Hereditary mixed polyposis syndrome 1

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: GREM1 (HGNC:2001)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 08/03/2018
• Curation Status: Released - Under Revision (1.2.3)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
GREM1	polyposis syndrome, hereditary mixed, 1 (0042486)	601228	Limited Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric. The majority of the evidence and recommendations available are specific to the GREM1 duplication. The assertion is due to limited direct evidence of penetrance as well as specific guidelines for medical management.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Colorectal Cancer / Colonoscopy with polypectomy	2	0D	3B	2	7DB

Severity of Outcome

Prevalence of the Genetic Condition

No information on the prevalence of hereditary mixed polyposis syndrome (HMPS) was identified. It is unclear what percent of colorectal cancer (CRC) cases are due to a duplication upstream of GREM1. Screening of 718 familial CRC cases identified 1 individual of Ashkenazi descent with the duplication.

Clinical Features (Signs / symptoms)

HMPS is a genetically heterogeneous condition characterized by the presence of a mixture of hyperplastic, atypical juvenile and adenomatous polyps that are associated with an increased risk of developing colorectal cancer if left untreated. HMPS can be caused by heterozygous upstream duplication on chromosome 15q13-q14 that results in increased ectopic expression of the GREM1 gene, a bone morphogenetic protein (BMP) antagonist. The pathogenesis of polyps in HMPS likely overlaps with juvenile polyposis syndromes caused by inactivating mutations in genes of the BMP pathway. Generally, extra-colonic manifestations have not been noted among families; however, some families have been found to present with clinical features which may overlap with familial adenomatous polyposis (FAP) or Lynch syndrome. Screening within families with an identified duplication upstream of GREM1 have found 1-81 polyps of mixed types.

Natural History (Important subgroups & survival / recovery)

A 40-kb duplication upstream of GREM1 has been identified among a series of Ashkenazi Jewish HMPS families and is considered a potential founder variant. The rearrangement appears to be extremely rare among unselected colonic cancer cases and among non-Ashkenazi patients with multiple hyperplastic polyps. However, additional duplications involving GREM1 have been reported in individuals of unknown or non-Ashkenazi Jewish ancestry. In general, the age of onset of polyps occurs in the late 20s or older; however, polyps have been reported in individuals as young as 10. Point mutations in GREM1 have also been found to confer an increased risk for CRC; however, this report is focused on individuals with a duplication upstream of GREM1.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown

No information was identified on the prevalence of upstream duplications of GREM1.

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown

No studies were identified indicating the percent of individuals with a duplication upstream of GREM1 who develop CRC.

Tier Not provided

Unknown

Within one large kindred ascertained through a 21-year-old proband with metastatic colon cancer, 18 family members were evaluated within a 3-generation pedigree. Polyps were seen in all 10 family members who tested positive for the duplication upstream of GREM1 (range: 1-40 polyps, mean: 14.1). Multiple polyps were identified in every affected family member over the age of 20.

Tier 5

Unknown

In a single extended family from an inherited CRC registry, 51 colonoscopies (range per individual: 1-15) were performed among 10 patients with a confirmed GREM1 duplication. Mean age of presentation of patients was 33.3 years (range 9-52) with patients tending to present because of family history of polyposis or rectal bleeding. One patient presented with CRC at age 52 before engaging in surveillance. No other carcinomas were detected during in the cohort surveillance (mean years of follow up 26.2, range 1-59 years). All individuals were found to have polyps (ranging from 4-81) mainly comprised of adenomas and mixed hyperplastic/inflammatory polyp types.

Tier 5

Unknown

Within a study of 16 individuals from 4 families with a GREM1 duplication, 2 individuals (probands) were identified with CRC (ages 41-49).

Tier 5

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

No information on relative risk was identified.

Expressivity

No information on expressivity was identified.

Intervention Effectiveness

Patient Management

Surveillance

Colonoscopy should be performed every 1-3 years starting at ages 25-30 with the interval based on the finding of polyps and with consideration of surgery if the polyp burden becomes unmanageable by colonoscopy. Data to support the surveillance recommendations are currently evolving, therefore colonoscopy regimens should consider patient preferences and new knowledge that may emerge.

Tier 2

No evidence was identified related to effectiveness of surveillance in individuals with a GREM1 duplication. However, the cancer risk and age of onset have been stated to be similar to that of attenuated familial adenomatous polyposis. Evidence indicates that screening in individuals with Lynch Syndrome and familial adenomatous polyposis (FAP) decreases the risk of CRC. In a systematic review, five out of six studies found a significantly reduced incidence rate of CRC with surveillance (OR estimates ranged from 0.11 to 0.35), while the sixth study reporting an OR of 0.93 was not significant. Two out of four studies showed a significant reduction in CRC-related mortality with surveillance (OR estimates range from 0.04 to 0.17), while three of the four studies reported no mortality in the study arm with surveillance. Among individuals with FAP, 26 of 27 studies showed a statistically significant reduction in CRC incidence with surveillance (ORs ranged from 0.01 to 0.37) in screened patients compared to those who presented symptomatically with polyposis/CRC outside of a screening program. Eight studies examined CRC mortality, all of which showed a significant reduction in CRC mortality (ORs ranged from <0.01 to 0.16) in screened (N= 1028) versus symptomatic groups (N= 947). Two studies provided evidence for complete prevention of CRC-related deaths during surveillance, although the duration of follow-up was short (2-4 years).

Tier 1

Circumstances to Avoid

Nature of Intervention

Nature of Intervention

The recommended interventions include colonoscopy with polypectomy.

Context: Adult

Chance to Escape Clinical Detection

The age recommended to begin screening for CRC and precursor lesions is earlier than that currently recommended for the general population. Therefore, it is likely that individuals could develop CRC before general screening would commence.

Context: Adult

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			GREM1			601228	0042486	0011023

References List

Barrow P, Khan M, Lalloo F, Evans DG, Hill J. (2013) Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. The British journal of surgery. 100(13):1719-31.

Hereditary mixed polyposis syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=157794

Lieberman S, Walsh T, Schechter M, Adar T, Goldin E, Beeri R, Sharon N, Baris H, Ben Avi L, Half E, Lerer I, Shirts BH, Pritchard CC, Tomlinson I, King MC, Levy-Lahad E, Peretz T, Goldberg Y. (2017) Features of Patients With Hereditary Mixed Polyposis Syndrome Caused by Duplication of GREM1 and Implications for Screening and Surveillance. Gastroenterology. 152(8):1876-1880.e1.

McKenna DB, Van Den Akker J, Zhou AY, Ryan L, Leon A, O'Connor R, Shah PD, Rustgi AK, Katona BW. (2018) Identification of a novel GREM1 duplication in a patient with multiple colon polyps. Familial cancer. 18(1573-7292):63-66.

National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Colorectal. Publisher: National Comprehensive Cancer Network (2017) Accessed: 2018-08-01. URL: https://NCCN.org

Plesec T, Brown K, Allen C, A Burke C, Church J, Kalady M, LaGuardia L, O'Malley M, Heald B. (2017) Clinicopathological features of a kindred with SCG5-GREM1-associated hereditary mixed polyposis syndrome. Human pathology. 60(1532-8392):75-81.

POLYPOSIS SYNDROME, HEREDITARY MIXED, 1; HMPS1. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 601228, (2013) World Wide Web URL: http://omim.org/

Ziai J, Matloff E, Choi J, Kombo N, Materin M, Bale AE. (2016) Defining the polyposis/colorectal cancer phenotype associated with the Ashkenazi GREM1 duplication: counselling and management recommendations. Genetics research. 98(1469-5073):e5.