Features of Patients With Hereditary Mixed Polyposis Syndrome Caused by Duplication of GREM1 and Implications for Screening and Surveillance

Abstract

Hereditary mixed polyposis syndrome is a rare colon cancer predisposition syndrome caused by a duplication of a noncoding sequence near the gremlin 1, DAN family BMP antagonist gene (GREM1) originally described in Ashkenazi Jews. Few families with GREM1 duplications have been described, so there are many questions about detection and management. We report 4 extended families with the duplication near GREM1 previously found in Ashkenazi Jews; 3 families were identified at cancer genetic clinics in Israel and 1 family was identified in a cohort of patients with familial colorectal cancer. Their clinical features include extracolonic tumors, onset of polyps in adolescence, and rapid progression of some polyps to advanced adenomas. One family met diagnostic criteria for Lynch syndrome. Expansion of the hereditary mixed polyposis syndrome phenotype can inform surveillance strategies for carriers of GREM1 duplications.

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017

“…33,34 HMPS is due to a 40-kb duplication upstream of the gremlin 1 gene (GREM1), which increases ectopic GREM1 expression in normal epithelium. 33 Exome sequencing combined with linkage analyses and detection of copy-number variations identified a 16-kb duplication upstream of GREM1 in a family of non-Ashkenazi Jewish descent with AFAP.…”

Defining New Colorectal Cancer Syndromes in a Population-based Cohort of the Disease

“…Evidence for rectal cancer as a separately inherited entity has been published (6), as well as a syndrome of familial CRC associated with serrated adenomas (7). A syndrome of mixed polyps, have recently been defined as distinct entity with the genetic background identified (8). Some familial CRCs and sporadic CRCs could be explained by defining CRC as a complex disease, and several genome-wide association studies (GWAS) have aimed to define this proportion (9).…”

Identification of a novel GREM1 duplication in a patient with multiple colon polyps

“…It is difficult to determine if the aforementioned families represent rare outliers or if polyp formation in adolescents should be included in the clinical spectrum of HMPS. Nonetheless, several groups have advocated for colonoscopy surveillance starting at age 18 or earlier for those with a GREM1 mutation [11, 12]. What also remains unclear is whether all GREM1 duplications have the same colon cancer risk, and ultimately additional research on the phenotypic spectrum of GREM1 associated HMPS is necessary to make appropriate medical management recommendations.…”