Highly prevalent TP53 mutation predisposing to many cancers in the Brazilian population: a case for newborn screening?
Maria Isabel Waddington Achatz, Pierre Hainaut, Patricia Ashton-Prolla
Lancet Oncol 2009; 10: 920-25
Department of Oncogenetics, Hospital AC Camargo and National Institute of Science and Technology in Oncogenomics, São Paulo, Brazil (M IW Achatz MD); Molecular Carcinogenesis Group, International Agency for Research on Cancer (IARC), Lyon, France (P Hainaut PhD); and Department of Genetics and Molecular Biology, Federal University of Rio Grande do Sul (UFRGS) and Medical Genetics Service, Hospital de Clínicas de Porto Alegre, and National Institute of Science and Technology in Populational Medical Genetics (INAGEMP), Porto Alegre, Brazil (P Ashton-Prolla MD) Correspondence to: Dr Patricia Ashton-Prolla, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Porto Alegre RS 90035-903, Brazil pprolla@hcpa.ufrgs.br
The unusually high population frequency of a germline TP53 mutation (R337H) predisposing to early cancer has led to mass newborn testing for this mutation in the State of Paraná, southern Brazil. Newborn screening for inherited cancer risk is complex and controversial. In this paper, we discuss the justifications for this screening by considering the medical and scientific evidence for this mutation. R337H has been identified in Brazilian families with Li-Fraumeni or related syndromes predisposing to cancers in childhood (ie, brain, renal, and adrenocortical carcinomas), adolescence (ie, soft tissue and bone sarcomas), and young adulthood (ie, breast cancer). R337H has also been detected in children with adrenocortical carcinoma without a documented family history of cancer. The mutation is estimated to occur in about 0.3% of the population in southern Brazil and is associated with increased cancer risk throughout life. Cancer patterns in families positive for R337H suggest strong genetic modifying effects, making it difficult to predict individual risk. Because protocols for cancer-risk management in Li-Fraumeni or related syndromes are debatable, extreme care should prevail in predictive testing of children for R337H. A detailed assessment of the risks, benefits, and costs is needed to ensure that medical, social, and ethical justifications for newborn screening are met.
Introduction
With the rapid development of genetic testing, mass newborn screening for inherited cancer risk is becoming feasible on an unprecedented scale. However, the scientific, medical, and ethical justifications of such screening approaches have not yet been fully considered and assessed (figure 1). A recent screening initiative for a germline TP53 mutation occurring at a high frequency in the population of southern Brazil highlights the complexity of these issues and provides a basis to discuss the implications of predictive newborn screening for cancer risk.
The justifications for presymptomatic and predictive genetic testing in children, including cancer predisposition testing, have been the focus of several systematic reviews.1,2 Guidelines for cancer predisposition testing in asymptomatic children have been published by the American Society of Clinical Oncology, the Canadian College of Medical Geneticists, and the European Society
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of Human Genetics.3-5 There is strong agreement that the justification for such testing should be the benefit of medical interventions or preventive measures for children. In the case of childhood-onset diseases, for which preventive or intervention measures are not available, the recommendation for predictive genetic testing remains open to discussion. Furthermore, the timing of the investigation is also a matter of debate, with a general consensus that it should not be done before the earliest age at which preventive measures are considered useful.
