Evidence for genetic predisposition to desmoid tumours in familial adenomatous polyposis independent of the germline APC mutation

Abstract

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.

Efficacy of Imatinib in Aggressive Fibromatosis: Results of a Phase II Multicenter Sarcoma Alliance for Research through Collaboration (SARC) Trial

“…They are rare tumors, occurring in two to four people per million, either sporadically or in association with Gardner's syndrome or familial adenomatous polyposis (FAP; refs. [1][2][3][4][5]. Although benign by definition, their propensity to recur locally and invade nearby structures can result in significant morbidity.…”

Sporadic desmoid tumor in an Ashkenazi patient homozygous for theAPC*I1307Kgene mutation

“…Loss of APC protein control may result in accumulation of beta-catenin protein and increased expression of several proliferation genes controlling cell adhesion and cell signaling. Desmoid tumors are frequent in FAP patients with germ line APC gene mutations occurring beyond codon 1309, particularly in the region of codons 1445Á1578 [4,5]. Latchford et al demonstrated both germ line and somatic APC mutations in 17 of 32 FAP patients with demoid tumors but did not report beta-catenin gene analyses on these tumors [6].…”

A Rare Case of Desmoid Tumor of Thigh

“…Despite their benign histologic appearance and negligible metastatic potential, the tendency of desmoid tumors to cause local infiltration is significant in terms of [1] deformity, morbidity, and mortality resulting from pressure effects and [2] potential obstruction of vital structures and organs. Although desmoid tumors most commonly arise from the rectus abdominis muscle in postpartum period and in scars due to abdominal surgery.…”