Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1

Abstract

The hereditary mixed polyposis syndrome (HMPS) was first described about 50 years ago in a large Ashkenazi Jewish family from St Mark’s Hospital, London. The family showed apparent autosomal dominant inheritance of multiple types of colorectal polyp, with colorectal carcinoma in a high proportion of individuals. In the last 15 years, we have mapped the HMPS gene to chromosome 15q13.3 and identified an ancestral haplotype common to all the known HMPS families. Here, we have used 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 large duplication spanning the 3′ end of the SCG5 gene and a region upstream of the GREM1 locus. This mutation has no effect on SCG5 expression, but is associated with greatly increased, allele-specific GREM1 expression. Whilst GREM1 is expressed in intestinal sub-epithelial myofibroblasts in controls, HMPS patients predominantly express GREM1 in the epithelium of the large bowel. The HMPS duplication contains predicted transcriptional enhancer elements; we have shown that some of these interact with the GREM1 promoter and are capable of driving gene expression in vitro. Increased GREM1 expression is predicted to lead to reduced bone morphogenetic protein pathway activity, a mechanism that also underlies tumorigenesis in juvenile polyposis of the large bowel. The pathogenic mechanism in HMPS is extremely unusual in Mendelian cancer syndromes and highlights ectopic gene expression as a mechanism of tumorigenesis.

GREM1 and POLE variants in hereditary colorectal cancer syndromes

“…The GREM1 duplication also confirms that alterations of regions giving rise to amplifications and up‐regulation of expression can have an effect on tumor initiation also in germ‐line cells. The genotype, phenotype, and also the increased expression levels of GREM1 in our family give further support to the suggested role of activation of GREM1 as a cause of initiation and development of colorectal tumors (Jaeger et al, 2012; Davis et al, 2015). …”

“…The disease haplotype is 3.7 Mb and is located between rs12912234 and rs2928022. Several genes are located in this region, among them the SCG5 gene, in which a duplication leading to a higher expression of the GREM1 gene has been found in a large HMPS family (Jaeger et al, 2012). Analysis of CNVs in the SCG5 and GREM1 gene regions by MLPA on the same individuals as those analyzed by whole exome sequencing revealed a duplication of approximately 20 kb in affected family members.…”

“…In our study an activating 16 kb duplication was found upstream of GREM1 . A duplication of approximately 40 kb of an upstream region containing parts of the SCG5 gene and also a region between, but not the GREM1 gene itself, has recently been shown to over express GREM1 in colorectal epithelium (Jaeger et al, 2012; Davis et al, 2015). The GREM1 gene encodes the secreted BMP antagonist Gremlin.…”

“…Ligands binding to BMP receptors are involved in the driving process of this pathway. Increased levels of GREM1 are expected to reduce BMP ligand levels and it is suggested that the cell favors a more stem cell‐like phenotype (Jaeger et al, 2012). The duplication which segregates with the disease phenotype in our family is about half the size (16.2 kb) of the duplication reported by Jaeger et al (2012), but includes the same enhancer element that cause the increased GREM1 expression in this larger duplication (Fig.…”

“…The genetic cause of this syndrome is still to a large extent unknown but a duplication of 40 kb including the 3′ region of the SCG5 gene and upstream region of GREM1 has been described as the disease‐causing mutation in families of Ashkenazi descent (Jaeger et al, 2012). …”