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Mecanismos genéticos en la predisposición
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Desmoids represent the most important cause of death, after colorectal cancer, in patients affected with familial adenomatous polyposis (FAP), an inherited disease due to mutations in the APC gene. The aims of our study were to estimate the risk of developing desmoids in FAP patients and to evaluate the association between desmoids and different risk factors. The occurrence of desmoids, colorectal cancer and other extra-colonic manifestations were assessed in 897 FAP patients, 653 of whom were also investigated for APC mutations. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were computed using an unconditional multiple logistic regression model. Desmoids developed in 107 patients (11.9%), with a cumulative risk of 20.6%. Females had a significantly higher risk than males (OR = 2.1; 95% CI 1.4–3.1). Family history of desmoids (OR = 8.75; 95% CI 5.66–13.51), osteomas (OR = 2.9; 95% CI 1.8–4.8) and epidermoid cysts (OR = 1.8; 95% CI 1.1–3.2) was also significantly associated with the occurrence of disease. Subjects with APC mutations beyond codon 1444 had a 12-fold increased risk, compared with patients with mutations located upstream. Mutations beyond codon 1309 conferred a 17-fold higher risk, compared with mutations upstream codon 452. Multivariate analysis identified as independent predictors mutation beyond codon 1444 (OR = 6.2; 95% CI 2.5–15.8), family history of desmoids (OR = 5.8; 95% CI 3.1–10.6), female gender (OR = 2.1; 95% CI 1.1–3.8) and the presence of osteomas (OR = 1.9; 95% CI 1.1–3.4). Our results indicate that integrating genetic and clinical data is helpful in defining subgroups of patients at higher risk for desmoids, who may benefit from specific prevention programs. © 2001 Wiley-Liss, Inc.
Recent studies suggest that one or more genes on chromosome 5q21 are important for the development of colorectal cancers,
particularly those associated with familial adenomatous polyposis (FAP). To facilitate the identification of genes from this
locus, a portion of the region that is tightly linked to FAP was cloned. Six contiguous stretches of sequence (contigs) containing
approximately 5.5 Mb of DNA were isolated. Subclones from these contigs were used to identify and position six genes, all
of which were expressed in normal colonic mucosa. Two of these genes (APC and MCC) are likely to contribute to colorectal
tumorigenesis. The MCC gene had previously been identified by virtue of its mutation in human colorectal tumors. The APC gene
was identified in a contig initiated from the MCC gene and was found to encode an unusually large protein. These two closely
spaced genes encode proteins predicted to contain coiled-coil regions. Both genes were also expressed in a wide variety of
tissues. Further studies of MCC and APC and their potential interaction should prove useful for understanding colorectal neoplasia.
