Objective: This study was performed to examine the relation between phenotypic expression in patients with familial adenomatous polyposis (FAP) and the site of mutations in the APC (adenomatous polyposis coli) gene. The ability of APC mutations to predict surgical outcome was also investigated.
Summary background data: Germline mutations in the APC gene cause FAP and can now be identified by direct mutational analysis. Such an analysis can identify affected persons for close surveillance and spare unaffected persons. Phenotypic expression varies within and among FAP kindreds, but certain mutations have been associated with severe disease. Patients with severe polyposis are frequently offered total proctocolectomy rather than colectomy and ileorectal anastomosis out of concern for increased rectal cancer risk. Mutation analysis may offer a more rational basis for these decisions.
Methods: The postsurgical courses of 58 patients from 19 FAP kindreds with identified APC gene mutations were reviewed. APC gene mutations were identified by analysis of leukocyte DNA using single-strand conformational analysis and DNA sequencing. FAP severity was defined according to the number of polyps in the colon at the time of resection (< 1000, mild; > 1000, severe). Operations included subtotal colectomy with ileorectal anastomosis (IRA), total proctocolectomy with ileal pouch/anal anastomosis, total proctocolectomy with end ileostomy, and partial colectomy (PC).
Results: Eight different APC mutations were identified. Mutations at codons 1309 and 1328 in exon 15G were associated with a uniformly severe polyposis phenotype. For other mutations, the phenotype was more variable. Patients with APC mutations at codons 1309 and 1328 more commonly underwent proctectomy. Among the 43 patients who initially underwent either IRA or PC, the rectum was later removed in 8. Seven of these patients had a mutation at codon 1309 or 1328. With one exception, all patients with mutations outside the 1309 or 1328 site who initially had IRA have retained their rectum.
Conclusions: Our data support an association between severe polyposis phenotype and mutations at APC gene codons 1309 and 1328. For patients with these mutations, the prognosis for retaining the rectum is poor.