ANATOMICAL PATHOLOGY No difference in the occurrence of mismatch repair defects and APC and CTNNB1 genes mutation in a multi-racial colorectal carcinoma patient cohort LU PING TAN*, BAN KIM NG*, PAULINE BALRAJ*, PATRICIA KIM CHOOI LIM* AND SUAT CHENG PEH{ *Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, and {Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia Summary Background and aims: Colorectal cancers of different subtypes involve different pathogenic pathways like the Wnt and the mutator pathways. In this study, we screened 73 colorectal cancer cases from a multi-racial group for genetic and expression profile defects with the aim of correlating these with patients’ clinicopathological characteristics. Methods: Mutation screening of the entire coding region of APC and exon 3 of CTNNB1, loss of heterozygosity (LOH) of APC, and microsatellite instability (MSI) status were assessed for 44 patients with available paired frozen normal and tumour tissues. In addition, 29 cases with available paraffin embedded tumour blocks were screened for muta- tion in exon 3 of CTNNB1, the APC mutation cluster region (codon 1286–1513), and hMLH1, hMSH2, hMSH6 protein expressions by immunohistochemistry method. Results: In our study, 15/73 cases showed APC mutations (20.5%), 1/73 cases had CTNNB1 mutation (1.4%), 5/32 cases had APC LOH (15.6%), and 16/70 (22.9%) cases revealed at least some form of mismatch repair (MMR) defect. Tumour grade (poor differentiation) was found to correlate significantly with right-sided tumour and mucinous histology (p50.01879 and 0.00320, respectively). Patients of younger age (below 45 years) more often had tumours of mucinous histology (p50.00014), while patients of older age (above 75 years) more often had tumours on the right side of the colon (p50.02448). Tumours of the mucinous histology subtype often had MMR defects (p50.02686). There was no difference in the occurrence of APC and CTNNB1 mutations and MMR defects found within our multi-racial colorectal cancer patient cohort. Conclusion: Our findings support the notion that racial factor may not be related to the occurrence of MMR defects and APC and CTNNB1 mutations in our multi-racial patient cohort. Key words: Adenomatous polyposis coli (APC), b-catenin (CTNNB1), DNA mismatch repair protein, colorectal neoplasms. Received 21 July, revised 5 October, accepted 15 October 2006 INTRODUCTION Colorectal cancer is one of the most common cancers seen worldwide. It ranked as the most common cancer among men and the third most common cancer among women (14.2 and 10.1% among cancers, respectively) in Malaysia. 1 As reported in the National Cancer Registry, the incidence of colorectal cancers in Chinese Malaysians was 1.9–3.4 times more when compared with other races (Table 1). Alterations in the Wnt pathway are often implicated in colorectal carcinogenesis, which controls cell-to-cell inter- action during embryonic development, cell polarity and migration, cell cycle regulation, cell fate specification, and cell growth. 2 The adenomatous polyposis coli (APC) gene plays a pivotal role as negative regulator in the Wnt pathway, and it has often been reported to be involved in colorectal carcinogenesis. 3 It is a tumour suppressor gene that is located on chromosome 5q21, with mRNA of 8529 nucleotides long which encodes a large protein of 312 kDa. The first 14 exons of the APC gene are relatively small while exon 15 is about 6.5 kb in length, and its enormous size reflects a multi-functionality of this protein. APC was found to be mutated in 41–72% of colorectal cancer patients 4–6 and 74–82% of familial adenomatous polyposis (FAP) patients. 7,8 In addition, the frequency of loss of heterozygosity (LOH) in APC was reported to be 20–40% in sporadic colorectal carcinomas. 9 b-catenin (CTNNB1), also a key player in the Wnt pathway, 10 is reported to be altered in 25–48% 4,11,12 of colorectal cancers lacking APC mutations and/or with high microsatellite instability (MSI) status. All mutations were located in the exon 3 phosphorylation sites. The presence of APC mutations and CTNNB1 mutations were reported to be mutually exclusive and it was proposed that genetic aberrations in CTNNB1 may substitute APC mutations for colorectal carcinogenesis. 10 Defects in the DNA mismatch repair (MMR) pathway is also a phenomenon often seen in colorectal cancer. MSI is a hallmark of aberrations in MMR proteins, and is presently used as a diagnostic criterion for hereditary non-polyposis colorectal cancer (HNPCC) disease. 13 MSI was reported in 11–20% of sporadic colorectal cancers 14,15 and 67% of familial colorectal cancers. 16 It was noted that loss of MMR protein indicated by immunohistochemistry (IHC) correlated well with MSI. 17 To date, the molecular profile of the Wnt pathway and the MSI status in Malaysian colorectal cancer patients remains unknown, since there has been no molecular study of this group reported yet. Considering the higher incidence Pathology (April 2007) 39(2), pp. 228–234 ISSN 0031-3025 printed/ISSN 1465-3931 # 2007 Royal College of Pathologists of Australasia DOI: 10.1080/00313020701230757