€ URRENT PINION
Surveillance recommendations for patients with germline TP53 mutations
Mandy L. Ballingera,b, Gillian Mitchella,b,c, and David M. Thomasa,b,d
Purpose of review
Li-Fraumeni syndrome is associated with germline TP53 mutations and carriers have a high lifetime risk of cancer, the most common being sarcoma, breast cancer, brain tumors, adrenocortical carcinoma and leukemia. Germline TP53 mutation carriers are increasingly being identified as more genomic sequencing is performed in both clinical and research settings. There is a pressing clinical need for effective cancer risk management approaches in this group.
Recent findings
Current clinical surveillance guidelines mainly focus on breast and bowel cancer risk with little consideration for the other cancers common to the syndrome. Imaging technologies are such that the utilization of whole-body MRI imaging for surveillance is viable. Globally, several research groups have included whole-body MRI along with other diagnostic measures in formulating surveillance protocols for TP53 mutation carriers. Early reports suggest a survival benefit.
Summary
Surveillance protocols for TP53 mutation carriers have the potential to improve outcomes in individuals and families. Further research is needed to guide the development of an effective and comprehensive surveillance schedule.
Keywords
Li-Fraumeni syndrome, TP53 gene, whole-body MRI
INTRODUCTION
Li-Fraumeni syndrome (LFS) is a familial cancer predisposition syndrome associated with germline TP53 mutations. Mutation carriers are at a signifi- cantly increased risk of several cancer types, the most common being breast cancer, sarcomas, brain tumors, adrenocortical carcinoma (ACC) and leuke- mias. Traditionally, LFS families have been ascer- tained through the presence of strong family cancer histories, but as genomic sequencing capacities improve and become less expensive, TP53 mutation carriers are increasingly being identified in other settings independent of family history. Unlike more common heritable cancers, such as breast and colo- rectal cancer in which well established organ- specific cancer prevention and early detection strategies exist, in LFS, the risk of multiorgan tumorigenesis cancer risk management presents a considerable challenge.
In the past, there has generally been a somewhat nihilistic attitude toward clinical management of TP53 mutation carriers, but there is now an increased call for renewed efforts in this area. This
is partly driven by the emergence of new screening methods. MRI first became clinically available in the 1980s and is now widely used for surveillance of individuals at risk of hereditary breast cancer. The availability of whole-body imaging protocols and the absence of ionizing radiation renders MRI potentially suitable for long-term surveillance in the radiosensitive TP53 mutation carrier popu- lation. This article covers the current clinical sur- veillance guidelines for germline TP53 mutation carriers, outlines previous surveillance studies and
ªSir Peter MacCallum Department of Oncology, University of Melbourne, bResearch Division, Peter MacCallum Cancer Centre, Melbourne, Vic- toria, Australia, “Hereditary Cancer Program, BC Cancer Agency, Van- couver, British Columbia, Canada and ªThe Kinghorn Cancer Centre and Cancer Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
Correspondence to Mandy L. Ballinger, Research Division, Peter Mac- Callum Cancer Centre, Locked Bag 1 A’Beckett Street, Melbourne, VIC 8006, Australia. Tel: +61 3 9656 5885; fax: +61 3 9656 5208; e-mail: mandy.ballinger@petermac.org
Curr Opin Oncol 2015, 27:332-337 DOI:10.1097/CCO.0000000000000200
KEY POINTS
· Germline TP53 mutation carriers are increasingly being identified through genomic testing.
· TP53 mutation carriers have a high lifetime cancer risk and comprehensive cancer risk management is a pressing clinical need.
· Globally, several comprehensive surveillance research protocols utilizing WB-MRI are underway.
· Longer-term evaluation of surveillance schedules for TP53 mutation carriers is needed.
details the research efforts currently underway. Last, a comprehensive surveillance schedule is endorsed, aimed at achieving an international consensus until the time when sufficient data will inform a standard of care for TP53 mutation carriers.
