Evidence for a novel tumour suppressor gene at 10q21 chromosome in sporadic colorectal adenocarcinoma
This thesis sought to define deletions of chromosome lOin sporadic colorectal
adenocarcinoma and determine their role in colorectal tumorigenesis.
This thesis has shown a region of frequent loss of heterozygosity (LOH) in the region
lOql1-21 centring on the marker D10S1790 at lOq21 suggesting this is the most likely
locus of a putative tumour suppressor gene in this region. It has also been shown that LOH
at this marker (D10S1790) is significantly associated with earlier presentation of patients.
Analysis of adenomas revealed a low frequency of LOH in this region with only two of
nine severely dysplastic adenomas showing LOH and none of those with mild or moderate
dysplasia. This suggests that loss of the putative tumour suppressor gene at this locus is a
late event in colorectal tumorigenesis.
Furthermore, deletions at the chromosome 17 locus containing the known tumour
suppressor gene, pS3, were examined together with pS3 expression by
immunohistochemistry, which are also known to occur late in colorectal tumorigenesis. The
frequency of LOH at the pS3 locus as well as pS3 expression were similar to previous
studies and there was no significant association with losses at lOq suggesting that loss of a
putative tumour suppressor gene at 10q occurs independently of loss of p53 function. LOH
at lOq21 was also found not to be associated with LOH at the APe gene locus on 5q21-22
which occurs in up to 50% of sporadic colorectal adenocarcinomas.
This thesis suggests that loss of the putative tumour suppressor genets) on lOq provides a
selective advantage for clonal expansion in the somatic evolutionary process of colorectal
tumorigenesis. Elucidation of the tumour suppressor genets) at this site will further help our
understanding of the series of genetic mutations that occur in the evolution of colorectal
cancer and will contribute to the efforts in the prevention, early detection and treatment of
this prevalent disease.