Li-Fraumeni syndrome (LFS) is an autosomal-dominant genetic condition which predisposes to a range of different types of cancer. Many members of Li-Fraumeni families have a germline mutation (an gene alteration you are born with) of the TP53 tumor suppressor gene. Compared to the general population, people who inherit a mutant TP53 allele have about a 25-fold increase in the chance of developing cancer by 50 yrs of age.
The LFS Association was founded in 2010 and provides information, advocacy, and support services for individuals and families with LFS. It is a consortium of researchers, medical providers and caregivers to further research and promote optimal care for LFS.
PubMed Central search for free-access publications about Li-Fraumeni syndrome MeSH term: Li-Fraumeni Syndrome US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
This list of publications is regularly updated (Source: PubMed).
Yoshida T, Tajika M, Tanaka T, et al. The Features of Colorectal Tumors in a Patient with Li-Fraumeni Syndrome. Intern Med. 2017; 56(3):295-300 [PubMed] Related Publications
A young woman with Li-Fraumeni syndrome (LFS) was referred to our hospital. On examination, multiple flat neoplasms were detected in addition to semi-pedunculated polyps. Restorative proctocolectomy was performed; one submucosal invasive cancer, two mucosal cancers, and several adenomas with high-grade dysplasia were detected. On immunohistochemical staining with p53, every part of all neoplasms, even the small adenomas, showed strong positive staining. Multiple flat neoplasms may be characteristic of patients with LFS and may have a much higher risk of rapid progression to invasive carcinomas than sporadic neoplasms. Thus, careful and frequent colonoscopy surveillance may be needed for patients with LFS.
BACKGROUND: Cases of multiple tumors are rarely reported in China. In our study, a 57-year-old female patient had concurrent squamous cell carcinoma, mucoepidermoid carcinoma, brain cancer, bone cancer, and thyroid cancer, which has rarely been reported to date. METHODS: To determine the relationship among these multiple cancers, available DNA samples from the thyroid, lung, and skin tumors and from normal thyroid tissue were sequenced using whole exome sequencing. RESULTS: The notable discrepancies of somatic mutations among the 3 tumor tissues indicated that they arose independently, rather than metastasizing from 1 tumor. A novel deleterious germline mutation (chr22:29091846, G->A, p.H371Y) was identified in CHEK2, a Li-Fraumeni syndrome causal gene. Examining the status of this novel mutation in the patient's healthy siblings revealed its de novo origin. CONCLUSION: Our study reports the first case of Li-Fraumeni syndrome-like in Chinese patients and demonstrates the important contribution of de novo mutations in this type of rare disease.
BACKGROUND: Little is known of the mutation and tumor spectrum of Korean patients with Li-Fraumeni syndrome (LFS). Owing to the rarity of LFS, few cases have been reported in Korea thus far. This study aimed to retrospectively review the mutations and clinical characteristics of Korean patients with LFS. METHODS: TP53 mutation was screened in 89 unrelated individuals at the Samsung Medical Center in Korea, from 2004 to 2015. Six additional mutation carriers were obtained from the literature. RESULTS: We identified nine different mutations in 14 Korean patients (male to female ratio=0.3:1). Two such frameshift mutations (p.Pro98Leufs*25, p.Pro27Leufs*17) were novel. The recurrent mutations were located at codons 31 (n=2; p.Val31Ile), 175 (n=3; p.Arg175His), and 273 (n=4; p.Arg273His and p.Arg273Cys). The median age at the first tumor onset was 25 yr. Ten patients (71%) developed multiple primary tumors. A diverse spectrum of tumors was observed, including breast (n=6), osteosarcoma (n=4), brain (n=4), leukemia (n=2), stomach (n=2), thyroid (n=2), lung (n=2), skin (n=2), bladder (n=1), nasal cavity cancer (n=1), and adrenocortical carcinoma (n=1). CONCLUSIONS: There was considerable heterogeneity in the TP53 mutations and tumor spectrum in Korean patients with LFS. Our results suggest shared and different LFS characteristics between Caucasian and Korean patients. This is the first report on the mutation spectrum and clinical characteristics from the largest series of Korean LFS patients.
Somatic mutations in the tumor suppressor gene p53 occur in more than half of all human cancers. Rare germline mutations result in the Li-Fraumeni cancer family syndrome. In this issue ofGenes&Development, Jennis and colleagues (pp. 918-930) use an elegant mouse model to examine the affect of a polymorphism, P47S (rs1800371), in the N terminus of p53 that is found in Africans as well as more than a million African Americans. Remarkably, the single nucleotide change causes the mice to be substantially tumor-prone compared with littermates, suggesting that this allele causes an increased risk of developing cancer. The defect in p53 function is traced to a restriction in downstream gene regulation that reduces cell death in response to stress.
