1. ¹Department of Medical Oncology, St Vincent's Hospital, Victoria Street, Darlinghurst, NSW 2010, Australia
2. ²School of Medicine, University of NSW, Sydney 2052, Australia
3. ³Department of Colorectal Surgery, St Vincent's Hospital, Victoria Street, Darlinghurst, NSW 2010, Australia
4. ⁴School of Medical Sciences, University of NSW, Sydney 2052, Australia

Correspondence: Professor RL Ward, E-mail: robyn@unsw.edu.au

Received 19 June 2006; Revised 29 August 2006; Accepted 29 August 2006; Published online 10 October 2006.

Abstract

Biallelic germline mutations in MYH are associated with colorectal neoplasms, which develop through a pathway involving somatic inactivation of APC. In this study, we investigated the incidence of the common MYH mutations in an Australian cohort of sporadic colorectal cancers, the clinicopathological features of MYH cancers, and determined whether inactivation of mismatch repair and base excision repair (BER) were mutually exclusive. The MYH gene was sequenced from lymphocyte DNA of 872 colorectal cancer patients and 478 controls. Two compound heterozygotes were identified in the cancer population and all three cancers from these individuals displayed a prominent infiltration of intraepithelial lymphocytes. In total, 11 heterozygotes were found in the cancer group and five in the control group. One tumour from an individual with biallelic germline mutation of MYH also demonstrated microsatellite instability (MSI) as a result of biallelic hypermethylation of the MLH1 promoter. Although MYH-associated cancers are rare in a sporadic colorectal population, this study shows that these tumours can develop through either a chromosomal or MSI pathway. Tumours arising in the setting of BER or mismatch repair deficiency may share a biological characteristic, which promotes lymphocytic infiltration.