The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations

Abstract

Background: Juvenile polyposis (JP) is an autosomal dominant syndrome predisposing to colorectal and gastric cancer. We have identified mutations in two genes causing JP, MADH4 and bone morphogenetic protein receptor 1A (BMPR1A): both are involved in bone morphogenetic protein (BMP) mediated signalling and are members of the TGF-b superfamily. This study determined the prevalence of mutations in MADH4 and BMPR1A, as well as three other BMP/activin pathway candidate genes in a large number of JP patients. Methods: DNA was extracted from the blood of JP patients and used for PCR amplification of each exon of these five genes, using primers flanking each intron-exon boundary. Mutations were determined by comparison to wild type sequences using sequence analysis software. A total of 77 JP cases were sequenced for mutations in the MADH4, BMPR1A, BMPR1B, BMPR2, and/or ACVR1 (activin A receptor) genes. The latter three genes were analysed when MADH4 and BMPR1A sequencing found no mutations. Results: Germline MADH4 mutations were found in 14 cases (18.2%) and BMPR1A mutations in 16 cases (20.8%). No mutations were found in BMPR1B, BMPR2, or ACVR1 in 32 MADH4 and BMPR1A mutation negative cases. Discussion: In the largest series of JP patients reported to date, the prevalence of germline MADH4 and BMPR1A mutations is approximately 20% for each gene. Since mutations were not found in more than half the JP patients, either additional genes predisposing to JP remain to be discovered, or alternate means of inactivation of the two known genes are responsible for these JP cases.

Bone Morphogenetic Proteins and Signaling Pathway in Inflammatory Bowel Disease

“…In a genotypephenotype correlation study of JP patients, a significant prevalence of gastric polyposis was found in patients with Smad4 mutations when compared to other subsets of patients (Friedel et al, 2002). Histologically, JP polyps are characterized by dilated glands, abundant stroma and inflammatory infiltrates in a thickened lamina propria with normal epithelial covering (Howe et al, 2004). SMAD4 is a known tumor suppressor gene in pancreatic and colon cancer, but in JP it was hypothesized that SMAD4 gene acts as a susceptibility gene, a "gatekeeper", its loss of function resulting in polyp formation through indirect mechanisms, suggesting an important role of the stromal inflammatory response in the regulation of epithelial tumorigenesis (Moskaluk et al, 1997;Takagi et al, 1996).…”

Signaling Receptors for TGF-β Family Members

“…Germline loss-of-function mutations in the ALK3 gene has been observed in 20% -25% of JPS patients (Howe et al 2001(Howe et al , 2004. BMP signaling is known to antagonize Wnt pathway function in the intestinal stem-cell compartment, causing a balanced generation of intestinal stem cells during the life span of the intestinal epithelium (He et al 2004).…”

Stromal inactivation of BMPRII leads to colorectal epithelial overgrowth and polyp formation

“…Germline mutations in BMPRIA and Smad4 have been identified in patients with juvenile polyposis, an autosomal-dominant condition characterized by gastrointestinal hamartomatous polyps and a predisposition for colorectal cancer (Howe et al, 1998(Howe et al, , 2004. Inhibition of BMP activity in mice via transgenic expression of noggin in the intestinal epithelium leads to formation of ectopic crypts and a histologic phenotype similar to human juvenile polyposis in both small and large intestine (Haramis et al, 2004;Batts et al, 2006).…”