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CDKN2A – risk management

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Familial melanoma due to a heritable pathogenic variant in the CDKN2A gene is an autosomal dominant condition, strongly modified by polygenic and environmental risk factors.

Following diagnosis of initial melanoma, CDKN2A carriers have an elevated lifelong risk of developing further melanomas.

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 carrier of a pathogenic variant in the CDKN2A gene. 
  • 50% risk of being a pathogenic variant carrier.

Exclusion criteria

  • Individuals in families with a likely pathogenic variant in other cancer predisposition genes associated with increased risks of melanoma. 
  • Individuals from families meeting familial melanoma diagnostic criteria where testing has not been done or where no pathogenic variant has been identified (see Skin cancers and lesions - referring to genetics)
  • Individual with a variant of uncertain significance.
Cancer/tumour type Risk for CDKN2A pathogenic variant carriers General population risk by age 80 years* 
Melanoma 52% by age 80 yearsr 5.2%**
Pancreatic

20.7% by age 70 years with the CDKN2A c.225_243del variantr

Insufficient evidence to quantify risk with other (likely) pathogenic variants 

 1.3%

*Source: Australian Institute of Health and Welfare (AIHW) 2022 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/contents/cancer-risk-data-visualisation> (2018 data, unadjusted for competing mortality)
**In Australia population melanoma risk varies by state (higher in QLD and WA).

The choice of risk management strategy should take current age, other health issues and age-related cancer risk into account. 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
Melanoma
Surveillance Age Strategy and frequency

From 18 years of age
  • Monthly self examination of skin
  • 6 monthly comprehensive skin examination, including scalp and genitalia, by a dermatologist, supplemented by total body photography and dermoscopy 
  • Minimise sun exposure and follow sun smart practices
Pancreatic Surveillance

From 45 years of age or 10 years younger than the youngest affected relative
  • There is lack of evidence of survival benefit from surveillance

  • Consider annual surveillance with endoscopic US or contrast enhanced MRI/MRCP from age 45 (or 10 years younger than the affected relative)r

  • Where possible surveillance should be carried out as part of a clinical trial.#

  • Avoid smoking and obesity and minimise alcohol consumption

Abbreviations: MRI - magnetic resonance imaging, MRCP - magnetic resonance cholangiopancreatography, US - ultrasound.

#Refer to Australian Pancreatic Cancer Genome Initiative for up-to-date screening trials. 

Melanoma

Surveillance

Several observational studies have demonstrated lower Breslow depth and lower risk of advanced or fatal melanoma in screen detected melanomas using either monthly self-examination or regular clinical examination of skin. Specificity of screening is higher with clinical rather than self-examination and improves with increased clinician training. A German study reported a 47% decrease in melanoma mortality in a screened population at average risk.r

Australian studies have shown that six-monthly specialist skin examination, supported by dermoscopy and total body photography, is effective in reducing thickness of prospectively detected melanomas, and in reducing the number of ineffectual skin lesion excisions in those at very high risk of melanoma (CDKN2A pathogenic variant carriers or equivalent).r The intervention was also cost-effective compared with current practice.r Follow Cancer Council Australia SunSmart Position statements. 

Relatives who are non-carriers of an identified familial CDKN2A pathogenic variant have a higher risk of cutaneous melanoma than the general population (but lower than carrier relatives). This is probably explained by inheritance of other less penetrant melanoma susceptibility variants combined with shared environmental risks amongst family members. Less frequent (annual) melanoma surveillance may still be warranted for non-carrier relatives. (Link to Alfred Health - Melanoma risk calculator for health professionals. Link to QIMR Berghofer - Melanoma Risk Predictor) 

Pancreatic cancer

Surveillance

In a Dutch based 20-year prospective follow-up study evaluating pancreatic screening with MRCP +/- EUS in CDKN2A carriers, 347 germline pathogenic variant carriers participated in surveillance and were followed for a median of 5.6 (interquartile range 2.3-9.9) years.r The cumulative incidence of pancreatic ductal adenocarcinoma (PDAC) by age 70 was 20.7%, with surveillance leading to detection of resectable, early stage PDAC; 80% of affected patients were found to have resectable disease with a third of patients diagnosed with stage I PDAC.r This compared favourably with general population data with only 10-15% of pancreatic cancers being resectable at diagnosis. 5-year overall survival rate in the study population was 32.4% compared with 5% 5-year OS in sporadic PDACs.r This study primarily consisted of patients with the CDKN2A c.225_243del variant and therefore there is still some uncertainty regarding the generalisation of this data to support surveillance in all CDKN2A pathogenic variant carriers. 

