Cimp-Positive Status is More Representative in Multiple Colorectal Cancers than in Unique Primary Colorectal Cancers

Abstract

Colorectal cancer (CRC) with CpG island methylator phenotype (CIMP) is recognized as a subgroup of CRC that shows association with particular genetic defects and patient outcomes. We analyzed CIMP status of 229 individuals with CRC using an eight-marker panel ( CACNA1G , CDKN2A , CRABP1 , IGF2 , MLH1 , NEUROG1 , RUNX3 and SOCS1 ); CIMP-(+) tumors were defined as having ≥ 5 methylated markers. Patients were divided into individuals who developed a “unique” CRC, which were subclassified into early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and patients with multiple primary CRCs subclassified into synchronous CRC (SCRC) and metachronous CRC (MCRC). We found 9 (15.2%) CIMP-(+) EOCRC patients related with the proximal colon (p = 0.008), and 19 (26.8%) CIMP-(+) LOCRC patients associated with tumor differentiation (p = 0.045), MSI status (p = 0.021) and BRAF mutation (p = 0.001). Thirty-five (64.8%) SCRC patients had at least one CIMP-(+) tumor and 20 (44.4%) MCRC patients presented their first tumor as CIMP-(+). Thirty-nine (72.2%) SCRC patients showed concordant CIMP status in their simultaneous tumors. The differences in CIMP-(+) frequency between groups may reflect the importance of taking into account several criteria for the development of multiple primary neoplasms. Additionally, the concordance between synchronous tumors suggests CIMP status is generally maintained in SCRC patients.

A clinico-pathological and molecular analysis reveals differences between solitary (early and late-onset) and synchronous rectal cancer

“…In this sense, also the large rate of CIMP-High tumors within this population (75%) might confirm the contribution of epigenetic alterations to field effects previously proposed 29 , 31 . These findings are also in accordance with our previous studies in which we concluded that CIMP+ tumors were more frequent in patients diagnosed with SCRC than in patients with an isolated CRC or MCRC 20 , 21 . Interestingly, we observed some molecular alterations that appeared to be linked with the SRC subset.…”

“…Several studies have demonstrated molecular concordance between tumors within the same individual although definitive results have not yet been achieved 15 – 19 . Indeed, our group recently published the possible clonal origin of a subset of SCRCs diagnosed in patients without hereditary forms of CRC 20 , and highlighting the significance of epigenomic patterns in the development of multiple primary neoplasms 21 . Because pathogenesis and clinical features largely depend on the location of the tumor in the colonic mucosa, a correlation between the hypothetical molecular basis of SCRC and the anatomical location in the colon has been proposed 22 .…”

Insulin-Like Growth Factor 2 (IGF2) Signaling in Colorectal Cancer—From Basic Research to Potential Clinical Applications

“…Other current studies apply IGF2 in a panel with other CRC-specific markers (e.g., CACNA1G , CDKN2A , CRABP1 , IGF2, MLH1 , NEUROG1 , RUNX3 , and SOCS1 ) to study the CpG island methylator phenotype (CIMP) phenotype in primary and metastatic CRC [25,70,160]. Recent study showed higher CIMP(+) frequency in patients diagnosed with multiple CRC than in patients with “unique” CRC [161]. It was proven that CIMP-high cancers had poor survival outcomes in CRC patients [160].…”

Automated Imaging Cytometry Reveals Dysplastic Indices of Colonic Serrated Adenomas

“…Aneuploidy can be a result of many factors, including chromosome segmentation defects at the mitotic checkpoint and inactivating mutations in DNA damage repair genes [13]. The heterogeneous nature of CRCs origin, specifically within terms of its genetic instability, provides both a challenge in diagnosis and an opportunity for risk stratification [14]. Genetic instability can occur in three different forms in CRC: CpG island methylation phenotype, microsatellite instability (MSI) resulting from defective repair of mismatched bases and chromosomal instability (CIN) leading to aneuploidy [15].…”

“…CpG island methylation phenotype is associated with the silencing of tumor suppressor and DNA repair genes. It is associated with the right colon, mucinous features, MSI, poor tumor differentiation, high BRAF mutation rates and the female population [14]. MSI tends to arise in the right colon, is associated with a slightly better prognosis and responds differently to chemotherapy; thus, its treatment is specialized [16].…”