LI-FRAUMENI SYNDROME AND TP53
Li and Fraumeni [1] initially described four families in which the high frequency of cancer suggested a familial syndrome of neoplastic diseases. In 1988, this was expanded to 24 families in which bone and soft tissue sarcomas, breast cancers, brain tumors, leukemia and ACCs were seen in high incidence [2] and this constellation became known as LFS. These and additional studies revealed the syndrome to be an autosomal dominant hereditary cancer predis- position condition [3,4]. The association between the tumor suppressor gene TP53 and LFS was made in 1990 when LFS families were found to harbor germline TP53 mutations [5,6]. To date, over 700 TP53 mutations have been described in the germline of approximately 760 families [7].
After LFS was originally defined [2], the obser- vation of Li-Fraumeni-like families has led to the formulation of alternate criteria. Approximately 70% of families meeting the classic LFS definition have germline TP53 mutations [8]. The Chompret criteria have evolved over time and aim to identify the most suitable candidates for TP53 genetic testing [9-11]. Importantly, the criteria take into account individuals with multiple malignancies (which may be due to de-novo mutations) with 21-35% of those meeting the updated criteria shown to be carriers [10,12,13].
CANCER RISK
There is a wide spectrum of TP53-associated malig- nancies observed in LFS families. The most common are premenopausal breast cancer and sarcomas
(bone and soft tissue) accounting for approximately 27 [14] and 25% [15] of cancers, respectively. Other characteristic LFS cancers are brain tumors and leu- kemias [7]. In childhood, the most common cancers are ACC, choroid plexus carcinoma, gliomas and medulloblastoma [16]. An increased incidence of melanoma, lymphoma, pancreatic, lung, prostate and ovarian cancers [7,17] has been recorded with gastric [18] and colorectal cancers [19] and malig- nant phyllodes breast tumors [20] also possibly associated. Recently, anaplastic rhabdomyosarcoma [15,21] and sonic hedgehog-subtype medulloblas- toma [22] have been associated with germline TP53 mutations.
Cancer risk estimates in TP53 mutation carriers have largely been based on families ascertained using classic or Chompret criteria that, by defi- nition, require significant family cancer histories. In such settings, 49% of women and 21% of men will develop cancer by the age of 30 years [23], increasing to almost 100% of women and 73% of men over a lifetime [24,25]. There is also an increased risk of second and subsequent cancers [12,26,27]. Sarcoma- affected TP53 mutation carriers are more likely to have multiple primary cancers than noncarriers [27]. Given the current cure rates in many cancers, there is clearly a need for adequate secondary sur- veillance in this population.
Genotype-phenotype correlations have been observed in TP53 mutation carriers. Early age at diagnosis is associated with nonsense, frameshift and splice mutations [17]. Missense mutations in the DNA-binding domain are often in families with breast cancer and brain tumors. The R337H variant that occurs in exon 10 is prevalent among TP53 mutation carriers in Southern Brazil and is strongly associated with ACC [28]. Choroid plexus carci- nomas, leukemia and breast cancers also occur at increased incidence in these families [20,29].
A number of genetic modifiers have been identified in TP53 mutation carriers that may play a role in cancer susceptibility. These include MDM2 SNP309 [30-32] and TP53 polymorphisms PIN2, PIN3 and PEX4 [33]. Telomere shortening has been associated with an increasingly earlier age of cancer onset in successive generations of TP53 mutation carriers [34,35], and DNA copy number variation may play a role in determining phenotype [36].
Individuals and families ascertained via approaches blinded to family history may have a reduced lifetime cancer risk compared with those ascertained on family history [17,27]. Indeed, as more TP53 mutation carriers are identified, the range of associated phenotypes will continue to expand and contribute to further understanding
the differences in TP53-related cancer susceptibility. Cancer risk estimates in TP53 mutation carriers will be revised over time, and these may need to be calculated and presented in an ascertainment- specific manner.
