Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 1.1.0
• GENE/GENE PANEL: POLE, POLD1
• Condition: POLE and POLD1 associated susceptibility to CRC
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• POLE ⇔ 615083: Assertion Pending
• POLD1 ⇔ 612591: Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Colorectal Cancer (POLE) / Colonoscopy with polypectomy	2	2B 1	3B 2	2	9BB
Colorectal Cancer (POLD1) / Colonoscopy with polypectomy	2	3B 3	3B 4	2	10BB

1. Level of evidence downgraded due to lack of precision.

2. Extrapolated from Lynch Syndrome.

3. Level of evidence downgraded due to lack of precision.

4. Extrapolated from Lynch Syndrome.

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The prevalence of colorectal cancer (CRC) cases associated variants in POLE and POLD1 is unclear. An estimated 3-5% of CRC cases are caused by high-penetrance germline mutations and only a small proportion of these would be expected to be associated with pathogenic variants in POLE or POLD1. A study of 858 familial/early-onset CRC cases and polyposis, one POLE and one POLD1 pathogenic variant were identified. [1, 2]

Clinical Features

POLE and POLD1 associated susceptibility to CRC is characterized by a predisposition to the development of colorectal polyposis, adenomas, carcinomas. Available data suggest a phenotype characterized by attenuated or oligoadenomatous colorectal polyposis with a reported range of 0-68 adenomas upon examination. The histologic features of the tumors may be unremarkable or show microsatellite instability. The phenotype appears to overlap with that of Lynch syndrome and attenuated adenomatous polyposis. A broader extracolonic spectrum of cancers has been noted as additional carrier families are identified, including cancers of the endometrium, ovaries, pancreas, brain, and small intestine. However, evidence on these associations is still limited. Thus, the recommendations in this report are focused on CRC. [1, 2, 3, 4]

Natural History

A study of 47 individuals (from 20 families) with a POLE pathogenic variant reported that 30 individuals developed CRC with a mean age of onset of 40.7 years. In 22 individuals (from 8 families) with a POLD1 pathogenic variant, 13 developed CRC with a mean age of onset of 35.9 years. [1, 5]

2. How effective are interventions for preventing harm?

Patient Management

No recommendations for patient management were identified.

Surveillance

Colonoscopy should be performed every 1-3 years starting at ages 20-30 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) [5, 6]

Evidence on the effectiveness of colonoscopy in individuals with a POLE and POLD1 associated susceptibility to CRC was not identified. However, evidence indicates that screening in individuals with Lynch Syndrome and familial adenomatous polyposis (FAP) decreases the risk of CRC. In a systematic review of individual with Lynch Syndrome, 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]

Circumstances to Avoid

No recommendations related to circumstances to avoid were identified.

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

No information on the prevalence of pathogenic variants in POLD1 or POLE was identified.

Penetrance

A systematic review of pedigree studies of families with a germline POLE or POLD1 variant modeled the cumulative risk of CRC based on segregation analysis adjusted for ascertainment of families. Not all individuals in these pedigrees were genotyped.
The cumulative risk of CRC to age 70 years for individuals with a POLE pathogenic variant was estimated to be 28% (95% CI: 10-42%) for males and 21% (95% CI: 7-33%) for females. For those specifically with the c.1270C >G, p.Leu424Val variant (19 families) the estimated risk of CRC by age 70 was 97% (95% CI: 85-99%) for males and 92% (95% CI: 75-99%) for females.
The cumulative risk of CRC to age 70 years for individuals with a POLD1 pathogenic variant was estimated to be 90% (95% CI: 33-99%) for males and 82% (95% CI: 26-99%) for females. (Tier 1) [1]

A smaller study with genotypic information on all participants found that among 47 individuals (from 20 families) with a POLE pathogenic variant, CRC was identified in 30/47 carriers (63.8%). Among 22 individuals (from 8 families) with a POLD1 pathogenic variant, CRC was identified in 13/22 carriers (59.1%). (Tier 5) [5]

Relative Risk

Compared with the general population the hazard ratios (HR) for development of CRC for individuals with a pathogenic variant in POLE was estimated to be 12.2 (95% CI: 7.35-20.2) with the HR decreasing with age: 38.7 (95% CI: 17.5-85.4) before age 50 and 8.21 (95% CI: 4.24-15.9) for ages ≥50. The estimated HR for pathogenic variants in POLD1 was 87.2 (95% CI: 15.3-495): 201 (95% CI: 62.0-651) before age 50 and 3.34 (95% CI: 0.22-50.1) for ages ≥50. No differences in hazard ratios were identified by sex. (Tier 1) [1]

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 setting of recommended care?

Chance to Escape Clinical Detection

The age recommended to begin screening for CRC is earlier than that currently recommended for the general population. Therefore, it is likely that individuals with POLE and POLD1 associated susceptibility to CRC could develop CRC before general screening would commence.

Date of Search: 07.05.2018

Reference List

1. Buchanan DD, Stewart JR, Clendenning M, Rosty C, Mahmood K, Pope BJ, Jenkins MA, Hopper JL, Southey MC, Macrae FA, Winship IM, Win AK. Risk of colorectal cancer for carriers of a germ-line mutation in POLE or POLD1. Genet Med. (2017)

2. Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. (2015) 110(2):223-62; quiz 263.

3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. COLORECTAL CANCER, SUSCEPTIBILITY TO, 10; CRCS10. MIM: 612591: 2018 Apr 06. World Wide Web URL: http://omim.org.

4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. COLORECTAL CANCER, SUSCEPTIBILITY TO, 12; CRCS12. MIM: 615083: 2018 Mar 13. World Wide Web URL: http://omim.org.

5. Bellido F, Pineda M, Aiza G, Valdes-Mas R, Navarro M, Puente DA, Pons T, Gonzalez S, Iglesias S, Darder E, Pinol V, Soto JL, Valencia A, Blanco I, Urioste M, Brunet J, Lazaro C, Capella G, Puente XS, Valle L. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet Med. (2016) 18(4):325-32.

6. Genetic/Familial High-Risk Assessment: Colorectal (version 1.2018). Publisher: National Comprehensive Cancer Network,. (2018) Website: https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf

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.