TP53 mutations
Germline TP53 mutations are the underlying genetic defect of Li-Fraumeni syndrome and its variant, Li-Fraumeni-like syndrome, which are complex autosomal dominant disorders characterised by the early occurrence of multiple cancers (Online Mendelian Inheritance in Man [OMIM] #151623).6-8
The spectrum of tumours in carriers of TP53 mutations includes childhood brain, renal, and adrenocortical cancers, soft tissue and bone sarcomas in adolescents, and breast and several other cancers in young adults. The penetrance at age 30 years is about 50%, with a greater than 90% lifetime risk of developing cancer in mutation carriers.9,10 Current estimates, based on a limited population sample, suggest that germline TP53 mutations occur in about one in 5000 individuals.11
Recent studies in cancer-prone families in southeast Brazil have identified a founder germline TP53 mutation at an unusually high prevalence.12 In a region of the country that encompasses the States of São Paulo, Paraná, Santa Catarina, and Rio Grande do Sul, a TP53 mutant at codon 337 (1010G→A, Arg337His) occurs at a frequency of about 1:300 individuals (0-3%), which is much higher than the estimated frequency of other germline TP53 mutations.11,13,14 Initial studies on the TP53 R337H mutation
| Criteria met? | Comments | |
|---|---|---|
| Condition to be screened should be a significant health problem | Yes | Risk of childhood cancer (ie, adrenal cortical carcinoma, renal cancer, and brain cancer): 10-15% by age 15 years; lifetime risk of multiple cancers: 80%. Estimated prevalence of the mutation in the population of southern Brazil: 0.3% |
| The natural history of the condition should be well known | No | Factors that determine individual risk are not sufficiently known, including the effect of modifier genes |
| Condition should have a detectable preclinical phase | Yes | Germline R337H is detectable ahead of any symptom and ahead of a cancer diagnosis. However, genetic testing merely identifies individuals who are at increased risk of developing cancer, because mutation penetrance is age-dependent and incomplete. Furthermore, mutation detection does not predict accurately cancer type or age of occurrence |
| Early detection should be beneficial compared with late detection | Yes | Early cancer detection ensures, in most cases, access to curative treatment protocols |
| An appropriate test should be available for application during the early phase | Yes | Mutation screening is feasible at birth, as a presymptomatic test |
| Test must follow an accepted procedure | Yes | Mutation testing can be done on a minimal blood sample |
| Benefits must outweigh physical and psychological risks | Not assessed | There might be considerable psychological and social risk associated with newborn detection for a mutation associated with a high lifetime risk of cancer, without provision of appropriate counselling to parents, patients, and at-risk relatives. However, the risks of R337H testing in the process of newborn screening have not been assessed |
| Costs must be modest compared with benefits | Not assessed | Costs of genetic testing are expected to be modest with respect to years of life saved, in particular for childhood cancer. However, with an R337H carrier frequency of about 0.3% in southern Brazil, the lifetime follow-up and screening of all mutation-positive individuals with adequate imaging and cancer detection methods entails considerable costs in infrastructure and manpower, which are not met at present |
| Table: Does newborn screening for the germline TP53 mutation R337H meet the Wilson and Jungner criteria? | ||
have claimed that the main, if not exclusive, cancer risk in carriers is childhood adrenal cortical carcinoma, occurring as early as a few months of age with a penetrance of about 10% by the age of 12 years.15,16 However, a more thorough ascertainment of many families with this mutation has shown that the cancer risk is much broader and can encompass the full spectrum of tumours associated with Li-Fraumeni syndrome and its variants, in particular early breast cancer (mean age at diagnosis below 40 years).12,17 Additionally, current data on overall cancer penetrance suggest that the age-related cancer risk is somewhat lower than in Li-Fraumeni syndrome, with tumours detected in about 25% of carriers at the age of 30 years and a lifetime risk of about 80% (S Garritano and colleagues, IARC, personal communication). The high carrier frequency of the TP53 R337H mutant is in the range of that noted for germline BRCA1 and BRCA2 mutations in the general population (1:300-1:600)18 and of the common K304E mutation in the acylcoenzyme A dehydrogenase (ACADM) gene associated with medium-chain acyl-coenzyme A dehydrogenase deficiency (1:100-1:200). Testing for the latter mutation has been introduced in newborn screening programmes in Australia, Germany, the USA, and the UK.19 The high population prevalence of the TP53 R337H mutation in southeast Brazil, in addition to evidence that adrenocortical carcinoma is a major risk in young carriers, has led to the implementation of systematic newborn screening in the Brazilian State of Paraná, which was implemented in 2005.14
Justifications for newborn screening
Newborn genetic screening has major clinical, ethical, and societal implications. In 1968, Wilson and Jungner20 presented clear criteria for setting up a framework for the development of newborn screening programmes. The table shows the scientific and medical evidence currently
available for the R337H TP53 mutant allele, its phenotypic effect in carriers, and its detection, in relation to each of Wilson and Jungner’s criteria. Although these criteria are under review and updated criteria and guidelines should be published shortly,21 the value of the original criteria published in 1968 remains undisputed.