CURRENT SURVEILLANCE RECOMMENDATIONS
Current clinical guidelines for cancer surveillance in mutant TP53 carriers focus predominantly on breast and bowel cancer for which surveillance regimes are recognized to be beneficial, albeit evaluated in other settings such as familial breast and familial bowel cancer (Table 1). For TP53 mutation carriers, the National Comprehensive Cancer Network recom- mends a surveillance schedule that includes clinical breast examination, breast MRI and mammogram in various age brackets from 20 years of age [37]. An annual comprehensive physical examination, colon- oscopy every 2-5 years and additional surveillance based on individual family histories is also recom- mended [37]. The UK National Institute for Health and Care Excellence recommends annual breast MRI [38]. In Australia, annual physical examination and breast MRI is recommended along with colonoscopy 2-5 yearly dependent on family history [39]. These surveillance recommendations do not take into account other common TP53-associated malignan- cies such as sarcomas and brain tumors, which both depend on effective surgery to achieve the best outcomes.
PREVIOUS SURVEILLANCE STUDIES
There have been few studies investigating a whole- body approach to surveillance in the TP53 popu- lation. Given the rarity of the condition, there are a relatively small number of eligible individuals for such studies and as such randomized, controlled, trial designs are not feasible. An early report utilized F18-fluorodeoxyglucose (FDG)-PET/computed tom- ography in a whole-body approach to surveillance [40]. Baseline scans detected malignancies in 3/15 (20%) TP53 mutation carriers. Although the levels of radiation exposure using F18-fluorodeoxyglucose- PET/computed tomography were acknowledged as not ideal in this population, the study nevertheless demonstrated the potential value in a whole-body approach to surveillance [40]. In 2011, Villani et al. [41”] described a comprehensive surveillance study employing whole-body MRI (WB-MRI) in 33 indi- viduals from eight mutant TP53 families. Of 33 adult and pediatric TP53 mutation carriers, 18 individuals self-selected for the comprehensive surveillance group with another 16 opting for standard care (one individual was in both the groups at different time points). Over a 3-year interval, 12 high-grade malignancies were observed in the nonsurveill- ance group compared with 10 tumors (five cancers, three low-grade gliomas, one myelodysplastic syn- drome and one thyroid adenoma) in seven individ- uals in the surveillance group. Overall survival (3 years) was 100% in the surveillance group compared with 21% in the nonsurveillance group [41”]. Despite some limitations including a small sample
| Organization | Country | |
|---|---|---|
| National Comprehensive Cancer Network (NCCN) | USA | Annual complete physical examination (including skin and neurologic examination) |
| Breast | ||
| Clinical examination every 6-12 months (age 20-25 years) | ||
| Annual MRI (preferred) or MMG (age 20-29 years) | ||
| Annual MRI and MMG (age 30-75 years) | ||
| Colorectal | ||
| Colonoscopy every 2-5 years (starting age 25 years) | ||
| National Institute for Health and Care Excellence (NICE) | United Kingdom | Breast |
| Annual MRI (age above 20 years) | ||
| eviQ | Australia | Annual complete physical examination |
| Breast | ||
| Annual MRI (age 20-50 years) | ||
| Colorectal | ||
| Colonoscopy every 2-5 years dependent on family history (age above 25 years) |
MMG, mammogram.
size, the inclusion of some retrospective patient data and participant self-selection into the comparator groups introducing a potential source of bias, the study demonstrated the feasibility of a comprehen- sive surveillance protocol in the TP53 population. A recent study in Southern Brazil offered neonatal screening for the TP53 R337H mutation and sub- sequent surveillance for adrenocortical tumors (ACTs) in mutation carriers [42""]. Of 699 mutation carriers, 347 (49.6%) self-selected for surveillance. The seven ACTs detected in the surveillance group were lesser in weight (P=0.003), lower in volume (P=0.007) and the children undergoing surveil- lance displayed less virilization compared with the nonsurveillance group (eight ACTs). All surveillance participants (n=7) diagnosed with ACTs remained disease free 31-48 months after diagnosis compared with two out of eight patients that relapsed in the nonsurveillance group and one of these who suc- cumbed to the disease [42""]. Although this study is large, population based and occurred across multiple centers, it applies to the TP53 R337H mutation only and focuses on ACTs that occur at increased frequency in this population. Extrapol- ation of the findings to other TP53 mutation carry- ing populations is potentially fraught.
