Germline bone morphogenesis protein receptor 1A mutation causes colorectal tumorigenesis in hereditary mixed polyposis syndrome.
OBJECTIVE
Hereditary mixed polyposis syndrome (HMPS) is characterized by polyps of mixed adenomatous/hyperplastic/atypical juvenile histology that are autosomal dominantly inherited and that eventually lead to colorectal cancer (CRC). Although CRC with adenomatous polyps is initiated by inactivating adenomatous polyposis coli (APC), the initiating event of CRC with mixed polyps remains unclear. We aimed to identify the underlying germline defect in HMPS.


METHODS
We screened for bone morphogenesis protein receptor 1A (BMPR1A) mutation by exonic sequencing, reverse-transcriptase polymerase chain reaction (PCR) followed by cDNA sequencing, and multiplex ligation-dependent probe amplification (MLPA) analysis in eight Singapore Chinese HMPS families.


RESULTS
Germline BMPR1A defects were found in four (50%) families. In two families, it is shown to co-segregate with the disease phenotype in all affected members over three generations, indicating that it is the disease-causing mutation. CRC incidence is 75%. The most defining characteristic is the presence of mixed hyperplastic-adenomatous polyps. Juvenile polyps are rarely reported, and if present, are usually of mixed components. Detailed histology of the polyps from one patient over 11 years distinguishes HMPS from juvenile polyposis syndrome (JPS). We report further the first cases of Wilms' tumor and papillary thyroid carcinoma associated with BMPR1A germline defect.


CONCLUSIONS
Germline BMPR1A defect is the disease-causing mutation in 50% of the HMPS families. If patients present with mixed morphology polyps in the large bowel that are autosomal dominantly inherited and corresponding absence of upper gastrointestinal abnormalities, the gene to begin mutation screening should be BMPR1A rather than APC.
Cheah
Peh Yean
PY
Department of Colorectal Surgery, Singapore General Hospital, Singapore. cheah.peh.yean@sgh.com.sg
Wong
Yu Hui
YH
Chau
Yuk Ping
YP
Loi
Carol
C
Lim
Kiat Hon
KH
Lim
Jit Fong
JF
Koh
Poh Koon
PK
Eu
Kong Weng
KW
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D018076:DNA, Complementary / Q000032:analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D021141:Nucleic Acid Amplification Techniques; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012042:Registries; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012846:Singapore; D051901:Smad4 Protein / Q000235:genetics
D018076:DNA, Complementary; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human