Hyperplastic Polyps and Sessile Serrated Adenomas as a Phenotypic Expression of MYH-Associated Polyposis

Background & Aims: MYH -associated polyposis (MAP) is a disorder caused by a bi-allelic germline MYH mutation, characterized by multiple colorectal adenomas. These adenomas typically harbor G:C→T:A transversions in the APC and K- ras genes caused by MYH deficiency. Occasional hyperplastic polyps (HPs) have been described in MAP patients but a causal relationship has never been investigated. We examined the presence of HPs and sessile serrated adenomas (SSAs) in 17 MAP patients and studied the occurrence of G:C→T:A transversions in the APC and K- ras gene in these polyps. Methods MAP patients were analyzed for the presence of HPs/SSAs. APC -mutation cluster region and K- ras codon 12 mutation analysis was performed in adenomas (n = 22), HPs (n = 63), and SSAs (n = 10) from these patients and from a control group of sporadic adenomas (n = 17), HPs (n = 24), and SSAs (n = 17). Results HPs/SSAs were detected in 8 of 17 (47%) MAP patients, of whom 3 (18%) met the criteria for hyperplastic polyposis syndrome. APC mutations were detected only in adenomas and comprised exclusively G:C→T:A transversions. K- ras mutations were detected in 51 of 73 (70%) HPs/SSAs in MAP patients, compared with 7 of 41 (17%) sporadic HPs/SSAs in the control group ( P < .0001). In HPs/SSAs, 48 of 51 (94%) K- ras mutations showed G:C→T:A transversions, compared with 2 of 7 (29%) sporadic HPs/SSAs in the control group ( P < .0001). Conclusions HPs and SSAs are a common finding in MAP patients. The detection of almost exclusively G:C→T:A transversions in the K- ras gene of HPs/SSAs strongly suggests that these polyps are related causally to MYH deficiency. This implies that distinct pathways, that is, APC -gene related in adenomas and nonrelated in HPs/SSAs, appear to be operational in MAP.