TY - JOUR T1 - Explaining differences in the severity of familial adenomatous polyposis and the search for modifier genes JF - Gut JO - Gut SP - 1 LP - 5 DO - 10.1136/gut.48.1.1 VL - 48 IS - 1 AU - R HOULSTON AU - M CRABTREE AU - R PHILLIPS AU - M CRABTREE AU - I TOMLINSON Y1 - 2001/01/01 UR - http://gut.bmj.com/content/48/1/1.abstract N2 - Familial adenomatous polyposis (FAP) has become the focus of several convergent lines of scientific and medical enquiry. The year 2000 has seen the completion of the human genome project and this coincides with the next major challenge of cancer genetics, non-mendelian inheritance. Colorectal cancer remains a major source of morbidity and mortality in developed countries. Despite huge advances in understanding the pathology of the disease, its mortality has remained virtually unchanged in 50 years. The disease is curable if detected early, yet screening strategies for the general population have been largely unsuccessful. FAP is a superb model for sporadic colorectal cancer. If the genetic and other causes of variation in the FAP phenotype can be understood, this knowledge will have a dividend for the general population and may lead to new approaches for screening for colorectal cancer. This article discusses current knowledge of how the clinical features of FAP patients vary, with emphasis on the role of modifier genes, and discusses strategies for their identification.FAP (OMIM 175100) is an autosomal dominant disorder with a population frequency of approximately 1 in 8000 and a penetrance of almost 100%. The disease is typified by florid adenomatous polyposis of the colon and rectum, although a less severe variant, attenuated adenomatous polyposis (AAPC), also exists. Patients typically present with hundreds to thousands of polyps in the colon. The minimum number for a diagnosis of classical FAP is 100. Progression of one or more of these polyps to carcinoma is almost inevitable unless prophylactic colectomy is undertaken. In addition, FAP is characterised by a number of extracolonic manifestations in some individuals: congenital hypertrophy of the retinal pigment epithelium (CHRPE); epidermoid skin cysts and benign craniofacial and long bone tumours (Gardner's syndrome); fibrous tumours (desmoids) classically sited in the retroperitoneum and abdominal wall; and upper … ER -