Genetic alterations of Wnt pathways in familial versus sporadic polyps

In previous work we supported the inclusion of germline ASE (allele specific expression) analysis and screening of polyposis genes in algorithms for genetic diagnosis of hereditary forms of colorectal cancer. In the present work we are analyzing gene expression in tissue samples from a series of patients with polyposis, familial and sporadic to gain insights into the role of somatic expression of APC and other components of canonical and non canonical Wnt pathways in colorectal polyposis. Individuals with age ≥ 18 years were included and patients with inflammatory bowel disease were exluded. Normal colonic mucosa were collected from donors with no family history of cancer as control. mRNA expression levels were investigated by qRT-PCR. The correlation among clinical and molecular features was evaluated. We analyzed APC expression in 11 patients with FAP (familial adenomatous polyposis) with and without APC mutation, and 25 with sporadic adenomas (overall, 26 colon tumour tissues and 19 adjacent mucosa) and in normal colonic mucosa from 12 healthy controls. qRT-PCR showed a reduced APC expression in colon tumour tissues as compared to the adjacent mucosa. The differences in APC expression between colon tumour tissues and adiacent mucosa in familial and sporadic cases were statistically significant in the familial group. We also correlated APC expression with age. In patients the expression levels tend to decrease more rapidly with age. Instead in control group there is a constant APC expression trend in life. Correlation with sex showed that the APC reduced expression is more evident in men than in female. Intriguingly the APC expression in polyp-adjacent colonic mucosa was higher also compared to healthy controls colonic mucosa. Wnt pathway BCL9 and LEF1 downstream components and Wnt5a and Wnt3a ligands showed a reduced expression in adjacent colonic mucosa vs adenomas. Expression analysis of other Wnt components is in progress. This study showed that the APC gene is less expressed in colon tumor tissue compared to the adjacent mucosa either in familial or in sporadic polyps, but it is more expressed in adjacent mucosa compared to the mucosa of healthy controls. The increased APC expression in adjacent mucosa could be due to a cross talk between tumor and surrounding colonic epithelium. BCL9, LEF1, Wnt5a and Wnt3a showed an opposite trend compared to APC, suggesting the involvement of noncanonical Wnt signalling in adenoma formation.