ArticlesMolecular genetic tests as a guide to surgical management of familial adenomatous polyposis
Introduction
Familial adenomatous polyposis (FAP) or Bussey-Gardner polyposis1 is an autosomal dominant disease characterised by hundreds of adenomas in the colon and by various extracolonic features.2 The disease is due to a mutation in the adenomatous polyposis coli (APC) gene which is located on chromosome 5.3, 4 The APC gene consists of 15 coding exons and probably influences interactions between cells. Most patients develop adenomatous polyps in their colon in the second and third decade of life2 and if untreated they get colorectal cancer in their thirties. We now know that individuals with identical mutations can show differences in phenotypic expression of the disease;5, 6 nevertheless, several investigators report correlations between mutations occurring within specific regions of APC and the phenotypic expression. Mutations within exons 3 and 4 are associated with a less severe form of FAP characterised by a low number of colorectal adenomas and a late age of onset of colorectal cancer.7 Nagase8 reports that patients with mutations located in a region between codons 1250 and 1464 at exon 15 tend to have more than 5000 adenomatous polyps and to develop colorectal cancer at an average age of 34. Whereas those with mutations outside this region have fewer than 2000 polyps and develop colorectal cancer at 41·8 years. A severe form of FAP has been associated with a deletion in codon 13099 and with mutations after codon 1250.10, 11
Might information on the location of the mutation be useful in determining the most appropriate surgical treatment? There has been a long debate about the extent of colonic surgery. If the rectum is carpeted with polyps or if the patient is unlikely to attend regularly for follow-up, there is a good case for restorative proctocolectomy (RPC). If the rectum is relatively free of adenomas, colectomy with ileorectal anastomosis (IRA) is the most attractive surgical procedure because of its satisfactory functional results. A drawback of IRA, however, is the substantial risk of cancer in the residual rectum;12, 13 moreover, a high proportion of the patients need rectal excision because of uncontrollable polyps. In the present study, we evaluated the cumulative risk of rectal cancer in a large series of patients in the Netherlands. We also assessed the rate of rectal excision after IRA and whether the probability of secondary surgery is associated with the location of the mutation.
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Methods
In 1985 a registry of families with familial adenomatous polyposis was set up in the Netherlands,14 and by July 1, 1995, genealogical studies had been performed in 200 families with FAP referred from all parts of the country. Medical and pathological data were collected to verify the family history. Data collection was complete in 150 of the 200 families and these families were selected for the present study.
Between 1956 and mid-1995, 230 patients had IRA performed as a primary procedure for
Results
Of the 230 patients who had an IRA, 5 had follow-up of less than one year after surgery and were excluded. The remaining 225 had a mean follow-up of 11 yr (range 1–38). Mean age at surgery was 28·3 yr (range 11–70). 16 of these patients developed a rectal cancer (mean age 45 yr; range 29–61). Of these 16 patients, information on screening was available in 12: 11 had undergone surveillance within the previous 12 months. The interval since the last endoscopic examination ranged from 3 to 14
Mutation analysis
DNA analysis was conducted in 105 of the 150 polyposis families and the pathogenic mutation was detected in 56 families. 32 of these families had at least one member who underwent an IRA. 21 families including 72 patients with an IRA (group A) had a mutation before codon 1250 and the remaining 11 families including 15 individuals with an IRA (group B) had a mutation after this codon. 14 of the patients from group A and eight of the patients from group B required rectal excision because of
Discussion
Although non-steroidal anti-inflammatory drugs may have some beneficial effect on colonic adenomas,17 prophylactic surgery of the colon is still the only curative treatment for polyposis. Restorative proctocolectomy might seem the ideal operation. By removal of all or nearly all the large-bowel mucosa the risk of cancer can be almost completely avoided. There are disadvantages, however, and the most important are the greater morbidity and duration of convalescence than with IRA and the possible
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