Background: Many patients with familial adenomatous polyposis (FAP) die from desmoid tumours which can arise spontaneously but often appear to be surgically induced by prophylactic colectomy. FAP results from germline adenomatous polyposis coli (APC) gene mutations and desmoids arise following biallelic APC mutation, with one change usually occurring distal to the second b-catenin binding/degradation repeat of the gene (39 to codon 1399). We have suggested that because families with germline mutations in this region already have the requisite change, they are more likely to develop desmoids. However, there are families with 59 germline mutations where desmoids are common. Patients and methods: We examined desmoid risk dependent on germline APC mutation, sex, history of abdominal surgery, and family history in FAP patients from the St Mark's Hospital Polyposis Registry. Results: Overall desmoid prevalence was 15%. Desmoids tended to cluster in susceptible individuals, irrespective of the germline APC mutation. Independent predictors of increased desmoid risk were: germline mutation distal to codon 1399; any family history of disease; and a strong family history of desmoids. A family history of multiple desmoids (.1) increased an individual's own risk of multiplicity. Females had twice the odds of developing desmoids compared with males. There was no significant interaction between any of the three explanatory variables. Conclusions: Our results indicate the influence of unknown genetic factors independent of APC in susceptibility to desmoid tumours in FAP. The data have implications in terms of clinical management of FAP patients and assessing the balance between chemoprevention and prophylactic colectomy.

Desmoid tumours are rare neoplasms of fibroblastic origin which arise with disproportionate frequency in patients with familial adenomatous polyposis (FAP). They are thought to develop in about 10-25% of FAP patients and may be the leading cause of death amongst those who have undergone colectomy. Risk factors include trauma, having a distal germline APC mutation, having a family history of desmoids, and probably oestrogens. In very high-risk individuals there may be a case for delay of colectomy or chemoprophylaxis at the time of surgery. Desmoids are now known to be true neoplasms but with normal telomere length and telomerase activity. FAP-associated tumours seem to carry biallelic APC mutations, one of which lies in the distal part of the gene. Such loss of wild-type APC seems to occur relatively late in tumour development. It is likely that beta-catenin plays an important role in tumourigenesis. FAP-associated desmoids tend to arise in the abdomen or abdominal wall. CT scanning gives the best information on tumour anatomy whilst T2-weighted MRI indicates likely behaviour. Treatment may simply consist of observation. Otherwise, usual first-line therapy is with sulindac with or without an anti-oestrogen. Cytotoxic chemotherapy is an option in unresectable tumours. Surgery is a reasonable first-line treatment in abdominal wall tumours but is risky for intra-abdominal tumours and may necessitate massive small bowel resection. Desmoids are the greatest remaining challenge in the management of FAP and further research into their aetiology needs to be combined with multicentre clinical trials of new treatments in order to improve management of the disease.

Surgery for intra-abdominal desmoids in selected patients is less hazardous than previously reported. Surgery for abdominal wall and extra-abdominal tumours is safe. However, disease recurrence remains a major problem.

Constitutive activation of the Wnt signaling pathway is a hallmark of many cancers, including familial adenomatous polyposis (FAP)-related desmoid tumors. Endostatin is a wellknown antiangiogenic protein that has been described recently as a potential inhibitor of this signaling pathway. Here, we show that endostatin directly induces apoptosis and inhibits the Wnt signaling pathway in colorectal cancer cell lines bearing mutations on the adenomatous polyposis coli (APC) gene as a model of FAP-related malignant cells. We then explore the relationship between apoptosis and inhibition of this pathway and show that they are not correlated. These results seem to contradict a well-recognized study, showing that reintroduction of the APC cDNA in APC-deficient cells leads to apoptosis. To reconcile our conclusions with the literature, we further show that a truncated fragment of APC capable of inhibiting the Wnt signaling pathway in SW480 cells is incapable of inducing apoptosis in these cells, confirming that APC-mediated apoptosis is uncoupled to the inhibition of the Wnt signaling pathway. Finally, we show that endostatin directly induces cell death on primary FAP-related desmoid tumor cells in culture. This phenomenon is also independent of the inhibition of the Wnt signaling pathway. Considering the current lack of effective treatment against desmoid tumors, we advocate that endostatin gene therapy represents an attractive new therapeutic approach for this disease. (Cancer Res 2006; 66(16): 8233-40)