CONSIDERATIONS IN SURVEILLANCE OF TP53 MUTATION CARRIERS
Assessing cancer susceptibility in TP53 mutation carriers presents challenges. Although TP53 mutations appear highly penetrant in LFS, as more mutation carriers are identified by family history- independent mechanisms, the TP53-associated phe- notypes are becoming more varied. This may be due to de-novo mutations, mosaicism, genetic modifiers or variations in TP53 allele penetrance, and long- term clinical information will be important in deter- mining the effect of these. Limiting radiation exposure also appears important in TP53 mutation carriers [43], so extended surveillance schedules should exclude radiation exposure as far as practi- cable. Working toward understanding the factors contributing to TP53-associated cancer risk is highly relevant as clinical management strategies aim to become increasingly personalized. At present, there are insufficient data on which to construct a set of clinical guidelines that accounts for a spectrum of TP53-associated risk, so any surveillance recommen- dations are necessarily targeted at the TP53 core cancers and tailored according to family history.
Children that harbor TP53 mutations are at significantly increased risk of cancer [24]. This susceptibility at an early age presents many psycho- logical and ethical issues for families and healthcare
professionals in terms of genetic testing and surveil- lance [44,45]. Consideration of all the implications and the provision of cross-disciplinary care are required to achieve effective management.
The psychological impact of participating in a comprehensive surveillance program on TP53 mutation carriers is unknown. Psychological benefit was reported in LFS individuals that had undergone a range of regular surveillance [46]. In other high cancer risk populations, both positive and negative impacts have been reported [47-49]. It is imperative that the acceptability and psychological impact of surveillance in TP53 mutation carriers be investi- gated and understood.
CURRENT SURVEILLANCE RESEARCH PROTOCOLS
Globally, many groups are currently implementing comprehensive surveillance protocols for TP53 mutation carriers in the clinical research setting. The ‘Toronto Protocol’ [41”] as detailed earlier con- tinues to recruit children and adults in Canada and several sites in the United States. In France, the LIFSCREEN project (eligibility 5-70 years of age) is randomizing asymptomatic TP53 mutation carriers to two arms: current recommended clinical surveillance or current recommended clinical surveillance with the addition of WB-MRI over 2 years, with evaluation of cancer incidence over 3 years being the primary objective [50]. The Magnetic Resonance imaging Screening in Li Fraumeni Syndrome (SIGNIFY) study in the United Kingdom is utilizing WB-MRI to com- pare cancer incidence in adult TP53 mutation carriers compared with control patients [51]. In Australia, the Surveillance Study in Multi-Organ Cancer Prone Syn- dromes (SMOC) study in adult TP53 mutation carriers has a surveillance schedule including annual WB- MRI, physical examination, fecal occult blood test, colonoscopy, breast MRI and full blood evaluation [52]. A comprehensive project investigating many aspects of LFS including development of a cancer surveillance program is being led by the National Institutes of Health Clinical Center in the United States [53]. A Li-Fraumeni WB-MRI study for children and adults is running out of the Dana-Farber Cancer Institute [54] and a Brazilian study based on the Toronto Protocol is also underway. A number of these studies are investigating the psychological impacts of undergoing comprehensive surveillance.
