Reply to 'Comment on 'Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system".

Sir,

We thank Tapial for their interest in our recent study. The authors applied our revised CIMP classification to their three different clinical data sets, which are composed of patients with early-onset colorectal cancer (EOCRC) (younger than 45 years), patients with late-onset CRC (LOCRC) (older than 70 years), and individuals diagnosed with synchronous CRC (SCRC). They addressed that only LOCRC cases showed similar tendency of increasing BRAF mutation, MSI-high and MLH1 methylation along with the increase in the number of methylated genes. Moreover, they insisted that prognostic results were only partially confirmed in SCRC.

Non-linearity of molecular alterations including BRAF mutation, MSI-high and MLH1 methylation in EOCRC and SCRC might originate from two reasons. First, EOCRC and SCRC have strong germline predispositions to CRC, even though they are not either familial adenomatous polyposis or Lynch syndrome (Cybulski ; de Voer ). Recent studies revealed that germline predisposition in EOCRC is greater than expected (Pearlman ); these germline predispositions are mainly associated with chromosomal instability rather than CIMP (Chan ; McGivern ). Second, CIMP-P2 CRCs usually occur in elderly patients. Two recent studies showed similar tendency in CRCs with BRAF mutation and concurrent MSI or MLH1 methylation (Seppala ; Vedeld ).

The authors tried to validate prognostic value of our revised CIMP classification in their EOCRC, LOCRC and SCRC subgroups. However, considering their previous publication, the sample size of each subgroup is too small to get enough statistical power for the subgroup of low prevalence, such as CIMP-P1 and CIMP-P2 (Ogino ; Perea ; Arriba ). Considering the low prevalence of EOCRC and SCRC, a multi-centre study might be necessary to validate the prognostic value of our revised CIMP classification.

Overall, Tapial et al’s results emphasise the fact that EOCRC and SCRC have different molecular landscapes compared with sporadic CRCs. Further comprehensive study might shed light on the complex interaction between germline predisposition, accumulation of somatic mutation and epigenetic alteration.