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Desmoids are rare, benign fibromatous lesions, which can arise in patients with familial adenomatous polyposis (FAP), a disorder caused by germline adenomatous polyposis coli (APC) gene mutation. This study investigated the risk of desmoids in FAP, the relation between specific APC gene mutations and desmoid formation, and the clinical characteristics of FAP patients with desmoids. Eighty three of 825 FAP patients (10%) from 49 of 161 kindreds (30%) had desmoids. The absolute risk of desmoids in FAP patients was 2-56/1000 person years; comparative risk was 852 times the general population. APC gene mutations were similar in families with and without desmoids. The female/male ratio was 1*4 (p=NS). Previous abdominal surgery was noted in 68% of patients with abdominal desmoids (55% developed within five years postoperatively). Desmoid risk in FAP family members of a desmoid patient was 25% in first degree relatives v 8% in third degree relatives. Desmoids are a comparatively common complication of FAP associated with surgical trauma and familial aggregation. Desmoid development was not linked to specific APC gene mutations and was not found predominantly in women. Studies of chemopreventive therapy, given within five years after abdominal surgery, should be considered in FAP patients with a family history of desmoid disease. (Gut 1994; 35: 377-381) Desmoids are benign fibromatous lesions that arise most often in the abdominal wall and mesentery but also occasionally in the extremities and trunk. Desmoids occur rarely, constituting less than 0-1% of all tumours'2 with an incidence of 2-4 cases/million/year,23 and develop mainly in women. Patients with familial adenomatous polyposis (FAP)

Nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive potential against colorectal carcinomas (CRCs). Inhibition of cyclooxygenase (COX)-2 underlies part of this effect, although COX-2-independent mechanisms may also exist. Nonsteroidal antiinflammatory drugs appear to inhibit the initial stages of the adenoma -carcinoma sequence, suggesting a link to the APC/b-catenin/ TCF pathway (Wnt-signalling pathway). Therefore, the effect of the NSAID sulindac on nuclear (nonphosphorylated) b-catenin and b-catenin/TCF-mediated transcription was investigated. Nuclear b-catenin expression was assessed in pretreatment colorectal adenomas and in adenomas after treatment with sulindac from five patients with familial adenomatous polyposis (FAP). Also, the effect of sulindac sulphide on b-catenin/TCF-mediated transcription was studied. Adenomas of FAP patients collected after treatment with sulindac for up to 6 months showed less nuclear b-catenin expression compared to pretreatment adenomas of the same patients. Sulindac sulphide abrogated b-catenin/TCF-mediated transcription in the CRC cell lines DLD1 and SW480, and decreased the levels of nonphosphorylated b-catenin. As a result, the protein levels of the positively regulated TCF targets Met and cyclin D1 were downregulated after sulindac treatment. This study provides in vivo and in vitro evidence that nuclear b-catenin localisation and b-catenin/TCF-regulated transcription of target genes can be inhibited by sulindac. The inhibition of Wnt-signalling provides an explanation for the COX-2-independent mechanism of chemoprevention by NSAIDs. . Also, in patients with familial adenomatous polyposis (FAP), an autosomal dominantly inherited disorder characterised by the development of numerous colorectal adenomas at a young age, the NSAIDs sulindac and indomethacin can cause regression of adenomas (Giardiello et al, 1993;Nugent et al, 1993;Spagnesi et al, 1994;Hirota et al, 1996;Winde et al, 1997;Picariello et al, 1998). The chemopreventive effect of NSAIDs appears mediated by the induction of apoptosis and cell cycle arrest (Pasricha et al, 1995;DuBois and Smalley, 1996;Piazza et al, 1997;Keller et al, 1999;Shiff and Rigas, 1999). The molecular mechanisms underlying these biological effects are not completely understood. Nonsteroidal anti-inflammatory drugs inhibit the enzymatic activity of cyclooxygenase (COX)-1 and -2, enzymes that convert arachidonic acid into prostaglandins (Shiff and Rigas, 1999). However, COX-independent mechanisms may also play a role, since NSAIDs inhibit the growth of colon cancer cell lines lacking COX-2 expression (Hanif et al, 1996;Zhang et al, 1999;Smith et al, 2000).Oncogenic activation of the Wnt-signalling pathway by mutations in Adenomatous polyposis coli (APC) or b-catenin, which results in the accumulation and nuclear translocation of b-catenin and in b-catenin/TCF4-regulated transcription of TCF target genes, is mandatory for the initial neoplastic transformation of intestinal epithelium (reviewed in Kinzler and Vogelstein, 1996...

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