Germline Mutations in BMPR1A/ALK3 Cause a Subset of Cases of Juvenile Polyposis Syndrome and of Cowden and Bannayan-Riley-Ruvalcaba Syndromes*

Abstract

Juvenile polyposis syndrome (JPS) is an inherited hamartomatous-polyposis syndrome with a risk for colon cancer. JPS is a clinical diagnosis by exclusion, and, before susceptibility genes were identified, JPS could easily be confused with other inherited hamartoma syndromes, such as Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden syndrome (CS). Germline mutations of MADH4 (SMAD4) have been described in a variable number of probands with JPS. A series of familial and isolated European probands without MADH4 mutations were analyzed for germline mutations in BMPR1A, a member of the transforming growth-factor beta-receptor superfamily, upstream from the SMAD pathway. Overall, 10 (38%) probands were found to have germline BMPR1A mutations, 8 of which resulted in truncated receptors and 2 of which resulted in missense alterations (C124R and C376Y). Almost all available component tumors from mutation-positive cases showed loss of heterozygosity (LOH) in the BMPR1A region, whereas those from mutation-negative cases did not. One proband with CS/CS-like phenotype was also found to have a germline BMPR1A missense mutation (A338D). Thus, germline BMPR1A mutations cause a significant proportion of cases of JPS and might define a small subset of cases of CS/BRRS with specific colonic phenotype.

The Activation of MEK/ERK Signaling Pathway by Bone Morphogenetic Protein 4 to Increase Hepatocellular Carcinoma Cell Proliferation and Migration

“…The loss of BMPR1A leads to embryonic lethality (31,32), but it is still not possible to distinguish between unique or redundant functions of BMPR1A and BMPR1B in the later stages of human development. Germ line mutations of BMPR1A have been associated with juvenile polyposis in humans and produce a significantly higher risk of gastrointestinal cancer (33). BMPR1B homozygous null mice are viable; however, mutants exhibit skeletal defects (34), and BMPR1B is epigenetically silenced in some patientderived tumor-initiating glioblastoma cell lines (35).…”

A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response

“…The BMP-Smad1 cascade has emerged as a novel tumour suppression pathway, but its pathological mechanisms remain elusive [21][22][23][25][26][27] . This study, by establishing Smad1 as a player in cell response to DNA damage, a major driving force of oncogenesis, and linking BMP-Smad1 signalling to the prominent Atm-p53 tumour suppression pathway 4,40,41 , unveils one such mechanism.…”

PTEN-deficient intestinal stem cells initiate intestinal polyposis

“…The roles of PTEN and Akt in intestinal homeostasis and polyposis have not been defined, but there is evidence that they could be key players in the interplay between BMP and Wnt signals. Mutation of BMPR1A can result in a Cowden-like syndrome resembling loss of PTEN 17 . BMP signaling may in part be mediated by inhibition of PI3K-Akt activity via positive regulation of PTEN 9,18,19 .…”