TP53 (Li-Fraumeni) – risk management (child)

Li-Fraumeni syndrome (LFS) is caused by a germline pathogenic variant in the TP53 gene and is inherited in an autosomal dominant pattern.

• Individuals under age 18 years with a pathogenic variant in TP53.

Exclusion criteria

• Individuals age 18 years and over - refer to TP53 (Li-Fraumeni) – risk management (adult).
• Individuals who tested negative for a familial TP53 pathogenic variant.
• Untested individuals under age 18 years at 50% risk of a known pathogenic variant in TP53.
• Individuals in families who meet classic LFS criteria but where a germline TP53 pathogenic variant has not been identified.
• Individuals with a variant of uncertain significance.

The cumulative incidence of developing a childhood malignancy is 22% by age 5 years and 41% by age 18 years.^rr

Cancer/tumour type	Risk to TP53 pathogenic variant carrier by age 18 years*r	General population risk to age 20 years**
Cancer (female)	27%	0.34% (female)
Cancer (male)	39%	0.37% (male)
Soft tissue sarcoma	5% (female) 12% (male)	0.02% (female) 0.03% (male)
Osteosarcoma	7.5% (female) 12.5% (male)	Rare
Brain - various	8%	0.04%
Adrenocortical carcinoma	8.7%	Rare
Haematological malignancies: (MDS, leukaemia)	3%	MDS - rare Leukaemia - 0.09%

* The published literature overestimates the cancer risks. These studies are based on retrospective analyses, are biased towards families with an excess of cancer diagnoses and do not exclude probands from analyses. With more TP53 testing being carried out, less penetrant LFS kindreds are being identified, which likely will lead to lower cancer risk estimates.
** 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/data>. (2017 data). Note that data to age 18 years is not available, so the general population risk is for persons to age 20 years.

International consensus guidelines recommend comprehensive screening from birth/time of diagnosis.^rr

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
		Age	Strategy and frequency
Sarcoma and other cancers	Surveillance	From diagnosis+	Recommend annual whole-body MRI++
Brain tumours	Surveillance	From diagnosis+	Recommend annual dedicated brain MRI++ alternating 6-monthly with whole-body MRIr
Adrenocortical tumours	Surveillance	Birth to age 18 years	Consider abdominal ultrasound every 4 months If ultrasound abnormal, adrenal glands poorly visualised or concerning clinical examination add hormonal screen (17-OH-progesterone, total testosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione and 24-hour urine cortisol)r
Haematological cancers	Surveillance	No evidence of benefit for screening of asymptomatic individuals
All	Surveillance	From diagnosis	Clinical review with physical examination every 4 months, including blood pressure, height, weight, signs of virilisation and neurological exam
	Prevention	Avoid unnecessary radiation exposure for screening or therapeutic purposes Avoid (active and passive) smoking and excessive sun exposure
	Education	Clinicians should be aware of the increased risk for rare malignancies and the increased risk of a second malignancy after a first diagnosis Awareness and prompt reporting of any new symptoms

Abbreviations: MRI - magnetic resonance imaging
⁺ Screening MRI should be weighed against the need for a general anaesthetic in young patients. However, expert consensus as well as published literature would now support the recommendation for screening whole-body MRI.
⁺⁺ Because of concern about Gadolinium accumulation, first brain MRI with contrast; follow up MRI without contrast unless needed to define new findings.^r

Adrenocortical carcinoma

Surveillance

The majority of TP53- associated adrenocortical carcinomas (ACC) develop by 12 years of age, with most of these occurring by 5 years of age. As greater than 90% of TP53 pathogenic variant carriers with ACC secrete androgens, or androgens plus cortisol, clinical examination for signs of virilisation and Cushingoid features is important.^r

Regular abdominal ultrasound screening is recommended in screening protocols for children with a TP53 pathogenic variant^rrr and in international consensus guidelines.^r Blood collection is invasive and does not appear to increase cancer detection rate compared with imaging and clinical examination alone, and therefore is not recommended as part of initial screening studies.^r

Other cancers

Surveillance

Children have been included in a number of recently reported studies of screening including MRI scanning. A prospective non-randomised study of a comprehensive screening program including regular biochemical and imaging surveillance (MRI of the whole body, brain and breast, and abdominal ultrasound) in germline TP53 pathogenic variant carriers reported 11 year follow-up results and a paediatric and adult cohort. Early tumour detection through surveillance was associated with improved survival; 5-year overall survival was 88.8% (95% CI 78.7-100) in the surveillance group vs 59.6% (95% CI 47.2-75.2) in the non-surveillance group (p=0.0132). Less than 5% of participants had a non-neoplastic (false positive) lesion detected when biopsy/resection was performed due to imaging findings. The total number of children included in this study of 89 participants was not reported, but 5 of the cancers in the surveillance group were detected before 18 years of age.^r 