There is no doubt that several of these criteria are met in the present context. First, cancer is a significant health problem, which, in principle, is treatable, and in some cases curable, if detected at an early stage. Second, according to current estimates, the R337H mutation is present in an important proportion of the population in southeast Brazil. Pilot prevalence studies in the States of Rio Grande do Sul and Paraná have both detected carrier frequencies in the range of 0.3%.13,14 However, its prevalence outside these areas, and its variations between communities and ethnic groups, is not known. Third, the test for this mutation (assessment of a single nucleotide change at codon 337) is easy to do using a minimal blood sample and involves procedures that do not cause physical harm for newborns and families. Fourth, the benefits of curing cancer in individuals who develop adrenocortical carcinoma as a result of early diagnosis and intervention would be expected to outweigh the cost of testing and subsequent early detection screening. On the basis of current estimates of age-related penetrance and the prevalence of the mutation in the population of southeast Brazil, the burden of early life cancers due to R337H in this region might represent 5-10% of all childhood and early adult cancers in the population, and 1% of all cancers before the age of 70 years.
However, although the R337H mutation meets many of criteria outlined by Wilson and Jungner, it does not meet them all, due not only to insufficient knowledge of the natural history of the disease, but also to the nature of the test, which identifies a cancer predisposing
A
I
☐ Female
Stomach dx 70
☐ Male
☒ Female affected
☒ Male affected Deceased
II
Lung dx 75
Lung dx 50
III
Liver dx 61
Lung dx 65
Kidney dx 54
IV
WT/R337H Breast dx 32
ACC dx 3
Pancreas dx 54
Lung dx 36
V
B
I
Prostate
II
Unknown
Unknown
III
Kidney dx 51
CRC dx 54
IV
Breast dx 27
ACC dx 13
SNC dx 27
WT/R337H ACC dx1
Kidney dx 31
WT/R337H (28)
V
mutation, but does not actually detect a preclinical phase of the disease.
First, studies on cancer-prone families carrying the R337H mutation show that the individual risk of cancer is extremely variable, and several adult carriers who are unaffected by cancer have been identified, suggesting that there is age-dependent (and possibly incomplete) penetrance of the mutant in certain situations (figure 2). There is evidence that different genetic traits act as penetrance modifiers of TP53 germline mutations, including a single nucleotide polymorphism in MDM2 (SNP309), the principal regulator of P53 protein stability and several intragenic TP53 polymorphisms.22,23 Other modifiers might also exist, as well as interactions with low
penetrance mutations associated with other forms of inherited cancer (eg, variations in PTEN or CHEK2, which predispose to breast cancer by genetic pathways that also involve TP53).24 Thus, the current knowledge is insufficient to accurately predict the individual risk of cancer based on the sole detection of the R337H mutation. In the absence of such knowledge, and in light of the existing evidence, individuals who carry the mutation should be followed up for risk of multiple cancers throughout their lifetime, which would be associated with a substantial cost.
Second, identification of the mutation does not in itself correlate directly with the diagnosis of cancer. Individuals who are positive for the mutation must be directed to medical follow-up within strict protocols, to detect early
cancer. However, the range and scope of the protocols applicable to patients with Li-Fraumeni syndrome, even those with the classical, highly penetrant form of the disease, are still a matter of debate. Early detection screening strategies in small series of families have been shown to be effective for several tumour types associated with the Li-Fraumeni syndrome and Li-Fraumeni-like syndrome spectrum, such as breast cancer, colorectal cancer, and adrenocortical carcinoma.17,25-27 Specifically, for adrenocortical carcinoma, there is a clear relation between stage at disease diagnosis and prognosis; complete surgical en-bloc resection of the tumour is essential to ensure curative results.28 Current guidelines suggest annual clinical follow-up with additional imaging (ie, mammography or colonoscopy) when appropriate.29 A study shows that whole-body PET CT imaging in carriers of TP53 germline mutations (other than R337H) can detect early, preclinical cancer lesions.27 However, one should note that an effective reduction of cancer- related morbidity and mortality in children and adults carrying TP53 mutations has not yet been formally shown. In the case of the R337H mutation, there is currently no data to establish the appropriate scope and method for cost-effective monitoring and follow-up in carriers of this mutation.
Third, newborn screening can be associated with considerable psychological and social risks to the screened individuals and their families, because the exact effect and outcomes of a positive result are not well defined. Current guidelines on Li-Fraumeni syndrome do not recommend newborn or childhood testing. There is no clear procedure to control the use and dissemination of the information on screening results, or to provide a counselling framework of when screening results will be shared with individuals and what the content of information will be on the lifetime attributable risks for developing cancer. Knowledge about carriage of a deleterious TP53 mutation can have a profound psychological effect in addition to adverse effects on employment, relationships, and social integration.