Walcott FL, Patel J, Lubet R, et al. Hereditary cancer syndromes as model systems for chemopreventive agent development. Semin Oncol. 2016; 43(1):134-45 [PubMed] Related Publications
Research in chemoprevention has undergone a shift in emphasis for pragmatic reasons from large, phase III randomized studies to earlier phase studies focused on safety, mechanisms, and utilization of surrogate endpoints such as biomarkers instead of cancer incidence. This transition permits trials to be conducted in smaller populations and at substantially reduced costs while still yielding valuable information. This article will summarize some of the current chemoprevention challenges and the justification for the use of animal models to facilitate identification and testing of chemopreventive agents as illustrated though four inherited cancer syndromes. Preclinical models of inherited cancer syndromes serve as prototypical systems in which chemopreventive agents can be developed for ultimate application to both the sporadic and inherited cancer settings.
Malkin D Li-Fraumeni Syndrome and p53 in 2015: Celebrating their Silver Anniversary. Clin Invest Med. 2016; 39(1):E37-47 [PubMed] Related Publications
In a typical morning in the Cancer Genetics Clinic at The Hospital for Sick Children in Toronto, the following array of patients and families might be seen: a family of three children, all harbouring a mutation of the succinyl dehydrogenase C gene inherited from their father who had had extensive surgery several years ago for a secreting paraganglioma; three families with Li-Fraumeni syndrome, each with at least one child harbouring a TP53 gene mutation conferring a lifetime risk of cancer approaching 100% and currently undergoing surveillance for early tumour detection; two children with Li-Fraumeni syndrome undergoing treatment for cancer - one having had three cancer diagnoses before 19 months of age and the other just completing therapy for metastatic adrenocortical carcinoma at age 3; two children with von Hippel-Lindau disease being monitored for persistent pancreatic neuroendocrine tumors and cerebellar hemangioblastomas, respectively; and one child with Beckwith-Wiedeman syndrome and Wilms tumor and another child completing therapy for a pleuropulmonary blastoma (PPB).
Macedo GS, Araujo Vieira I, Brandalize AP, et al. Rare germline variant (rs78378222) in the TP53 3' UTR: Evidence for a new mechanism of cancer predisposition in Li-Fraumeni syndrome. Cancer Genet. 2016; 209(3):97-106 [PubMed] Related Publications
Germline mutations in TP53 are the underlying defects in Li-Fraumeni syndrome (LFS) and its variant, Li-Fraumeni-like (LFL) Syndrome, autosomal dominant disorders that are characterized by predisposition to multiple early onset cancers. Here, we identified rs78378222 (A > C), a rare variant that is located in the 3' untranslated region (3' UTR) of TP53, in 7 probands (5.4%) of a cohort from LFS/LFL patients without TP53 germline mutations in the coding regions. To support its association with the LFS/LFL phenotype, we assessed p53 expression in tumor specimens and fibroblasts from rs78378222[C] carriers. Additionally, we investigated using in silico tools the evolutionary conservation and whether rs78378222[C] affects microRNA (miRNA) binding sites in the 3' UTR of TP53 mRNA. We found lower p53 protein levels in biological samples from rs78378222[C] carriers. Additionally, we showed that rs78378222[C] could interfere with a putative target site of miR-545-3p, a novel miRNA that is predicted to directly target the 3' UTR TP53. To our knowledge, this is the first description of rs78378222[C] in LFS/LFL patients. Moreover, these findings suggest that rs78378222[C] lead to haploinsufficiency of p53, a new mechanism of carcinogenesis in LFS/LFL.
Li Fraumeni syndrome (LFS) is a rare familial cancer predisposition syndrome with autosomal-dominant inheritance, occurring as frequently as one in 5,000-20,000 individuals. However, no LFS case has been reported from mainland China although it constitutes one quarter of population on earth. In this study, we identified, to our best knowledge, the first Li Fraumeni syndrome family in China. Six family members were affected with various tumors. A TP53 mutation (c.730G > A; p.G244S) co-segregated with the tumor phenotype within this family. Functional analysis indicated that G244S mutation disrupted the transactivity, DNA-binding and cell growth inhibition activity of p53 protein. Two available tumor samples (medulloblastoma and choroid plexus papilloma) underwent large rearrangement in the chromosomes and loss of wild-type TP53. Our data warranted further studies on the prevalence of germline TP53 mutation in various tumor patients in China.