The French LIFSCREEN study, which randomised participants to clinical examination, MRI brain (and breast if over 20 years of age) and abdominal ultrasound, with or without annual whole-body MRI, for 5 years recruited children as young as 5 years of age. Nineteen of 107 (18%) participants were children, with the interim analysis reporting detected cancers in participants as young as 6 years of age.^r 

In a meta-analysis of 13 studies that included baseline whole-body MRI in Li-Fraumeni syndrome (LFS) patients, 134 of 578 participants were children. Twelve cancers were detected with single screening test, of which all were localised and treated with curative intent. The false positive rate with baseline whole-body MRI in LFS patients was 15-87%.^rr Studies in other conditions showed the initial screening MRI has a higher false positive rate than subsequent rounds of screening.

There is growing international consensus for routine screening for core cancers in children with LFS using whole-body MRI, however this has to be weighed against the need for a general anaesthetic in young patients. Early paediatric data suggests whole-body MRI surveillance is safe and feasible. However, studies are ongoing and medium and long-term outcomes are awaited, particularly with respect to survival, and psychosocial impact on patients and their families.^r Ideally surveillance should be coordinated through a multidisciplinary service with expertise in LFS, with discussion of enrolment in clinical trials encouraged.

Other cancers including Wilms tumour, neuroblastoma, lung, colorectal, stomach and pancreatic cancers have an increased risk compared with the general population, however, this risk is not quantified.

Prevention

TP53 pathogenic variants may cause radiation sensitivity due to impaired recognition and repair of DNA damage, and there are numerous reports of second primary malignancies developing in a radiation field. Minimising radiation therapy is recommended where possible, especially if other treatment modalities with comparable cure rates are available. Tests using ionising radiation should be avoided if other effective modalities are available.

There is evidence that smoking increases the risk of lung cancers in TP53 pathogenic variant carriers by 3-fold.

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Bibliography

Mai, P. L., A. F. Best, J. A. Peters, et al. 2016. "Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort." Cancer 122(23):3673-3681.

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BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome characterized by a very high lifetime cancer risk and an early age at diagnosis of a wide cancer spectrum. Precise estimates for the risk of first and subsequent cancers are lacking. METHODS: The National Cancer Institute's Li-Fraumeni Syndrome Study includes families meeting the diagnostic criteria for LFS or Li-Fraumeni-like syndrome, and individuals with a germline TP53 mutation, choroid plexus carcinoma, adrenocortical carcinoma, or >/=3 cancers. Herein, we estimated the cumulative risk and annual hazards for first and second cancers among TP53 mutation carriers (TP53 positive [TP53+]) using MATLAB statistical software. RESULTS: This study evaluated 286 TP53+ individuals from 107 families. The cumulative cancer incidence was 50% by age 31 years among TP53+ females and 46 years among males, and nearly 100% by age 70 years for both sexes. Cancer risk was highest after age 20 years for females, mostly due to breast cancer, whereas among males the risk was higher in childhood and later adulthood. Among females, the cumulative incidence rates by age 70 years for breast cancer, soft tissue sarcoma, brain cancer, and osteosarcoma were 54%, 15%, 6%, and 5%, respectively. Among males, the incidence rates were 22%, 19%, and 11%, respectively, for soft tissue sarcoma, brain cancer, and osteosarcoma. Approximately 49% of those with 1 cancer developed at least another cancer after a median of 10 years. The average age-specific risk of developing a second cancer was comparable to that of developing a first cancer. CONCLUSIONS: The cumulative cancer risk in TP53 + individuals was very high and varied by sex, age, and cancer type. Additional work, including prospective risk estimates, is needed to better inform personalized risk management. Cancer 2016;122:3673-81. (c) 2016 American Cancer Society.

Hwang, S. J., L. S. Cheng, G. Lozano, et al. 2003. "Lung cancer risk in germline p53 mutation carriers: association between an inherited cancer predisposition, cigarette smoking, and cancer risk." Hum Genet 113(3):238-243.

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We recently observed a significantly increased risk for lung cancer in carriers of p53 germline mutations. Because cigarette smoking is known to play an important role in increasing the risk for lung cancer in the general population, we wanted to determine the role of cigarette smoking in lung cancer risk in people with a genetic susceptibility based on a p53 germline mutation. We studied 1263 people from 97 families enrolled in a cohort study of families systematically ascertained through childhood soft-tissue sarcoma patients treated at the M.D. Anderson Cancer Center, University of Texas, between 1944 and 1975. We assessed the incidence of lung and smoking-related cancers in 33 carriers of germline p53 mutations and in 1,230 noncarriers to determine whether there was an association between an inherited cancer predisposition, cigarette smoking, and cancer risk. We analyzed the association between cigarette smoking, mutation status, and lung and other smoking-related cancers by the Kaplan-Meier method and the Cox proportional hazards model with adjustments for birth year, race, and sex. In the hazards model, we incorporated a robust variance estimation to adjust for familial correlation. We observed an increased risk of a variety of histological types of lung cancer in the carriers of the p53 germline mutation. Mutation carriers who smoked had a 3.16-fold (95% confidence interval =1.48-6.78) higher risk for lung cancer than the mutation carriers who did not smoke. Our results demonstrate that cigarette smoking significantly increases lung cancer risk in carriers of a germline p53 mutation. This finding could be useful in designing strategies for early detection and treatment of lung and smoking-related cancers in individuals with this inherited cancer predisposition.

