Molecular genetic of colorectal cancer : association between P53 restricted over expression and mismatch repair deficiency

The first question addressed in this work pertains to evaluating the relevance of p53 immunohistochemistry in phenotyping colorectal tumors in the daily practice of the pathologist. Further, we attempt to shed light on the relationship between alterations in p53-MDM2-p14ARF pathway and DNA mismatch repair sytem (MMR) deficiency in colorectal cancer (CRC). We demonstrated the existence of a particular pattern of p53 immunohistochemical expression that we defined as “restricted p53 overexpression”, characterized by a limited number of homogenously scattered and strongly positive tumor cells. We clearly demonstrated that this pattern of p53 expression is distinct from the two classical p53 immunostaining profiles usually described in the literature, namely the diffuse p53 overexpression associated with TP53 missense mutations and the negative p53 immunostaining associated with truncating TP53 mutations. We showed that the restricted pattern of p53 overexpression is significantly associated with microsatellite instability high (MSI-H) phenotype, suggesting that this pattern of p53 immunostaining could be an additional morphological feature of MSI-H CRCs. Although the restricted p53 overexpression pattern is also observed in a subset of microsatellite stable (MSS) CRCs and does not predict the origin of MMR deficiency, our data point to a significant role of p53 immunohistochemistry in the routine practice of the pathologist, as assessing the pattern of p53 protein expression could provide a more refined tumor classification and help the pathologist in categorizing CRCs in large scale screening. Despite the known relationship between wild-type TP53 and MMR deficiency, we showed that restricted p53 overexpression inversely correlated with TP53 mutation irrespective of MSI-status. We found that restricted p53 overexpression pattern is strongly associated with concomitant MDM2 overexpression and inversely correlated with p21 loss, independently of MSI-status. Moreover, while hypermethylation of proximal CpG sites within the 5’CpG island of p14ARF promoter flanking exon 1β seems to be a rare event in CRCs, this epigenetic event was more likely observed in CRCs displaying the restricted pattern of p53 overexpression, irrespective of MSI-status. Our results indicate a significant alternative mechanism of p53-MDM2-p14ARF axis deregulation in a subgroup of CRCs, including the majority of colorectal tumors evolving through the MSI-pathway. Taken together, the findings from this work could provide a more refined classification of colorectal tumors in the future, which would significantly impact the therapeutic management of CRC patients.(SBIM 3) -- UCL, 201