PROPOSED COMPREHENSIVE SURVEILLANCE SCHEDULE
There is currently no level 1 evidence [55,56] on surveillance methods and their efficacy in TP53 mutation carriers. Principles to inform the
| Cancer | Starting age | Surveillance method | Frequency |
|---|---|---|---|
| ACC | Birth - 10 years | Abdominal ultrasonography | 3-4 monthly |
| Breast | 18 years | Breast self-examination | |
| 20-25 years | Clinical breast examination | 6-12 monthly | |
| 20-25 years until 50 years | Breast MRI | Annually | |
| Brain | Potentially childhood | WB-MRI | Annually |
| Sarcoma | Potentially childhood | WB-MRI | Annually |
| Leukemia | 18 years | Full blood evaluation | Annually |
| Colorectal | 25 years (earlier if indicated by family history) | Colonoscopy | 2-5 yearly |
| Fecal occult blood test | Intervening years | ||
| Gastric | 25 years (earlier if indicated by family history) | Endoscopy | 2-5 yearly |
ACC, adrenocortical carcinoma; WB-MRI, whole-body MRI.
development of surveillance schedules are well established [57,58] and appear consistent with sur- veillance for most TP53-associated malignancies. An evidence-based surveillance schedule has been pro- posed previously that aims at providing a template for international consensus whereas research efforts into the many facets of participating in a compre- hensive surveillance protocol for TP53 mutation carriers are ongoing [59”]. The proposed schedule (Table 2) includes annual physical examination, WB-MRI including brain, additional breast MRI and clinical breast examination for females, fecal occult blood test, full blood evaluation, abdominal ultrasound, blood hormone levels (optional) and additional investigations deemed clinically appro- priate that may include colonoscopy and upper gastrointestinal endoscopy.
The use of WB-MRI as part of a comprehensive surveillance strategy for TP53 mutation carriers is attractive for a number of reasons including the lack of ionizing radiation, the ability to scan the entire body and the sensitivity of the technique to many of the LFS cancers, especially sarcomas. However, the need for further investigations in this group that has a concerning a-priori cancer risk, and therefore arouses a high level of clinical suspicion, is some- thing that must be managed cautiously, particularly if invasive further investigations are being contem- plated. These issues are being addressed specifically in the SIGNIFY and SMOC research protocols detailed previously.
CONCLUSION
Comprehensive surveillance in TP53 mutation carriers may improve clinical outcomes. Research into some aspects of surveillance is underway but further work is needed to evaluate surveillance schedules in this cancer-prone population more
fully. Owing to the small number of mutant TP53 carriers, unified efforts across multiple centers will most likely be necessary to investigate all aspects of surveillance satisfactorily. In the meantime, a con- sistent approach to surveillance in TP53 mutation carriers may provide further insights while more detailed studies are underway.
Acknowledgements
The authors wish to acknowledge useful discussions with Mary-Anne Young, Paul James, Kate McBride and Sue Shanley.
Financial support and sponsorship
This work was supported by grants from Cancer Aus- tralia (APP1067094), the Johanna Sewell Research Foundation and the Rainbows for Kate Foundation. D.M.T. is supported by an Australian National Health and Medical Research Council Senior Research Fellow- ship (GNT1003929).
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
of special interest
of outstanding interest
1. Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neo- plasms. A familial syndrome? Ann Intern Med 1969; 71:747-752.
2. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988; 48:5358-5362.
3. Lynch HT, Mulcahy GM, Harris RE, et al. Genetic and pathologic findings in a kindred with hereditary sarcoma, breast cancer, brain tumors, leukemia, lung, laryngeal, and adrenal cortical carcinoma. Cancer 1978; 41:2055-2064.
4. Strong LC, Stine M, Norsted TL. Cancer in survivors of childhood soft tissue sarcoma and their relatives. J Natl Cancer Inst 1987; 79:1213-1220.
5. Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990; 250:1233-1238.
6. Srivastava S, Zou ZQ, Pirollo K, et al. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 1990; 348:747-749.
7. Petitjean A, Mathe E, Kato S, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 2007; 28:622-629.
8. Varley JM. Germline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat 2003; 21:313-320.
9. Chompret A, Abel A, Stoppa-Lyonnet D, et al. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 2001; 38:43-47.
10. Bougeard G, Sesboue R, Baert-Desurmont S, et al. Molecular basis of the Li- Fraumeni syndrome: an update from the French LFS families. J Med Genet 2008; 45:535-538.
11. Tinat J, Bougeard G, Baert-Desurmont S, et al. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 2009; 27:e108-e109.
12. Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 2009; 27:1250-1256.
13. Ruijs MW, Verhoef S, Rookus MA, et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet 2010; 47:421-428.
14. Masciari S, Dillon DA, Rath M, et al. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat 2012; 133:1125-1130.
15. Ognjanovic S, Olivier M, Bergemann TL, Hainaut P. Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Cancer 2012; 118:1387-1396.
16. Tabori U, Shlien A, Baskin B, et al. TP53 alterations determine clinical subgroups and survival of patients with choroid plexus tumors. J Clin Oncol 2010; 28:1995-2001.
17. Olivier M, Goldgar DE, Sodha N, et al. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 2003; 63:6643-6650.
18. Masciari S, Dewanwala A, Stoffel EM, et al. Gastric cancer in individuals with Li-Fraumeni syndrome. Genet Med 2011; 13:651-657.
19. Wong P, Verselis SJ, Garber JE, et al. Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome. Gastroenterology 2006; 130:73-79.
20. Giacomazzi J, Selistre SG, Rossi C, et al. Li-Fraumeni and Li-Fraumeni-like syndrome among children diagnosed with pediatric cancer in Southern Brazil. Cancer 2013; 119:4341-4349.
21. Hettmer S, Archer NM, Somers GR, et al. Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer 2014; 120:1068-1075.
22. Zhukova N, Ramaswamy V, Remke M, et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol 2013; 31:2927-2935.
23. Hwang SJ, Lozano G, Amos CI, Strong LC. Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet 2003; 72:975-983.
24. Chompret A, Brugieres L, Ronsin M, et al. P53 germline mutations in child- hood cancers and cancer risk for carrier individuals. Br J Cancer 2000; 82:1932-1937.
25. Wu CC, Shete S, Amos CI, Strong LC. Joint effects of germ-line p53 mutation and sex on cancer risk in Li-Fraumeni syndrome. Cancer Res 2006; 66:8287-8292.
26. Hisada M, Garber JE, Fung CY, et al. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 1998; 90:606-611.
27. Mitchell G, Ballinger ML, Wong S, et al. High frequency of germline TP53 mutations in a prospective adult-onset sarcoma cohort. PLoS One 2013; 8:e69026.
28. Ribeiro RC, Sandrini F, Figueiredo B, et al. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcino- ma. Proc Natl Acad Sci USA 2001; 98:9330-9335.
29. Achatz MI, Olivier M, Le Calvez F, et al. The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. Cancer Lett 2007; 245:96-102.
30. Bond GL, Hu W, Bond EE, et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accel- erates tumor formation in humans. Cell 2004; 119:591-602.
31. Ruijs MW, Schmidt MK, Nevanlinna H, et al. The single-nucleotide polymorph- ism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes. Eur J Hum Genet 2007; 15:110-114.
32. Bougeard G, Baert-Desurmont S, Tournier I, et al. Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li- Fraumeni syndrome. J Med Genet 2006; 43:531-533.
33. Marcel V, Palmero EI, Falagan-Lotsch P, et al. TP53 PIN3 and MDM2 SNP309 polymorphisms as genetic modifiers in the Li-Fraumeni syndrome: impact on age at first diagnosis. J Med Genet 2009; 46:766-772.
34. Tabori U, Nanda S, Druker H, et al. Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Cancer Res 2007; 67:1415-1418.
35. Trkova M, Prochazkova K, Krutilkova V, et al. Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age. Cancer 2007; 110:694-702.
36. Shlien A, Tabori U, Marshall CR, et al. Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome. Proc Natl Acad Sci USA 2008; 105:11264-11269.
37. National Comprehensive Cancer Network. Genetic/familial high risk assess- ment: breast and ovarian. Li Fraumeni syndrome management. NCCN Clinical Practice Guidelines in Oncology; Version 2. 2014.
38. National Institute for Health and Care Excellence (NICE). Familial breast cancer: classification and care of people at risk of familial breast cancer and management of breast cancer and related risks in people with a family history of breast cancer. NICE Clinical Guideline 164; June 2013. pp. 29-32.