Version 10

Date	Summary of changes
15/09/2023	New eviQ cancer genetics risk management template changes applied - PDF of changes. Version number changed to V.10.

Version 9

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.9.

Version 8

Date

Summary of changes

13/05/2022

Protocol reviewed at July 2021 paediatric cancer genetics reference committee. Discussions continued via email and MS Teams. Approved for publication with the following changes made: Target group - Exclusion criteria: Added 'Untested individuals under age 18 years at 50 % risk ....' Added 'Individuals in families who meet classic LFS criteria but where...' Lifetime risk of cancer/tumour: Figures for 'TP53 pathogenic variant carriers to age 20 years' changed to '...from age 18 years' and reference changed 'Wilms tumour, neuroblastoma, lung, colorectal, stomach and pancreatic cancer' removed from last row of table General population risk updated with AIHW 2017 data Cancer/tumour risk management guidelines Sarcoma and other cancer - Surveillance: 'Consider annual whole-body MRI' changed to 'recommend annual...' Brain tumours - Surveillance: 'Consider annual MRI brain' changed to 'Recommend annual dedicated brain MRI alternating 6 monthly with whole-body MRI' Adrenocortical tumours - Surveillance: 'Birth to 10 years' changed to 'Birth to age 18 years' All - Surveillance: 'Biannual clinical review...' changed to 'clinical review with physical examination every 4 months' All - Education: row added to table Footnotes: wording revised Evidence for risk management guidelines: revised Version increased to V.8. Review in 2 years.

Version 7

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.7.
28/01/2021	The following sections of the protocol were updated to align with the revised eviQ cancer genetics risk management template: Summary: template sentence added 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 into account current age, other health issues and residual cancer risk."  Support and information: template wording updated

Version 6

Date	Summary of changes
01/12/2012	Discussed at August 2012 reference committee meeting. Protocol approved for publication.
30/04/2013	Cancer risk management guidelines  surperflous sentence "The nature of the local service will depend on local circumstances" deleted.
26/11/2013	Frequency of review discussed at March 6, 2013 reference committee meeting and discussion continued via email:  Review second yearly.
31/07/2015	Link to AGSA changed to Genetic Alliance Australia.
21/10/2015	Discussed at March 6, 2013 reference committee meeting and the following changes made: Summary - wording updated and TP53 testing criterian ACI link added. Target group - updated. Exclusion criteria - updated. Lifetime risk of cancer - references updated. Cancer risk management guidelines: summary paragraph added table of recommendations added.  Evidence for risk management - wording and references updated. Support and information - referral sentence updated. References - updated.
07/01/2016	Sentence added to Risk Management template: "The impact of lifestyle on cancer risk should be discussed".
14/04/2016	Sentence added to Risk Management template: "This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour.  The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up".
17/02/2017	Protocol discussed at cancer genetics reference committee meeting and the following changes made: Title - changed to Risk Management for children with a TP53 mutation Target group - updated Lifetime risk of cancer - updated Cancer risk management guidelines - updated Evidence for risk management guidelines - updated References - updated. Changed to version 3. Next review in 1 year.
31/05/2017	Transferred to new eviQ website. Version number changed to V.4.
20/02/2019	Protocol reviewed at the May 2018 RC meeting and discussions continued over email.  Version number increased to V.5 and the following sections were amended: Target population - untested individuals <18 years at 50% risk of a known pathogenic mutation in TP53 moved to exclusion criteria Lifetime risk of cancer - figures updated as per references.   Cancer risk management guidelines - Comment re internation consensus guidelines added. Table updated as per references, comment re gadolinium added as footnote to table. Evidence - updated as per recommendations References - updated
29/03/2019	Cancer risk management guidelines section updated outside regular review, to include 'age' to begin surveillance - "from diagnosis++" added to "Consider annual whole body MRI", "Consider annual MRI brain" and "Biannual clinical review...". Table footnote also added - "++Screening MRI should be weighed against the need for a general anaesthetic in young patients." Version kept at V.5. Review date to be kept the same.
28/08/2019	Protocol title changed from 'Risk management for children with a TP53 mutation' to 'TP53 (Li-Fraumeni) – risk management (child)' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.6.