The present study was carried out to characterize the causative genetic mutation in a medium-sized Malaysian Chinese pedigree of three generations affected with familial adenomatous polyposis (FAP). Clinical data and genetic studies revealed considerable phenotypic variability in affected individuals in this family. Blood was obtained from members of the FAP-01 family and genomic DNA was extracted. Mutation screening of the adenomatous polyposis coli (APC) gene was carried out using the single strand conformation polymorphism (SSCP) technique. The possibility of exon skipping was predicted by splicing motif recognition software (ESEfinder release2.0). SSCP results showed mobility shifts in exon 8 of the APC gene which segregated with affected members of the family. Sequence analysis revealed that the affected individuals are heterozygous for a C847T transition, whilst all the unaffected family members and control individuals are homozygous C at the same position. This nucleotide substitution generates a stop codon at amino acid position 283, in place of the usual arginine (Arg283Ter). We conclude that an Arg283Ter mutation in the APC gene is causative of the FAP phenotype in this family, although there is considerable variation in the presentation of this disease among affected individuals. Computational analysis predicts that this mutation occurs within sequences that may function as splicing signals, so that the sequence change may affect normal splicing.
PURPOSE:
This study examined the mutational profile of the adenomatous polyposis coli gene in relation to the development of desmoid tumors in familial adenomatous polyposis patients from a predominantly Chinese population.
METHODS:
This is a retrospective review of all patients with familial adenomatous polyposis coli from the Singapore Polyposis Registry. Identification of specific adenomatous polyposis coli gene mutation was performed and clinical course of associated desmoid disease obtained from case records and a computerized database.
RESULTS:
Two hundred five patients from 75 families afflicted with familial adenomatous polyposis coli were reviewed, with gene mutations identified in 107 patients. Of these, 23 (11.2 percent) developed desmoids. The male-to-female ratio was 1:1.3 and the ethnic distribution was Chinese (n=17) and Malay (n=6). Of the 92 patients with mutations 5' to codon 1444, 11 patients (12 percent) developed desmoids compared with 6 of 15 (40 percent) patients with adenomatous polyposis coli gene mutations 3' to codon 1444 (P<0.01). The clinical course of desmoid tumors can be divided into stable (n=11), variable (n=3), progressive (n=6), and aggressive growth (n=3). Only 3 (13 percent) patients with aggressive tumor growth required chemotherapy. There was no correlation between the site of mutation and the clinical progression of the desmoids. Seventy-four percent of these desmoids (17/23) developed at a mean interval of 2.98 years after restorative proctocolectomy, while only 30 percent (7/23) were diagnosed preoperatively or discovered during the initial surgery. The most common complications related to the mesenteric desmoids were intestinal obstruction (21.7 percent), ureteric obstruction (17.4 percent), and encasement of superior mesenteric vessels (13 percent).
CONCLUSION:
The clinical course of desmoids in an individual familial adenomatous polyposis patient remains unpredictable and no reliable genetic marker is available for prognostication in desmoid disease.
There has been a growing awareness of the association between papillary thyroid carcinoma and familial adenomatous polyposis (FAP). The cases of four young patients with papillary thyroid carcinoma occurring with FAP are presented. Three patients underwent surgery to provide specimens for detailed histological examination. The surgical specimens showed well-encapsulated multicentric tumours exhibiting a predominantly papillary architectural growth pattern. In some areas, follicular architecture and cribriform patterns were noted. Atypical areas of spindle cells in a trabecular or solid configuration, which are not normally seen in classical papillary thyroid carcinoma, were evident. Malignant cells exhibited a graduation of cuboidal to tall cells with abundant amphophilic cytoplasm. The nuclei did not exhibit the typical nuclear clearing as seen in papillary thyroid carcinoma, but nuclear grooving and inclusions were noted. Psammoma bodies were not seen in any of the specimens. In a limited review of these patients, features such as young age at presentation, multicentricity and unusual histology suggest that thyroid carcinoma associated with FAP may represent a distinct form of thyroid cancer.
Two patients, members of one family, with Peutz-Jeghers syndrome are described who underwent surgery for bowel obstruction. Both had multiple polyps in the gastrointestinal tract. Severe dysplasia and adenomatous change were present in two hamartomatous polyps adjacent to a stenosing colonic carcinoma in one patient and moderate dysplasia and adenomatous change were observed in two hamartomatous rectal polyps in his son. These changes support recent reports in the literature of progression towards neoplasia in these lesions.