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.
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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.
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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) doi:10.1038/ng.2263
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