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POLE or POLD1 (polymerase proofreading polyposis) – risk management

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Polymerase proofreading-associated polyposis (PPAP) is an autosomal dominant condition caused by a small number of germline pathogenic missense variants in the exonuclease domain of POLE or POLD1 genes.

The care of an individual who has developed a related tumour or cancer should be individualised based on their clinical situation, their family history and the monitoring they need as part of their treatment and post-treatment follow-up.

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

  • Known or obligate POLE or POLD1 pathogenic variant carrier
  • Individuals at 50% risk of inheriting a POLE or POLD1 pathogenic variant

Exclusion criteria

  • Individuals diagnosed with other polyposis syndromes
  • Individuals with a variant of uncertain significance
Cancer/tumour type* Risk for this group by age 75 years* General population risk by age 75 years**
Colorectal  Increased but not quantified 3.7%
Duodenal adenomas and/or cancer Increased but not quantified Unable to obtain
Endometrial  Increased but not quantified 1.7%
Brain (astrocytoma and glioblastoma) Increased but not quantified 0.52% (all brain cancers)

* Although POLE and POLD1 are considered together, lifetime risk of cancer may vary by gene.rr
** Source: Australian Institute of Health and Welfare (AIHW) 2021 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/contents/cancer-risk-data-visualisation> (2017 data).

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional.

The impact of lifestyle on cancer risk should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

Cancer/tumour type^ Recommendations#
Colorectal Surgical Consider prophylactic colectomy if polyp burden not manageable with polypectomy
Surveillance Age Strategy and frequency
From age 25 years
  • Colonoscopy every 2 yearsr unless polyps found
  • If polyps detected, colonoscopy frequency should be determined by treating gastroenterologist based on polyp number, size and pathology
Risk-reducing medication Unless contraindicated, aspirin should be actively considered to reduce the risk of colorectal cancer. A low dose (100–300 mg per day) is recommended from commencement of colonoscopy screening
Duodenal Surgical Consider duodenectomy for stage IV adenoma
Surveillance Age Strategy and frequency
From age 25 yearsr Upper gastrointestinal endoscopy every 5 years, or as directed by polyp load and/or dependent on Spigelman criteria
Risk-reducing medication There is no evidence to support the utilisation of risk-reducing medication outside a clinical trial
Endometrial Surgical Option of risk-reducing hysterectomy +/- bilateral salpingo-oophorectomy after childbearing complete or from age 40 years should be discussed
Surveillance There is no evidence for transvaginal ultrasound (TVU) and/or aspiration biopsy

^ Increased risk of other tumour types has been suggested (including cancer of the breast, stomach, ovary and brain) but more research is required due to ascertainment bias in these initial studies.rr Screening and advice should therefore be based on the family history of these tumours.
# These recommendations are based on expert opinion as there are small cases numbers and limited data available.

The effectiveness of cancer screening in individuals with POLE and POLD1 pathogenic variants is still unclear. Recommendations have been extrapolated from cancer screening studies in other related hereditary cancer syndromes such as Lynch syndrome, MUTYH associated polyposis (MAP) and attenuated familial adenomatous polyposis (AFAP).

Colorectal cancer

Surgical

Data suggests polyposis may be more severe in POLE pathogenic variant carriers.rr For individuals with significant polyps (3 polyps before age 30 years or greater than 10 polyps in a lifetime), recommendations are based on MAP and includes colectomy when polyp burden becomes unmanageable.r

Surveillance

There is limited data regarding the appropriate surveillance frequency for individuals with POLE and POLD1 pathogenic variants. The recommendation for 2-yearly surveillance is thought to represent the best balance between risks and benefits of colonoscopy in individuals who have not yet had polyps identified.r

Risk-reducing medication

There have been no studies providing beneficial evidence for the use of aspirin in POLE and POLD1 pathogenic variant carriers. However, considerable evidence supports the effectiveness of aspirin as risk-reducing medication for colorectal cancer (CRC) in high-risk patients with Lynch syndrome (greater than 50% reduction in CRC risk).r Revised guidelines from the Cancer Council Australia have also made a strong recommendation to consider universal aspirin chemoprevention except where contraindicated, especially for those with excess cardiovascular risk.r Therefore, these recommendations have been included for individuals with POLE and POLD1 pathogenic variants.

