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Updated: Jun 8, 2026
A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
Published on: July 6, 2017
Evaluation of germline BMP4 mutation as a cause of colorectal cancer
Steven J Lubbe1, Alan M Pittman, Cornelis Matijssen
1Institute of Cancer Research, Sutton, UK.
Abstract:
Transforming growth factor-β (TGF-β) signalling plays a key role in colorectal cancer (CRC). Bone morphogenetic protein-4 (BMP4) is a member of the TGF-β family of signal transduction molecules. To examine if germline mutation in BMP4 causes CRC we analysed 504 genetically enriched CRC cases (by virtue of early-onset disease, family history of CRC) for mutations in the coding sequence of BMP4. We identified three pathogenic mutations, p.R286X (g.8330C>T), p.W325C (g.8449G>T) and p.C373S (g.8592G>C), amongst the CRC cases which were not observed in 524 healthy controls. p.R286X localizes to the N-terminal of the TGF-β1 prodomain truncating the protein prior to the active domain. p.W325C and p.C373S mutations are predicted from protein homology modelling with BMP2 to impact deleteriously on BMP4 function. Segregation of p.C373S with adenoma and hyperplastic polyp in first-degree relatives of the case suggests germline mutations may confer a juvenile polyposis-type phenotype. These findings suggest mutation of BMP4is a cause of CRC and the value of protein-based modelling in the elucidation of rare disease-causing variants.
Insights
Germline mutations in Bone morphogenetic protein-4 (BMP4) are identified as a cause of colorectal cancer (CRC). These BMP4 mutations may also be linked to a juvenile polyposis-like phenotype, suggesting a broader role in gastrointestinal polyposis.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- Transforming growth factor-β (TGF-β) signaling is crucial in colorectal cancer (CRC) development.
- Bone morphogenetic protein-4 (BMP4), a member of the TGF-β superfamily, has an uncharacterized role in CRC pathogenesis.
Purpose of the Study:
- To investigate whether germline mutations in the BMP4 gene contribute to the development of colorectal cancer.
- To analyze the functional impact of identified BMP4 mutations using protein homology modeling.
Main Methods:
- Genetic analysis of the BMP4 coding sequence in 504 CRC cases with a strong family history or early-onset disease.
- Screening of 524 healthy controls for comparison.
- Protein homology modeling using BMP2 as a reference to predict the functional consequences of BMP4 mutations.
Main Results:
- Three pathogenic germline mutations in BMP4 (p.R286X, p.W325C, p.C373S) were identified in CRC cases but not in controls.
- The p.R286X mutation truncates the BMP4 protein before its active domain.
- p.W325C and p.C373S mutations are predicted to impair BMP4 function, and p.C373S segregated with adenoma and hyperplastic polyps in a family, suggesting a juvenile polyposis-like phenotype.
Conclusions:
- Germline mutations in BMP4 are a novel cause of colorectal cancer.
- Protein homology modeling is a valuable tool for understanding the impact of rare genetic variants.
- BMP4 mutations may be associated with a spectrum of gastrointestinal polyposis, including CRC and potentially juvenile polyposis.
