Adverse prognostic impact of the CpG island methylator phenotype in metastatic colorectal cancer

Abstract

Background:The association between the CpG island methylator phenotype (CIMP) and clinical outcomes in metastatic colorectal cancer remains unclear. We investigated the prognostic impact of CIMP in patients with metastatic colorectal cancer treated with systemic chemotherapy.Methods:Eight CIMP-specific promoters (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, CDKN2A, CRABP1, and MLH1) were examined. The CIMP status was determined by the number of methylated promoters as high (⩾5), low (1–4), and negative (0).Results:A total of 153 patients were included (men/women, 103/50; median age, 61 years; range, 22–80 years). The CIMP status was negative/low/high in 77/ 69/7 patients, respectively. Overall survival (OS) was significantly different among the three CIMP groups, with median values of 35.7, 22.2, and 9.77 months for the negative, low, and high groups, respectively (P<0.001). For patients treated with fluoropyrimidine and oxaliplatin first-line chemotherapy (N=128), OS and progression-free survival (PFS) were significantly different among the three CIMP groups; the median OS was 37.9, 23.8, and 6.77 months for the negative, low, and high groups, respectively (P<0.001), while the median PFS was 9.97, 7.87, and 1.83 months, respectively (P=0.002). Response rates were marginally different among the three CIMP groups (53.4% vs 45.1% vs 16.7%, respectively; P=0.107). For patients treated with fluoropyrimidine and irinotecan second-line chemotherapy (N=86), only OS showed a difference according to the CIMP status, with median values of 20.4, 13.4, and 2.90 months for the negative, low, and high groups, respectively (P<0.001).Conclusions:The CIMP status is a negative prognostic factor for patients with metastatic colorectal cancer treated with chemotherapy.

CpG island methylator phenotype identifies high risk patients among microsatellite stable BRAF mutated colorectal cancers

“…We additionally observed that patients with stage IV CIMP positive tumors had a poorer prognosis, irrespective of BRAF and/or MSI status. This has also been observed by others, suggesting that CIMP may be used as a poor prognostic marker for advanced disease.…”

An Exon Signature to Estimate the Tumor Mutational Burden of Right-sided Colon Cancer Patients

“…In line with previous studies [4][5][6][7][8], we observed that the TMB-high groups have significantly higher prevalences of MSI status and CIMP phenotype than the TMB-low groups (Fisher's exact test, p<0.01) in the RCC datasets. And tumors with TMB-high exhibited higher BRAF and lower KRAS mutation rate than the TMB-low patients as well.…”

“…The different origins consequently contribute to tumors with a different gene expression and mutation profile. RCC patients are reported to be a higher incidence of BRAF, POLE/POLD1 mutation, CIMP, MSI and genome hypermutation [4][5][6][7][8]. Conversely, LCC tumors are characterized by higher frequency of KRAS mutation and chromosomal instability [9].…”

Caracterización de pacientes con cáncer colorrectal esporádico basado en la nueva subclasificación molecular de consenso

“…La vía CIMP se caracteriza por una amplia hipermetilación de los islotes CpG en los promotores de genes supresores de tumores, provocando la inactivación de ellos. Se presenta en 15%-20% de CCR esporádicos y se le asocia a mal pronós-tico 13,14 . Debido a la heterogeneidad y complejidad de los tumores, diversos estudios han propuesto subgrupos moleculares de CCR basados en las 3 vías antes descritas [15][16][17][18][19] .…”