker for endoscopic surveillance.

Novel insights into tumorigenesis revealed by molecular analysis of Lynch syndrome cases with multiple colorectal tumors

“…This tight link with defective MMR system and changes in genomic methylation is often seen in LS; LS-associated adenomas and carcinomas acquire hypermethylation of select genes ( 41 ), and sometimes CIMP ( 15 , 30 ). In the sporadic setting, the presence of CIMP has been shown to associate with worse prognosis irrespective of MSI, as well as an increased risk of developing metachronous advanced colorectal lesions ( 42 , 43 ). Interestingly, Murcia et al.…”

“…Interestingly, Murcia et al. note that a positive CIMP status also predicted the formation of serrated polyps in unselected group of CRC patients ( 43 ). Conversely, studies of sporadic CRC cases revealed an association between frequent metastases at diagnosis and the absence of CIMP ( 44 ).…”

“…In the sporadic setting, the presence of CIMP has been shown to associate with worse prognosis irrespective of MSI, as well as an increased risk of developing metachronous advanced colorectal lesions (42, 43). Interestingly, Murcia et al note that a positive CIMP status also predicted the formation of serrated polyps in unselected group of CRC patients (43). Conversely, studies of sporadic CRC cases revealed an association between frequent metastases at diagnosis and the absence of CIMP (44).…”

“…Somatic RNF43 variants in sporadic CRC are frequently observed and show strong correlation with MSI (27,62). They have also been reported in strong association with the BRAF V600E somatic mutation as well as an aggressive tumor biology, and sporadic CRC patients with both mutations seem to benefit from a specific therapy regimen (43,54,63,64). Though BRAF V600E has a very tight association with the CIMP tumor phenotype in sporadic CRC, LS tumors very rarely harbor the BRAF V600E driver mutation, to the extent that the presence of BRAF V600E can be used as a marker predicting the absence of LS (65).…”