Germline mutations in BMPR1A/ALK3 cause a subset of cases of Juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes
Zhou XP., Woodford-Richens K., Lehtonen R., Kurose K., Aldred M., Hampel H., Launonen V., Virta S., Pilarski R., Salovaara R., Bodmer WF., Conrad BA., Dunlop M., Hodgson SV., Iwama T., Järvinen H., Kellokumpu I., Kim JC., Leggett B., Markie D., Mecklin JP., Neale K., Phillips R., Piris J., Rozen P., Houlston RS., Aaltonen LA., Tomlinson IPM., Eng C.
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 β-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.