Somatic alterations in juvenile polyps from BMPR1A and SMAD4 mutation carriers. Issue 9 (14th July 2015)

• Record Type: Journal Article
• Authors: Blatter, Robert H. E.; Plasilova, Martina; Wenzel, Friedel; Gokaslan, Sefik T.; Terracciano, Luigi; Ashfaq, Raheela; Heinimann, Karl
• Is Part Of: Genes, chromosomes & cancer. Volume 54:Issue 9(2015:Sep.)
• Page Start: 575
• Page End: 582
• Publication Date: 2015-07-14
• Subjects: Cancer -- Genetic aspects -- Periodicals; 616.994042
• DOI: 10.1002/gcc.22270
• Languages: English
• ISSNs: 1045-2257

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder predisposing to gastrointestinal hamartomatous polyps and cancer with a pathogenic <italic>SMAD4</italic> or <italic>BMPR1A</italic> germline mutation (1st‐hit) being identified in about 40–50% of patients. Little is known, however, about the occurrence and nature of somatic alterations (2nd‐hit) in <italic>SMAD4</italic>‐/<italic>BMPR1A</italic>‐related juvenile polyps. In this study, we screened 25 polyps from three patients carrying either a pathogenic <italic>SMAD4</italic> (c.1244‐1247delACAG) or <italic>BMPR1A</italic> (c.583C>T; p.Gln195*) germline mutation for somatic alterations. The <italic>SMAD4</italic>‐related polyps were also analyzed for SMAD4 protein expression by immunohistochemistry. Despite comprehensive screening for loss of heterozygosity (LOH), mutations in the coding sequence, chromosomal rearrangements, and promoter methylation, no somatic alterations could be identified in 14 <italic>SMAD4</italic>‐related polyps. SMAD4 protein expression, however, was lost in 8 (57%) of 14 juvenile polyps with 6 showing concomitant loss in both, the epithelial and stromal, compartments. In the <italic>BMPR1A</italic>‐related polyps, five out of nine (56%) displayed LOH. Further analysis of selected polyps revealed that LOH was gene copy number neutral and had occurred in the epithelial compartment. The heterogeneity of genetic mutations and protein expression levels indicates that different modes of gene inactivation can be operational in <italic><sc>SMAD4</sc></italic>‐ and <italic>BMPR1A</italic>‐related polyp formation. Our observation, that about half of <italic>BMPR1A</italic>‐related polyps displayed LOH, predominantly in the epithelial compartment, is compatible with <italic>BMPR1A</italic> acting as a tumour suppressor gene. Still, it remains to be determined whether juvenile polyp development generally requires loss of BMPR1A expression or, as observed in some <italic>SMAD4</italic>‐related polyps, can occur despite normal protein expression. © 2015 Wiley Periodicals, Inc.</p> </abstract>