TP53, 17P and 18Q alterations as prognostic markers in MSS colorectal adenocarcinomas

Anna Colomer1, Nadina Erill1, Montse Verdú2, Ruth Román1, August Vidal1,2, Xavier Puig1,2.

1BIOPAT, Biopatologia Molecular, Barcelona, Spain. 2Histopat Laboratoris, Barcelona, Spain.

Two different patterns have been described for colorectal tumorigenesis. The main one -affecting 85% of sporadic tumors- is based on the familial adenomatous polyposis (FAP) model, a multistep process that involves at least APC, K-RASDCC andTP53 genes. The second pathway shares its etiology with hereditary non-polyposis colorectal cancer (HNPCC), and is characterized by mutations at the mismatch repair genes (MMR) that lead to an unstable phenotype, predictable by high degree of microsatellite instability (MSI-H). Since tumors displaying this phenotype have lower incidence of p53 mutation and rarely present allelic deletions, we decided to evaluate the impact of alterations at p53, 17p and 18q in a series of colorectal tumors previously categorized for MSI status.

A hundred ninety seven primary colorectal adenocarcinomas were studied to assess their MSI status using a panel of five microsatellites (BAT25, BAT26, D5S346, D2S123, D17S250). The series was also analyzed to identify p53 alterations using immunohistochemistry (PAb 1801) and PCR-SSCP (exons 4-8) followed by direct sequencing of shifted bands, and to detect allelic losses at 17p and 18q looking for LOH of the p53CA dinucleotide (TP53 locus) and D18S55, D18S58, D18S61, D18S64, D18S69 microsatellite markers, respectively.

MSI status could be assessed in 181/197 tumors (92%), 18 (10%) of which displayed MSI-H. The combination of IHQ and SSCP/sequencing allowed the detection of p53 alterations in 70% of MSS tumors, but only in 50% of cases exhibiting unstable phenotype. No dependence was observed between the presence of p53 abnormalities and histological grade, degree of invasion, nodal involvement or staging of MSS tumors. Regarding their allelic status, LOH at 17p was detected in 54%, and at 18q in 75%. The correlation of LOH results with the pathological data showed a high tendency for MSS tumors with nodal involvement to loose both 17p and 18q allelic regions, being this statistically significant. Stage (TNM) appeared also to be linked to these molecular markers.

 Our results obtained from tumors that display MSI-H agree with those demonstrating an inferior rate of TP53 mutation as well as a prevalence of good prognostic features. Nevertheless, more cases should be analyzed to statistically confirm these trends. Since 17p and 18q allelic losses have been related to pathological features that determine prognosis, we recommend including them into the panel of prognostic markers for colorectal tumors. Moreover, we outline the convenience of categorizing tumors for MSI status previously to the assessment of such molecular markers. 

Abstract exhibited at the:


12-15 September 2002. Barcelona-Spain.