If surveillance is undertaken, it should be done in a high-volume centre after discussion of the limitations of screening, including the risk of detecting benign or indeterminate pancreatic abnormalities, the potential complications of the surveillance modality used and the uncertainties about the benefit of surveillance (if any) on mortality and morbidity from pancreatic cancer.  Most surveillance detected cystic lesions are small and will not warrant biopsy, surgical resection, or any other intervention. A community-based screening study of 75 high-risk individuals based on family history and underlying germline pathogenic variant (in a range of pancreatic cancer predisposition genes) detected pancreatic lesion in 58.7% of study participants on initial MRCP with 52% representing simple cysts.r The remaining 5 (6.7%) participants were further investigated with EUS+/- FNA biopsy confirming benign etiology. One participant proceeded to pancreatoduodenectomy; pathology revealed an intraductal papillary mucinous neoplasm and a low-grade pancreatic intraepithelial neoplasia (PanIN-1A).r  

Not smoking is recommended because pancreatic cancer has a known association with smoking and there are reports of an increased risk of smoking-related head-and-neck cancers in CDKN2A pathogenic variant positive families.r

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 5

Date Summary of changes
28/08/2023

Protocol reviewed at October 2022 reference committee meeting. Discussions continued via email and MS Teams. Approved for publication with the following changes made:

  • 2023 cancer genetics risk management template changes applied throughout document
  • Target group: Link to 'ID 3193 familial melanoma referral criteria' replaced with link to 'ID 4106 Skin cancers and lesions - referring to genetics'
  • Lifetime risk of cancer table: pancreatic CDKN2A PV carrier data updated
  • Cancer risk management guidelines: pancreatic surveillance recommendations updated to align with recent data/publications
  • Evidence for risk management guidelines: addition of study by Klatte et al.

Version increased to V.5. Approved on 8/08/2023, published on 28/08/2023. Review in 1 year.

Version 4

Date Summary of changes
4/10/2019

Protocol reviewed at May 2019 reference committee meeting. Discussions continued over email. Protocol approved for publication with the following changes made:

  • Summary: updated
  • Lifetime risk of cancer table: general population data updated
  • Cancer risk management guidelines: recommendations updated to align with recent data/publications
  • Evidence for risk management guidelines: updated to align with recent data/publications. Link to melanoma risk calculators added
  • References: new references added
  • New template changes applied
  • "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.

Protocol version number increased to V.4. Review in 2 years
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 table:
    • 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 current age, other health issues and residual cancer risk into account" 
    • Surveillance: "Age to begin" changed to "Age"
  • Support and information: template wording updated.
04/08/2021

The following changes were made to align with ID 656 BRCA1 or BRCA2 – risk management (male):

  • Cancer risk management guidelines:
    • Pancreatic - Surveillance: "There is no evidence to support a benefit from screening. Screening should only be undertaken as part of a clinical trial." changed to "Lack of evidence of benefit from screening. Should be undertaken only as part of a clinical trial".
    • Footnote added "Refer to Australian Pancreatic Cancer Genome Initiative website for up-to-date screening trials. Link in Website resources section."
  • Website resources:
    • Added link to Australian Pancreatic Cancer Genome Initiative website

Version 3

Date Summary of changes
30/11/2016

New protocol discussed at October 2015 and March 2016 cancer genetics reference committee meeting. Approved and published on eviQ. Next review in 2 years.
31/05/2017 Transferred to new eviQ website. Version changed to V.2.
28/08/2019 Protocol title changed from 'Risk management for a CDKN2A mutation carrier' to 'CDKN2A – risk management' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.3.

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/1516

11 Oct 2024