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Journal of the New Zealand Medical Association, 12-December-2008, Vol 121 No 1287

MYH-associated polyposis—a new familial colorectal cancer syndrome without a family history

Graeme Dickson, Ian Wilson, Julie Arnold, Susan Parry

Familial colorectal cancer can be associated with multiple colonic adenomas, as is the case in Familial Adenomatous Polyposis (FAP). This condition has an autosomal dominant mode of inheritance so patients often have a positive family history.

We present a case of multiple colonic adenomas associated with a mutation involving the MutY Homologue (MYH) base-excision-repair gene.

MYH associated polyposis (MAP) is an autosomal recessive condition with different implications for familial screening.

Case report

A 36-year-old man presented with diarrhoea and was found to have polyps on sigmoidoscopy. A subsequent colonoscopy identified multiple adenomatous colonic polyps and he proceeded to total colectomy with ileorectal anastomosis—the provisional diagnosis being FAP. Histology revealed more than 50 colonic tubular/tubular villous adenomas. The larger polyps contained foci of high-grade dysplasia and invasive cancer, one being classified as Duke’s A cancer. Postoperatively, ongoing rectal surveillance by flexible sigmoidoscopy was planned.

As duodenal adenomas are present in 90% of individuals affected with FAP,6 surveillance gastroscopy was also recommended. The initial procedure revealed three discrete antral gastric adenomas and these were removed by submucosal resection.

There was no family history of cancer and his parents and four siblings were well. In approximately 25% of individuals presenting with FAP a spontaneous mutation will be present. Consequently, after appropriate counselling, genetic testing for this condition was requested.

The majority of cases of FAP are associated with mutations in the APC gene on the long arm of chromosome 5q21.7 However, sequencing of this did not identify a disease causing mutation. This is the situation in up to 20% of individuals with FAP. As FAP is a dominantly inherited condition, regular surveillance flexible sigmoidoscopy was recommended for his children from their early teens.

Given the negative genetic testing for FAP, and the recent description in the UK of the phenotypically similar MYH polyposis, blood samples were sent for MYH mutation testing. This detected a single mutation (G382D) and subsequent testing found a second frameshift mutation (c1092delC) confirming the diagnosis of MYH associated polyposis.

As this condition is associated with an autosomal recessive pattern of inheritance, as opposed to the autosomal dominant inheritance of FAP, the screening recommendations for the family were dramatically changed. His children were no longer at risk and his siblings were offered genetic testing.

Discussion

MYH is a base-excision-repair gene. Mutations have been associated with recessive inheritance of multiple colorectal adenomas. The first report was in a British family in which three of seven siblings had either colorectal cancer or multiple adenomatous polyps.1 Importantly, no-one from the previous or subsequent generations was affected. Analysis of the APC gene in 11 tumours showed an unusually high proportion of a specific somatic mutation— the G:C to T:A transversion. This suggested a defect in the base excision repair mechanism in these patients (Figure 1). Reactive oxygen species, which occur during normal metabolism, cause damage to DNA forming 8-oxoguanine (8-oxoG). This pairs with cytosine during DNA replication but can also mispair with adenine thus resulting in conversion of G:C base pairs into T:A base pairs (transversion). Base excision repair is the cell’s mechanism for preventing this.

MYH is responsible for base pair excision of adenine mismatched with 8-oxoG allowing insertion of normal base pairs.

All affected members of the family were found to be compound heterozygotes for MYH germline mutations. Subsequent studies have found that MYH mutations are associated with both multiple adenomas (>3 adenomas) and classical polyposis (>100 adenomas).4 The phenotype is typical for autosomal recessive inheritance with studies demonstrating polyposis in approximately 1 in 4 siblings (27%) of affected biallelic MAP cases.5

Heterozygotes do not appear to be at increased risk of cancer and studies have not found polyposis in these patients. Genetic testing for both FAP and MAP is recommended if colonic polyposis is present (>15 adenomas) without a family history of polyposis or cancer. If significant polyposis is present (>100) then gastroscopy should be performed to look for upper gastrointestinal polyps.

As MAP is an autosomal recessive condition, genetic testing should only be offered to siblings of affected patients with appropriate counselling through a genetic service. Patients should be managed as if they have attenuated or classical FAP. Further studies are needed to clarify the risk in heterozygotes.

Author information: Graeme Dickson, Gastroenterologist, Waikato Hospital, Hamilton; Ian Wilson, Gastroenterologist, Wakefield Hospital, Wellington; Julie Arnold, Co-ordinator, Familial Gastrointestinal Cancer Registry, Auckland City Hospital, Auckland; Susan Parry, Gastroenterologist & Clinical Advisor to the Familial Gastrointestinal Cancer Registry, Auckland City Hospital, Auckland

Correspondence: Dr Susan Parry, Gastroenterologist and Clinical Advisor to the Familial Gastrointestinal Cancer Registry, Genetic Services, Auckland City Hospital, PO Box 92024, Auckland, New Zealand. Email: sparry@adhb.govt.nz

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