GREM1 Duplication Analysis

A large duplication upstream of GREM1 is associated with hereditary mixed polyposis syndrome (HMPS).  Individuals with HMPS are predisposed to multiple types of colorectal polyps and colorectal cancer.  

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A large duplication upstream of GREM1 is associated with hereditary mixed polyposis syndrome (HMPS).  Individuals with HMPS are predisposed to multiple types of colorectal polyps and colorectal cancer.  

Disease Name 
Colorectal cancer
Polyposis
Disease Information 

Hereditary mixed polyposis syndrome (HMPS) is an autosomal dominantly inherited syndrome associated with multiple types of colorectal polyps, including adenomas, serrated polyps, juvenile polyps, and Peutz-Jeghers polyps. Individuals with HMPS also have increased risk for colorectal cancer (CRC), but do not seem to develop extra-colonic cancers or other clinical features.1

Recently, a large duplication of approximately 40kb located upstream of GREM1 has been identified in hereditary mixed polyposis families of Ashkenazi Jewish descent. This duplication was demonstrated to increase ectopic GREM1 expression.2 The gremlin 1 (GREM1) gene is a bone morphogenic protein (BMP) antagonist, which plays a role in organogenesis, body patterning, and tissue differentiation.

To date, only this founder mutation has been reported, but the possibility of GREM1 mutations in individuals of other ethnicities has not been excluded. At this time, manifestations of the GREM1 duplication appear to be limited to the intestinal tract and include mixed morphology colorectal polyps and cancer; however, lifetime risk estimates for mutation carriers are not currently available.2,3

Testing Benefits & Indication 

Genetic testing is useful to determine the cause of cancer and/or polyposis in symptomatic individuals and for testing of at-risk family members. Genetic testing may help to identify those with increased risk for cancer and polyposis and offer early intervention measures for these individuals to significantly reduce their risk of cancer.

No clear guidelines for GREM1 testing have been established; however, the American College of Medical Genetics and Genomics (ACMG) and National Society of Genetic Counselors (NSGC) have recently recommended referral for consideration of GREM1 testing for anyone with >10 colorectal polyps of mixed histology.4 Ashkenazi Jewish ancestry in addition to mixed polyposis should increase consideration of GREM1.

Test Description 

Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized kit and quantified. Gross deletion/duplication analysis is performed to determine copy number utilizing a custom targeted chromosomal microarray. Only the status of the 40kb 5’UTR gross duplication is analyzed and reported.

Mutation Detection Rate 

Ambry’s GREM1 duplication analysis can detect >99.9% of described duplications (as listed above) in the gene, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
TEST CODE TECHNIQUE CALENDAR DAYS
8878 GREM1 Duplication Analysis 14 - 21 days

 

Specialty 
Genes 
GREM1
References 

1.  Whitelaw SC, et al. Clinical and molecular features of the hereditary mixed polyposis syndrome. Gastroenterology. 1997; 112: 327-334.
2.  Jaeger E, 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. 2012; 44(6): 699-705.
3.  David H, et al. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat Med. 2015; 21(1): 62-70.
4.  Hampel H, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015; 17(1):70-87.