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

Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
Gastroenterology (Impact Factor: 16.72). 09/2008; 135(6):2014-8. DOI: 10.1053/j.gastro.2008.09.020
Source: PubMed


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.
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).
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).
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.

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    • "Though there appear to be at least two phenotypic subtypes which correspond to the first and last criteria (Text Box 2), a previous report from the UK clearly demonstrates that the predominant molecular change in the polyps is that of BRAF mutation, even in patients with numerous polyps [25], and therefore suggesting that oncogene mutations are of little value in subtyping this disorder. However, rare cases of serrated polyposis are reported where KRAS mutations predominate [25], and current evidence suggests that, in at least some of these patients, biallelic germline mutation of MUTYH may be responsible [25, 26, 90, 91]. "
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