If you or someone you know may have Hereditary Mixed Polyposis Syndrome, there is some interesting news from the research world that is worth knowing about.
What is Hereditary Mixed Polyposis Syndrome?
Hereditary Mixed Polyposis Syndrome (HMPS) is a very rare inherited cancer predisposition syndrome in which a significant number of polyps develop in the large bowel (colon and rectum) in affected individuals. Also, many of these affected individuals develop colorectal cancer.
A good gastrointestinal pathologist is critical to assisting a Clinical Geneticist or Gastroenterologist in making a proper diagnosis, because it is the nature of how the polyp tissue looks under the microscope that is key to making the diagnosis and differentiating from some other similar and partially overlapping genetic syndromes. Individuals with HMPS tend to develop multiple types of colorectal polyps (often at a relatively young age), including those called adenomas, juvenile polyps, serrated lesions, and others including polyps that have mixed appearances intermediate between two of these polyp types.
HMPS is thought to be inherited in an autosomal dominant manner. This means that children of an affected individual have a 50 percent chance of inheriting the condition.
At Least Two Distinct Genetic Causes for Hereditary Mixed Polyposis Syndrome
It now appears that a disease-causing genetic change impacting one of at least two (and possible more) genes can cause Hereditary Mixed Polyposis Syndrome. The first HMPS gene to be identified was BMPR1A (see link to PubMed abstract for study in “Selected References” below). Mutations in BMPR1A were shown to be the cause of Hereditary Mixed Polyposis Syndrome in a study of 2 Singaporean families (only 1 family had a clearly identifiable and deleterious mutation of BMPR1A in that study, although genetic linkage studies in both families pointed researchers to the area of chromosome 10 where the gene is located and the researchers did not look for certain types of gene mutations [deletions and duplications] in the other family).
Notably, certain BMPR1A mutations were already known to be one cause of a related and overlapping condition called Juvenile Polyposis Syndrome. Thus, it appears that individuals who are born with BMPR1A mutations can have polyps that are consistent with a diagnosis of Juvenile Polyposis Syndrome or – in some cases – Hereditary Mixed Polyposis Syndrome.
Although the Singaporean family was the first HMPS family to have a specific genetic mutation identified, Dr. Ian Tomlinson and colleagues had been looking for a cause of HMPS in families that happened also to be of Ashkenazi Jewish heritage for quite some time. Dr. Tomlinson and his colleagues previously showed with genetic mapping techniques that in several Ashkenazi Jewish families with HMPS, the condition was due to an unknown genetic change in a specific area of chromosome 15. Of note, all of the affected individuals in these famlies inherited the same “haplotype” in this region. In layman’s terms, this means that the affected individuals in these families all inherited the same short segment of chromosome 15 from a distant, but shared, common ancestor.
New Research Suggests the GREM1 Gene May Be the Cause of Hereditary Mixed Polyposis Syndrome in Some Families of Jewish Descent
(Note: this section is somewhat technical. If you are not interested in all the details or if you find it to be too technical, you may want to just skip to the following section)
In a new research paper published online in the journal Nature Genetics, Dr. Emma Jaeger, Dr. Simon Leedham, Dr. Tomlinson, and colleagues report the work that they’ve now done to narrow down the genetic cause of Hereditary Mixed Polyposis Syndrome in the Ashkenazi Jewish families that they’ve been studying. A great deal of work has led to what appears to be the true genetic cause of the condition in these families.
Not surprisingly, one of the first things that they did was sequence the 3 genes in the short region of chromosome 15 that was shared from a common ancestor in several affected individuals from these families. There were no potentially causative mutations in these genes (GREM1, SCG5, and FMN1).
Reasoning that a large-scale rearrangement of the DNA sequence or copy number change might be causative, they found that affected individuals had a duplication of a DNA segment including the tail end of the SCG5 gene extending towards the beginning of the GREM1 gene.
Given the complexity of this particular change in the genome of the patients, they had some work to do in order to be relatively sure that it was behind the HMPS in the families.
First, they noted that this duplication was found in two of the initially tested family members with HMPS and none of the 3 unaffected relatives that they tested.
Then, since the duplication involved an area from the middle of the SCG5 gene to quite close to the start of the GREM1 gene, it was possible that this duplication could be causing the condition by one of several mechanisms involving the SCG5 gene, the GREM1 gene, or both. As the duplication involved a portion of SCG5, they looked to see whether any aberrant SCG5 messenger RNA transcripts were produced; however, apparently there were none.
They then looked to see whether the duplication led to changes in gene transcription levels (i.e., the amount of messenger RNA produced) from any of the 3 nearby genes. For this analysis, they looked at the amount of mRNA for the three genes in colon crypt tissue from colonoscopy biopsies from several affected individuals from the families with HMPS, several unrelated individuals with normal colonoscopies and one individual from the HMPS families who was unaffected. The GREM1 mRNA levels were massively elevated in the patients with HMPS compared to normal colonic biopsies and the unaffected family member. There were no significant differences in mRNA levels from the other genes. The abnormal elevation of GREM1 mRNA levels was characterized in several other ways that are beyond the scope of this post, but which may ultimately prove interesting for developing a better understanding of the molecular mechanisms of development of HMPS.
Bottom Line for Individuals and Families with Polyps and Clinical Features that May be Consistent with Hereditary Mixed Polyposis Syndrome
1. The new research paper by Jaeger et al appears to have pinned down a second genetic cause for Hereditary Mixed Polyposis Syndrome.
2. This specific new finding is most relevant at this time to individuals and families with Ashkenazi Jewish ancestry who have clinical features suggestive of Hereditary Mixed Polyposis Syndrome. If you have Ashkenazi Jewish ancestry and have previously been told by a physician that you have may have Hereditary Mixed Polyposis Syndrome, this new finding may be worth discussing with them at your next appointment.
3. It will be interesting to see whether mutations in GREM1 itself are ultimately found to be causative of HMPS in other families. These could plausibly be of distinct types – different duplications, mutations in enhancers or other regulatory sequences, or perhaps mutations within the GREM1 gene coding sequence. If Dr. Tomlinson and colleagues are correct about increased (and ectopic) overexpression of GREM1 being responsible for the development of HMPS in these families, other genetic and genomic alterations leading to this are likely to impact development of HMPS and potentially colorectal cancer.
4. Because of the nature of the particular genetic change causing the condition in the Ashkenazi Jewish families that Dr. Tomlinson and colleagues studied, clinical laboratory testing for the HMPS-causing duplication may be a bit slow to emerge. Nevertheless, in families with HMPS and Ashkenazi Jewish ancestry, it should be quite technically feasible to test for the duplication as an aid to identifying individuals at risk within the family.
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. Nature Genetics 2012 (published online before print May 6 2012)
Cao X, Eu KW, Kumarasinghe MP, et al. Mapping of hereditary mixed polyposis syndrome (HMPS) to chromosome 10q23 by genomewide high-density single nucleotide polymorphism (SNP) scan and identification of BMPR1A loss of function. Journal of Medical Genetics 2006; 43:e13.
Howe JR, Bair JL, Sayed MG et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nature Genetics 2001; 28:184-7.