Direct genetic testing for Smad4 mutations in patients at risk for juvenile polyposis

• Published in: Surgery Vol. 126; no. 2; pp. 162 - 170
• Main Authors: Howe, James R., Ringold, John C., Hughes, Jonathan H., Summers, Robert W.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Mosby, Inc 01-08-1999; Elsevier
• Subjects: Adolescent; Adult; Aged; Biological and medical sciences; Child; Colectomy; Colonic Polyps - genetics; Colonic Polyps - surgery; DNA-Binding Proteins - genetics; Gastroenterology. Liver. Pancreas. Abdomen; Genetic Counseling; Germ-Line Mutation; Heterozygote; Humans; Medical sciences; Middle Aged; Polymorphism, Single-Stranded Conformational; Risk; Smad4 Protein; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Trans-Activators - genetics; Tumors; Human; Family study; Juvenile character; Medical screening; Polyposis; Gene; Digestive diseases; Intestinal disease; Genetics; Benign neoplasm; Colon; Endoscopy; Mutation; Therapeutic protocol
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1016/S0039-6060(99)70150-9

Background: The identification of germline mutations in juvenile polyposis (JP) families has made presymptomatic genetic testing possible. In this study we report the results of genetic testing in two large JP families and develop an algorithm for the clinical management of these patients.
Methods: DNA was extracted from 55 members of 2 JP kindreds, and the Smad4 mutations in the germline were determined by direct sequencing. All family members were then tested for mutations with use of single-strand conformational polymorphism analysis and were invited for genetic counseling.
Results: All 18 affected members of both kindreds had a 4-bp deletion in exon 9 of the Smad4 gene. In 30 patients at risk for JP, 17 had previously had negative endoscopic screening results and 13 had never been screened. Five patients at risk had inherited germline Smad4 mutations. Two carriers have had hematochezia but have not been screened, whereas 3 were asymptomatic. The mean age of carriers was 29.8 years (range 9.1-49.5 years), whereas that of noncarriers was 41.0 years (range 8.1-76.5 years).
Conclusions: Compliance has been a problem with endoscopic screening for JP. With genetic testing noncarriers may no longer require frequent screening endoscopy, whereas gene carriers can be targeted for close endoscopic surveillance and early intervention to prevent the development of gastrointestinal cancers. Direct genetic testing significantly improves the presymptomatic diagnosis of gene carriers in JP families with Smad4 mutations. (Surgery 1999;126:162-70.)