Juvenile polyposis syndrome (JPS) is a syndrome characterized by the appearance of multiple polyps in the gastrointestinal tract, usually in a child, adolescent or young adults. While the majority of the polyps found in Juvenile Polyposis Syndrome are non-neoplastic, hamartomatous, self-limiting and benign, there is an increased risk of adenocarcinoma. JPS can occur sporadically in families or be inherited in an autosomal dominant manner.
The SMAD4 gene provides instructions for making a protein involved in transmitting chemical signals from the cell surface to the nucleus. This signaling pathway, called the transforming growth factor beta (TGF-β) pathway, allows the environment outside the cell to affect how the cell produces other proteins. The signaling process begins when a TGF-β protein attaches to a receptor on the cell surface, which activates a group of related SMAD proteins. The SMAD proteins bind to the SMAD4 protein and form a protein complex, which then moves to the cell nucleus. In the nucleus, the SMAD protein complex binds to specific areas of DNA where it controls the activity of particular genes and regulates cell growth and division. By controlling gene activity and regulating cell proliferation, the SMAD4 protein serves both as a transcription factor and as a tumor suppressor. Transcription factors help control the activity of particular genes, and tumor suppressors keep cells from growing and dividing too fast or in an uncontrolled way.
The BMPR1A gene provides instructions for making a protein called bone morphogenetic protein receptor 1A. Specifically, the BMPR1A protein attaches to ligands in the transforming growth factor beta (TGF-β) pathway. This signaling pathway allows the environment outside the cell to affect how the cell produces other proteins. The BMPR1A receptor protein and its ligands are involved in transmitting chemical signals from the cell membrane to the nucleus. When the BMPR1A protein is bound to a ligand, it activates a group of related protein called SMAD proteins. The activated SMAD protein complex is then transported into the cell's nucleus, where it regulates cell growth and division and the activity of particular genes.
||Over 60 known variants of BMPR1A associated with JPS. Mutations result in the production of a nonfunctional protein. As a result, the BMPR1A protein cannot bind to ligands in the TGF-β pathway. This disruption in binding interferes with the activation of the SMAD protein complex. This inactive complex is not transported to the nucleus, where it is needed to regulate cell growth and the activity of certain genes, which leads to polyp formation.
60 known variants of SMAD4 associated with JPS. Mutations cause a short, non-functional protein. A lack of functional SMAD4 protein prevents activation and cannot be transported to the nucleus, where it is needed to regulate cell proliferation and the activity of certain genes. This unregulated cell growth can lead to polyp formation.
Purpose: Confirm a genetic basis for cancer/Identify at-risk family members
Methodology: Next-Generation Sequencing
Test Requisition: Sequencing Requisition
Specimen Requirements: 2-5 mL Blood-Lavender Top Tube
Panel CPT Codes: 81479, 81406 Cost: $1080.00 (Oklahoma Medicaid requires preauthorization for this test)
Turn-around-time: 5 weeks
1. Calva-Cerqueira D, Chinnathambi S, Pechman B, Bair J, Larsen-Haidle J, Howe JR.(2009) "The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis". Clin Genet. 75(1):79-85.
2. Chow E, Macrae F. (2005) "A review of juvenile polyposis syndrome". J Gastroenterol Hepatol. 20(11):1634-40. Review.
3. Woodford-Richens KL, Rowan AJ, Poulsom R, Bevan S, Salovaara R, Aaltonen LA, Houlston RS, Wright NA, Tomlinson IP. (2001) "Comprehensive analysis of SMAD4 mutations and protein expression in juvenile polyposis: evidence for a distinct genetic pathway and polyp morphology in SMAD4 mutation carriers". Am J Pathol. Oct;159(4):1293-300.