MLH1 gene promoter methylation status partially overlaps with CpG methylator phenotype (CIMP) in colorectal adenocarcinoma

Le résumé fourni par la source

RAS / BRAF mutations, mismatch DNA repair complex deficiency (MMRd)/microsatellite instability (MSI), and CpG methylator phenotype (CIMP) are key molecular actors in colorectal carcinogenesis. To date, conflicting evidence about the correlations between these molecular features has been reported. A retrospectively selected cohort of 123 CRCs was divided into 3 groups based on the molecular characteristics: MMR proficient (MMRp)/ BRAF p.V600E mutated ( BRAF mut ), MMRd/ BRAF mut , and MMRd/ BRAF wild type (BRAF wt ) . MLH1 promoter (p MLH1 ) methylation status was assessed by pyrosequencing. For 82 samples the CIMP phenotype was evaluated using the EpiTect® MethyLight kit. The MMRd/ BRAF mut group showed a higher p MLH1 methylation rate compared to both the MMRd/ BRAF wt and the MMRp/ BRAF mut groups. Overall, the two MMRd groups had a higher methylation rate compared to the MMRp cases independently from the mutational status of BRAF ( p -value <0.0001). The MMRd/ BRAF mut group was characterized by a 90.0 % of CIMP high (CIMP-H) tumors of which 97.2 % were p MLH1 methylated. Instead, the MMRd/ BRAF wt group presented 50.0 % of CIMP-H adenocarcinomas. Our study demonstrates that p MLH1 hypermethylation, MMRd, BRAF mut and CIMP phenotype do not completely overlap in CRC. These findings further refine the knowledge on the molecular landscape of CRC and may have critical implications also for the clinical management of the disease.

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