Duodenal adenomas and/or cancer

There are no studies to show the efficacy of gastrointestinal endoscopy in reducing the risk for duodenal cancer. Surveillance recommendations have been based on the risk management guidelines for MUTYH-associated polyposis (MAP) and attenuated familial adenomatous polyposis (AFAP).r

Consider polypectomy in polymerase proofreading-associated polyposis (PPAP) when adenomas are 1cm or greater in size.r

Endometrial cancer

Endometrial cancer risk is increased in POLE and POLD1 pathogenic variant carriers. Surveillance starting at age 40 years has been suggested although there is no evidence to support screening for endometrial cancer in other high risk groups such as individuals with Lynch syndrome.r There is limited evidence that there is an increased risk of ovarian cancer in POLD1 pathogenic variant carriers. The risk of endometrial and ovarian cancer warrants a discussion regarding risk-reducing hysterectomy and bilateral salpingo-oophorectomy.

First degree blood relatives (parents/brothers/sisters/children) are at up to 50% risk of having inherited the pathogenic variant. More distant relatives may also be at risk of inheriting the pathogenic variant. Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss predictive genetic testing.

Informing family members about hereditary cancer

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Version 8

Date Summary of changes
15/09/2023

New eviQ cancer genetics risk management template changes applied - PDF of changes.

Version number changed to V.8.

Version 7

Date Summary of changes
13/02/2023

The following sections of the document were updated to align with the new eviQ cancer genetics risk management template:

  • Summary:
    • Template sentence updated.
  • Target population:
    • Added to exclusion criteria "Individual with a variant of uncertain significance".
  • Cancer/tumour risk management guidelines:
    • Template sentence updated. 
    • Lifestyle factors sentence moved above table.

Version number increased to V.7.

Version 6

Date Summary of changes
01/03/2022

Protocol reviewed at September 2021 cancer genetics reference committee meeting. Discussions continued via MS Teams. Approved for publication with the following changes made: 

  • Summary: Minor wording changes
  • Lifetime risk of cancer/tumour: 
    • 'Gastric fundic gland polyps' removed from table
    • Endometrial risk changed from 'May be increased' to 'Increased but not quantified'
    • 'Brain (astrocytoma and glioblastoma)' added to the table
    • General population risk column updated to include AIHW 2017 data
  • Cancer/tumour risk management guidelines:
    • Colorectal - Surveillance: '3 yearly colonoscopy...' changed to 'Colonoscopy every 2 years...'
    • Endometrial - Surgical and Surveillance rows added to table
    • Footnote added to table 'These recommendations are based on expert opinion as there are small cases numbers and limited data available.'
  • Evidence for risk management guidelines: section reviewed and updated.

Version increased to V.6. Review in 2 years.

Version 5

Date Summary of changes
18/12/2019 "Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up. Version number increased to V.5.
18/12/2020 The following sections of the protocol were updated to align with the revised eviQ cancer genetics risk management template:
  • Lifetime risk of cancer:
    • Heading changed to "Lifetime risk of cancer/tumour"
    • Risk for general population updated to include AIHW 2016 data
  • Cancer risk management guidelines:
    • Heading changed to "Cancer/tumour risk management guidelines"
    • Sentence added above table "The choice of risk management strategy should take into account current age, other health issues and residual cancer risk." 
    • Surveillance: "Age to begin" changed to "Age"
    • Other table formatting changes
  • Support and information: template wording updated.

Version 4

Date Summary of changes
19/10/2016 Discussed at 10 March 2016, reference committee meeting and protocol finalised over email, with 2 yearly review.  
31/05/2017 Transferred to new eviQ website. Version changed to V.2.
24/04/2019

Protocol reviewed and presented at Nov 2018 cancer genetics RCM. Discussion continued over email with the following changes made:

  • Summary: Specific mutations removed from first sentence. Sentence added at bottom to align with template changes.
  • Target group: Specific mutations removed from both target group and exclusion criteria.
  • Lifetime risk of cancer table: Statistics updated, risk age for general population changed to 75 yrs to align with POLE/POLD1 risk age. Specific mutations again removed.
  • Cancer risk management guidelines: Recommendations updated. Sentence below table updated to align with template changes.
  • Evidence for risk management guidelines: Evidence updated, namely colorectal surveillance and risk-reducing medication, and duodenum.
  • Support and information: Minor wording updates.
  • References: updated.

Version changed to V.3. To be reviewed in 2 years.
28/08/2019 Protocol title changed from 'Risk management for a PPAP (POLE/POLD1) mutation carrier' to 'POLE or POLD1 (polymerase proofreading polyposis) – risk management' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.4.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/1913

10 Sep 2024