The implementation of a test into mandatory newborn screening programmes should begin with evidence to show the clinical validity (ie, the test correctly identifies future disease risk) and clinical usefulness (ie, a clear guideline of effective interventions to reduce risk or improve the health of those with positive results) of the test. Historically, many newborn screening tests were introduced under the assumption that they would lead to improved health and pose little or no risk to the individuals being tested, without previous population-based studies addressing both clinical validity and usefulness.3º As a result of that fact that exposure to unforeseen and unnecessary risks has been shown to occur, there has been an increasing effort to undertake crucial and comprehensive pilot studies on the implementation of such tests before their introduction in newborn screening programmes.31-33 The Quebec Neuroblastoma Screening
Project (QNSP) emphasises this point. Mass screening for neuroblastoma in about 500 000 infants born in the province of Quebec, Canada, during a period of 6 years, did not result in a reduction of disease-related mortality and caused adverse health effects. Moreover, an assessment of the benefits and costs of QNSP showed that, by not implementing similar screening programmes in the USA and other provinces of Canada, substantial savings in health costs were made and unnecessary treatments, and anxiety due to false-positive findings, were avoided in thousands of families. 34,35
An important consideration within the scope of predictive genetic testing in newborn screening programmes is the need for individual informed consent, and, ideally, pretest genetic counselling, which are currently not obtained or available in routine newborn screening programmes for other disorders (ie, phenylketonuria, hypothyroidism, and sickle-cell disease) in many countries, including Brazil. Such procedures are especially important in the situation of the R337H mutation, which involves predictive testing of children for a cancer predisposing allele whose penetrance is not entirely determined. In clinical settings, there is a strong recommendation for offering predictive and even diagnostic germline TP53 mutation testing only after genetic counselling by a trained professional has been completed and informed consent has been obtained.36-39 Additionally, the beneficial and harmful effects associated with the process of predictive testing itself on the newborn’s parents and family, which have been shown in several studies and are independent from the actual test findings, must be considered, but would be difficult to address in a setting of mass population screening.38-41 Finally, the issues of insurance coverage, need for confidentiality, and restricted access of insurance companies to the information obtained in newborn screening programmes, to prevent discrimination, should be addressed. 42,43
Conclusion
On the basis of current scientific and medical knowledge, the R337H mutation does not meet all the criteria for mass newborn screening outside a comprehensive familial cancer-risk assessment, and screening and counselling programmes, based on the exclusive risk of childhood adrenal cortical carcinomas, are not sufficient, in view of the potentially broad range of adult cancers associated with this mutation. We emphasise the need for increased awareness, information, and training of the medical community to better identify families with a high cancer risk and refer them to programmes for a detailed assessment of hereditary cancer patterns. Due to the high prevalence of the R337H mutation in southeast Brazil, testing in a familial context should be considered as an alternative for families from this geographical region that match the clinical definition of any syndrome with multiple inherited tumours and in whom mutation testing
Search strategy and selection criteria
References for this Health-care Development were found by searches of the PubMed and SciELO online library (http:// www.scielo.br/) by use of the search terms “hereditary cancer”, “newborn screening”, “cancer predisposition testing” and “minors”, and “predictive genetic testing”. Results from PhD thesis or reports from meetings were included only when they related directly to previously published work. Papers published in Portuguese and English between October, 1968 and January, 2009 were reviewed and considered for inclusion.
for candidate genes, such as BRCA1, BRCA2, or mismatch repair genes, has given negative results. We therefore believe that newborn or childhood predictive genetic testing for R337H should not be done in mass screening programmes; although this might be a suitable approach in some families on a case-by-case basis, and within counselling and follow-up strategies that take into account the wide diversity of tumour patterns in mutation carriers. Implementation of genetic testing on a wider scale will need much more detailed knowledge of the prevalence of the mutation, of its age-dependent penetrance, and of the effects of genetic modifiers. Evidence of the clinical validity and usefulness of such interventions and well-designed assessments of its risks, benefits, and costs, will be important to ensure that the scientific, social, and ethical justifications of such screening approaches are met.
Contributors
All authors contributed equally to concept, discussion, writing, and review of the paper.
Conflicts of interest
The authors declared no conflicts of interest.
Acknowledgments
The authors thank Ricardo Renzo Brentani, José Roberto Goldim, Magali Olivier, and Edenir Palmero for stimulating discussions on this theme, and Patricia Izetti Ribeiro and Amanda Nóbrega for help with the pedigrees.
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