39. eviQ Cancer Treatments Online. Risk management for Li-Fraumeni syndrome. http://www.eviq.org.au. [Accessed 31 January 2015].
40. Masciari S, Van den Abbeele AD, Diller LR, et al. F18-fluorodeoxyglucose- positron emission tomography/computed tomography screening in Li-Frau- meni syndrome. J Am Med Assoc 2008; 299:1315-1319.
41. Villani A, Tabori U, Schiffman J, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 2011; 12:559-567.
The nature of the research and the rarity of the condition mean that studies run over a number of years.
42. Custodio G, Parise GA, Kiesel Filho N, et al. Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J Clin Oncol 2013; 31:2619-2626.
First study reporting population-based neonatal screening for the TP53 R337H mutation and subsequent surveillance for ACTs.
43. Heymann S, Delaloge S, Rahal A, et al. Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syn- drome. Radiat Oncol 2010; 5:104.
44. Fresneau B, Brugieres L, Caron O, Moutel G. Ethical issues in presympto- matic genetic testing for minors: a dilemma in Li-Fraumeni syndrome. J Genet Couns 2013; 22:315-322.
45. Alderfer MA, Zelley K, Lindell RB, et al. Parent decision-making around the genetic testing of children for germline TP53 mutations. Cancer 2015; 121:286-293.
46. Lammens CR, Bleiker EM, Aaronson NK, et al. Regular surveillance for Li- Fraumeni syndrome: advice, adherence and perceived benefits. Fam Cancer 2010; 9:647-654.
47. Hutton J, Walker LG, Gilbert FJ, et al. Psychological impact and acceptability of magnetic resonance imaging and X-ray mammography: the MARIBS Study. Br J Cancer 2011; 104:578-586.
48. Maheu C, Vodermaier A, Rothenmund H, et al. Pancreatic cancer risk counselling and screening: impact on perceived risk and psychological functioning. Fam Cancer 2010; 9:617-624.
49. Gopie JP, Vasen HF, Tibben A. Surveillance for hereditary cancer: does the benefit outweigh the psychological burden? A systematic review. Crit Rev Oncol Hematol 2012; 83:329-340.
50. LIFSCREEN: evaluation of whole body MRI for early detection of cancers in subjects with P53 mutation. https://clinicaltrials.gov/ct2/show/record/ NCT01464086. [Accessed 27 January 2015].
51. Magnetic resonance imaging screening in Li Fraumeni syndrome (SIGNIFY). https://clinicaltrials.gov/ct2/show/NCT01737255. [Accessed 27 January 2015].
52. Australian New Zealand Clinical Trial Registry. A pilot surveillance study investigating whole body magnetic resonance imaging and other diagnostic procedures in people at high risk of cancer, ACTRN12613000987763. https://anzctr.org.au/. [Accessed 27 January 2015].
53. Clinical and genetic studies of Li-Fraumeni syndrome. https://clinicaltrials .- gov/ct2/show/record/NCT01443468. [Accessed 27 January 2015].
54. Cancer genetics and prevention, Li-Fraumeni whole body BRI study. http:// www.dana-farber.org. [Accessed 27 January 2015].
55. Sackett DL. Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest 1989; 95 (Suppl 2):2S-4S.
56. OCEBM Level of Evidence Working Group. The Oxford 2011 levels of evidence. Oxford Centre for Evidence-Based Medicine. http://www.cebm. net. [Accessed 23 January 2015].
57. Wilson JM, Jungner YG. Principles and practice of mass screening for disease [in Spanish]. Bol Oficina Sanit Panam 1968; 65:281-393.
58. Gray JA. New concepts in screening. Br J Gen Pract 2004; 54:292-298.
59. McBride KA, Ballinger ML, Killick E, et al. Li-Fraumeni syndrome: cancer risk
assessment and clinical management. Nat Rev Clin Oncol 2014; 11:260- 271.
Comprehensive overview of cancer risk and surveillance in TP53 mutation carriers.