Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes |
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| Authors: | Zhou X P Woodford-Richens K Lehtonen R Kurose K Aldred M Hampel H Launonen V Virta S Pilarski R Salovaara R Bodmer W F Conrad B A Dunlop M Hodgson S V Iwama T Järvinen H Kellokumpu I Kim J C Leggett B Markie D Mecklin J P Neale K Phillips R Piris J Rozen P Houlston R S Aaltonen L A Tomlinson I P Eng C |
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| Affiliation: | Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center, and the Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA. |
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| 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. |
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