Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP)

Abstract

Objective: To investigate the contribution of MYH associated polyposis coli (MAP) among polyposis families in the Netherlands, and the prevalence of colonic and extracolonic manifestations in MAP patients. Methods: 170 patients with polyposis coli, who previously tested negative for APC mutations, were screened by denaturing gradient gel electrophoresis and direct sequencing to identify MYH germline mutations. Results: Homozygous and compound heterozygous MYH mutations were identified in 40 patients (24%). No difference was found in the percentage of biallelic mutation carriers between patients with 10-99 polyps or 100-1000 polyps (29% in both groups). Colorectal cancer was found in 26 of the 40 patients with MAP (65%) within the age range 21 to 67 years (median 45). Complete endoscopic reports were available for 16 MAP patients and revealed five cases with gastro-duodenal polyps (31%), one of whom also presented with a duodenal carcinoma. Breast cancer occurred in 18% of female MAP patients, significantly more than expected from national statistics (standardised morbidity ratio = 3.75). Conclusions: Polyp numbers in MAP patients were equally associated with the attenuated and classical polyposis coli phenotypes. Two thirds of the MAP patients had colorectal cancer, 95% of whom were older than 35 years, and one third of a subset of patients had upper gastrointestinal lesions. Endoscopic screening of the whole intestine should be carried out every two years for all MAP patients, starting from age 25-30 years. The frequent occurrence of additional extraintestinal manifestations, such as breast cancer among female MAP patients, should be thoroughly investigated.

MutYH mutation carriers have increased breast cancer risk

“…The mutation prevalence of 4.4% in our study replicates a similar prevalence estimate from participants in our Middle East Cancer Consortium study of colorectal cancer (unpublished Abbreviations: G396D, glycine-to-aspartic acid substitution at codon 396; MutYH, mutY homolog gene; SD, standard deviation; Y179C, tyrosine-to-cysteine substitution at codon 179. 9,11,13 did demonstrate an association with breast cancer in special populations with familial cancer 9 or polyposis. 11,13 It is interesting to note that no interaction was noted between family history status and the breast cancer risk of mutations in MutYH in our study.…”

“…9,11,13 did demonstrate an association with breast cancer in special populations with familial cancer 9 or polyposis. 11,13 It is interesting to note that no interaction was noted between family history status and the breast cancer risk of mutations in MutYH in our study. One explanation may be that a significant proportion of cases with a family history who have wild-type MutYH may be carriers of mutations in other genes, such as the breast …”

“…7 It is known that mutations in mismatch-repair genes increase susceptibility to cancer in organs other than the colon, but former data published regarding a possible association between MutYH mutations and breast cancer risk are conflicting. [8][9][10][11][12][13][14] We studied the prevalence of the 2 commonly described founder mutations in MutYH, a glycine-to-aspartic acid substitution at codon 396 (G396D) and a tyrosine-to-cysteine substitution at codon 179 (Y179C), in a case-control study of breast cancer that was restricted to Sephardi Jews in whom we noted a high prevalence of these mutations (unpublished results).…”

The role of MYH and microsatellite instability in the development of sporadic colorectal cancer

“…To date, the 168 MAP tumours (includes 48 colorectal cancers) reported in the literature were microsatellite stable Fleischmann et al, 2004;Wang et al, 2004;Nielsen et al, 2005). This is expected given that mutations of MYH predisposes to inactivation of APC through G:C to A:T transversions (Al-Tassan et al, 2002).…”

“…condition (Al-Tassan et al, 2002) associated with the development of multiple adenomas and carcinomas of the colon and rectum, as well as other possible malignancies and extra-colonic manifestations (Enholm et al, 2003;Sampson et al, 2003;Sieber et al, 2003;Gismondi et al, 2004;Nielsen et al, 2005). The syndrome is caused by germline biallelic mutations in MYH, a gene that codes for a DNA glycosylase involved in base excision repair (BER) (Al-Tassan et al, 2002).…”