GREM1 – Hereditary Mixed Polyposis Syndrome

Hereditary Mixed Polyposis Syndrome (HMPS) is an autosomal dominant colorectal polyposis syndrome characterized by mixed histological colonic polyps (adenomatous, hyperplastic, and juvenile subtypes) and elevated colorectal cancer risk (PMID:9024286). Initial linkage localized the HMPS locus to chromosome 15q13–q14, implicating the GREM1 regulatory region (PMID:12696020).

A 40 kb founder duplication upstream of GREM1 was first identified in Ashkenazi Jewish HMPS families and shown to segregate with disease in multiple kindreds (PMID:25992589). Screening of 472 Ashkenazi individuals revealed a 0.7% prevalence of this duplication among Lynch syndrome–phenotype carriers, underscoring its role in hereditary colorectal cancer in this population (PMID:25992589).

Four extended families from Israeli and North American cancer genetics clinics confirmed this founder event in carriers with early-onset mixed polyps, extracolonic neoplasms, and rapid adenoma progression; one kindred also met Amsterdam II criteria for Lynch syndrome (PMID:28242209). These data establish autosomal dominant segregation of GREM1 regulatory duplications in HMPS across diverse cohorts.

Non-founder tandem duplications of 16 kb and 24 kb within the GREM1 upstream regulatory region have been reported in an attenuated/atypical polyposis family and a non-Ashkenazi patient meeting Amsterdam II criteria, respectively, both segregating with mixed polyposis (PMID:26493165; PMID:29804199).

Functional analyses demonstrate that these duplications abrogate normal transcriptional control, resulting in 2–4-fold overexpression of GREM1 in colonic mucosa, consistent with a dosage-dependent pathogenic mechanism (PMID:26493165).

No refuting evidence has been published. The convergence of genetic segregation across at least five unrelated families, reproducible regulatory duplications, and concordant functional overexpression supports a Strong level of clinical validity. Key take-home: GREM1 regulatory duplications are a clinically actionable, autosomal dominant cause of HMPS, warranting targeted testing of the 5′ regulatory region in patients with mixed colorectal polyps or unexplained familial colorectal cancer.

References

• Gastroenterology • 1997 • Clinical and molecular features of the hereditary mixed polyposis syndrome. PMID:9024286
• American Journal of Human Genetics • 2003 • An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome. PMID:12696020
• Genetics Research • 2015 • GREM1 germline mutation screening in Ashkenazi Jewish patients with familial colorectal cancer. PMID:25992589
• Gastroenterology • 2017 • Features of Patients With Hereditary Mixed Polyposis Syndrome Caused by Duplication of GREM1 and Implications for Screening and Surveillance. PMID:28242209
• Genes, Chromosomes & Cancer • 2016 • GREM1 and POLE variants in hereditary colorectal cancer syndromes. PMID:26493165
• Familial Cancer • 2019 • Identification of a novel GREM1 duplication in a patient with multiple colon polyps. PMID:29804199

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