Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Incomplete (WARNING: Incomplete Stage 2 curation.)

GENE/GENE PANEL: GREM1
Condition: Hereditary mixed polyposis syndrome 1
GENEDISEASE PAIRS: GREM1601228
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
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.
1
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.
1 2 3
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.
3 4 5
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
No patient management recommendations have been provided.
 
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)
6
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)
7
Family Management
No family management recommendations have been provided.
 
Circumstances to Avoid
No circumstances-to-avoid recommendations have been provided.
 
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Prevalence of Genetic Mutations
No information was identified on the prevalence of upstream duplications of GREM1.
 
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
No studies were identified indicating the percent of individuals with a duplication upstream of GREM1 who develop CRC.
 
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)
4
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)
8
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)
3
No information on relative risk was identified.
 
 
Expressivity
No information on expressivity was identified.
 
4. What is the Nature of the Intervention?
Nature of Intervention
The recommended interventions include colonoscopy with polypectomy.
 
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
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.
 

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Colorectal Cancer / Colonoscopy with polypectomy
2
0D
3B 1
2
7DB
1. Extrapolated from Lynch Syndrome and familial adenomatous polyposis.
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Polyposis syndrome, hereditary mixed, 1; hmps1. MIM: 601228: 2013 Oct 16. World Wide Web URL: http://omim.org.
2. Hereditary mixed polyposis syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=157794
3. 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. Features of patients with hereditary mixed polyposis syndrome caused by duplication of grem1 and implications for screening and surveillance. Gastroenterology. (2017) 152(8):1876-1880.
4. Ziai J, Matloff E, Choi J, Kombo N, Materin M, Bale AE. Defining the polyposis/colorectal cancer phenotype associated with the ashkenazi grem1 duplication: counselling and management recommendations. Genet Res (Camb). (2016) 98:e5.
5. McKenna DB, Van Den Akker J, Zhou AY, Ryan L, Leon A, O'Connor R, Shah PD, Rustgi AK, Katona BW. Identification of a novel grem1 duplication in a patient with multiple colon polyps. Fam Cancer. (2018)
6. National Comprehensive Cancer Network. Genetic/familial high-risk assessment: colorectal. Publisher: National Comprehensive Cancer Network. (2017) Accessed: 2018-08-01. Website: NCCN.org
7. Barrow P, Khan M, Lalloo F, Evans DG, Hill J. Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and lynch syndrome. Br J Surg. (2013) 100(13):1719-31.
8. Plesec T, Brown K, Allen C, A Burke C, Church J, Kalady M, LaGuardia L, O'Malley M, Heald B. Clinicopathological features of a kindred with scg5-grem1-associated hereditary mixed polyposis syndrome. Hum Pathol. (2017) 60:75-81.
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