Hereditary mixed polyposis syndrome (HMPS) is characterized by apparent autosomal dominant inheritance of multiple types of colorectal polyp, with colorectal carcinoma occurring in a high proportion of affected individuals. Here, we use genetic mapping, copy-number analysis, exclusion of mutations by high-throughput sequencing, gene expression analysis and functional assays to show that HMPS is caused by a duplication spanning the 3′ end of the SCG5 gene and a region upstream of the GREM1 locus. This unusual mutation is associated with increased allele-specific GREM1 expression. Whereas GREM1 is expressed in intestinal subepithelial myofibroblasts in controls, GREM1 is predominantly expressed in the epithelium of the large bowel in individuals with HMPS. The HMPS duplication contains predicted enhancer elements; some of these interact with the GREM1 promoter and can drive gene expression in vitro. Increased GREM1 expression is predicted to cause reduced bone morphogenetic protein (BMP) pathway activity, a mechanism that also underlies tumorigenesis in juvenile polyposis of the large bowel.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Whitelaw, S.C. et al. Clinical and molecular features of the hereditary mixed polyposis syndrome. Gastroenterology 112, 327–334 (1997).
Jaeger, E.E. et al. An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome. Am. J. Hum. Genet. 72, 1261–1267 (2003).
Tomlinson, I. et al. Inherited susceptibility to colorectal adenomas and carcinomas: evidence for a new predisposition gene on 15q14-q22. Gastroenterology 116, 789–795 (1999).
Jaeger, E. et al. Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nat. Genet. 40, 26–28 (2008).
Cheah, P.Y. et al. Germline bone morphogenesis protein receptor 1A mutation causes colorectal tumorigenesis in hereditary mixed polyposis syndrome. Am. J. Gastroenterol. 104, 3027–3033 (2009).
East, J.E., Saunders, B.P. & Jass, J.R. Sporadic and syndromic hyperplastic polyps and serrated adenomas of the colon: classification, molecular genetics, natural history, and clinical management. Gastroenterol. Clin. North Am. 37, 25–46, v (2008).
Colella, S. et al. QuantiSNP: an Objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data. Nucleic Acids Res. 35, 2013–2025 (2007).
Tomlinson, I.P. et al. COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer. Br. J. Cancer 102, 447–454 (2010).
Kosinski, C. et al. Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc. Natl. Acad. Sci. USA 104, 15418–15423 (2007).
Segditsas, S. et al. Putative direct and indirect Wnt targets identified through consistent gene expression changes in APC-mutant intestinal adenomas from humans and mice. Hum. Mol. Genet. 17, 3864–3875 (2008).
Tomlinson, I.P. et al. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. PLoS Genet. 7, e1002105 (2011).
Tian, Q., He, X.C., Hood, L. & Li, L. Bridging the BMP and Wnt pathways by PI3 kinase/Akt and 14-3-3ζ. Cell Cycle 4, 215–216 (2005).
Hobert, J.A. & Eng, C. PTEN hamartoma tumor syndrome: an overview. Genet. Med. 11, 687–694 (2009).
Venkatachalam, R. et al. Identification of candidate predisposing copy number variants in familial and early-onset colorectal cancer patients. Int. J. Cancer 129, 1635–1642 (2011).
Papaemmanuil, E. et al. Deciphering the genetics of hereditary non-syndromic colorectal cancer. Eur. J. Hum. Genet. 16, 1477–1486 (2008).
Zuniga, A. et al. Mouse limb deformity mutations disrupt a global control region within the large regulatory landscape required for Gremlin expression. Genes Dev. 18, 1553–1564 (2004).
Howe, J.R. et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat. Genet. 28, 184–187 (2001).
Howe, J.R. et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280, 1086–1088 (1998).
Lo, H.S. et al. Allelic variation in gene expression is common in the human genome. Genome Res. 13, 1855–1862 (2003).
Poulsom, R., Longcroft, J.M., Jeffery, R.E., Rogers, L.A. & Steel, J.H. A robust method for isotopic riboprobe in situ hybridisation to localise mRNAs in routine pathology specimens. Eur. J. Histochem. 42, 121–132 (1998).
Miele, A., Gheldof, N., Tabuchi, T.M., Dostie, J. & Dekker, J. Mapping chromatin interactions by chromosome conformation capture. Curr. Protoc. Mol. Biol. Chapter 21, Unit 21.11 (2006).
We are grateful to all the study subjects and their relatives from the families with HMPS and to those who have provided their medical care. We are particularly grateful to those who have provided samples from endoscopy or operation. We acknowledge the invaluable roles of all colleagues who have worked on HMPS in the nearly 50 years since it was first described. The following institutions and/or individuals have generously provided samples or resources for this project over the years, and are therefore regarded as part of the broad HMPS Consortium: Maggie Stevens, Carole Cummings and colleagues (St Mark's Hospital Family Cancer Clinic); members of St Mark's Hospital Polyposis Registry; members of St Mark's Hospital Endoscopy Unit; Ian Talbot, Thomas Guenther and colleagues (St Mark's Hospital Histopathology Department); Ghislaine Davies (Wycombe General Hospital Endoscopy Department); Maggie Gorman and colleagues (Molecular and Population Genetics Laboratory, University of Oxford); Peter Zauber (St Barnabas, New Jersey); Carrie Melvin Drovdlic and Charis Eng (Ohio State University); Melissa Southey (University of Melbourne); Paul Rozen (Tel Aviv Medical Center); Rosemary Jeffery, Richard Poulsom and colleagues (Cancer Research UK London Research Institute In Situ Hybridisation Service); and Sally Cottrell, Andrew Rowan, Walter Bodmer and colleagues (ICRF Cancer Genetics Laboratory). We also gratefully acknowledge the support of the Ashkenazi Bowel Cancer study committee. This work was principally funded by Cancer Research UK. We also acknowledge core funding to the Wellcome Trust Centre for Human Genetics from the Wellcome Trust (090532/Z/09/Z).
The authors declare no competing financial interests.
About this article
Cite this article
Jaeger, E., Leedham, S., Lewis, A. et al. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat Genet 44, 699–703 (2012). https://doi.org/10.1038/ng.2263
Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell
Intronic Breakpoint Signatures Enhance Detection and Characterization of Clinically Relevant Germline Structural Variants
The Journal of Molecular Diagnostics (2021)
Bone Morphogenetic Protein pathway antagonism by Grem1 Regulates Epithelial Cell Fate in Intestinal Regeneration
Oral Diseases (2021)
SNPs associated with colorectal cancer at 15q13.3 affect risk enhancers that modulate GREM1 gene expression
Human Mutation (2021)