Li X, Kang J, Pan Q, et al. Genetic analysis in a patient with nine primary malignant neoplasms: a rare case of Li-Fraumeni syndrome. Oncol Rep. 2016; 35(3):1519-28 [PubMed] Related Publications
To identify rare mutations and retrospectively estimate the cancer risk of a 45-year old female patient diagnosed with Li-Fraumeni syndrome (LFS), who developed nine primary malignant neoplasms in a period of 38 years, we conducted next-generation sequencing in this patient. Whole-genome and whole-exome sequencing were performed in DNA of whole blood obtained a year prior to the diagnosis of acute myeloid leukemia (AML) and at the time of diagnosis of AML, respectively. We analyzed rare mutations in cancer susceptibility genes using a candidate strategy and estimated cancer risk using the Risk-O-Gram algorithm. We found rare mutations in cancer susceptibility genes associated with an increased hereditary cancer risk in the patient. Notably, the number of mutated genes in p53 signaling pathway was significantly higher than expected (p=0.02). However, the phenotype of multiple malignant neoplasms of the studied patient was unlikely to be caused by accumulation of common cancer risk alleles. In conclusion, we established the mutation profile in a rare case of Li-Fraumeni syndrome, illustrating that the rare mutations rather than the cumulative of common risk alleles leading to an increased cancer risk in the patient.
Paskulin DD, Giacomazzi J, Achatz MI, et al. Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) Founder Mutation: Clues from Haplotyping of Short Tandem Repeats on Chromosome 17p. PLoS One. 2015; 10(11):e0143262 [PubMed] Free Access to Full ArticleRelated Publications
Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil. This mutation is associated with partially penetrant LFS traits and is found in the germline of patients with early cancers of the LFS spectrum unselected for familial history. To characterize the extended haplotypes carrying the mutation, we have genotyped 9 short tandem repeats on chromosome 17p in 12 trios of Brazilian p.Arg337His carriers. Results confirm that all share a common ancestor haplotype of Caucasian/Portuguese-Iberic origin, distant in about 72-84 generations (2000 years assuming a 25 years intergenerational distance) and thus pre-dating European migration to Brazil. So far, the founder p.Arg337His haplotype has not been detected outside Brazil, with the exception of two residents of Portugal, one of them of Brazilian origin. On the other hand, increased meiotic recombination in p.Arg337His carriers may account for higher than expected haplotype diversity. Further studies comparing haplotypes in populations of Brazil and of other areas of Portuguese migration are needed to understand the historical context of this mutation in Brazil.
Phang BH, Othman R, Bougeard G, et al. Amino-terminal p53 mutations lead to expression of apoptosis proficient p47 and prognosticate better survival, but predispose to tumorigenesis. Proc Natl Acad Sci U S A. 2015; 112(46):E6349-58 [PubMed] Free Access to Full ArticleRelated Publications
Whereas most mutations in p53 occur in the DNA-binding domain and lead to its functional inactivation, their relevance in the amino-terminal transactivation domain is unclear. We show here that amino-terminal p53 (ATp53) mutations often result in the abrogation of full-length p53 expression, but concomitantly lead to the expression of the amino-terminally truncated p47 isoform. Using genetically modified cancer cells that only express p47, we demonstrate it to be up-regulated in response to various stimuli, and to contribute to cell death, through its ability to selectively activate a group of apoptotic target genes. Target gene selectivity is influenced by K382 acetylation, which depends on the amino terminus, and is required for recruitment of selective cofactors. Consistently, cancers capable of expressing p47 had a better overall survival. Nonetheless, retention of the apoptotic function appears insufficient for tumor suppression, because these mutations are also found in the germ line and lead to Li-Fraumeni syndrome. These data from ATp53 mutations collectively demonstrate that p53's apoptosis proficiency is dispensable for tumor suppression, but could prognosticate better survival.
Giacomazzi CR, Giacomazzi J, Netto CB, et al. Pediatric cancer and Li-Fraumeni/Li-Fraumeni-like syndromes: a review for the pediatrician. Rev Assoc Med Bras (1992). 2015 May-Jun; 61(3):282-9 [PubMed] Related Publications
INTRODUCTION: cancer is the second leading cause of death in children between the ages of 0 and 14 years, corresponding to approximately 3% of all cases diagnosed in Brazil. A significant percentage (5-10%) of pediatric cancers are associated with hereditary cancer syndromes, including Li-Fraumeni/Li-Fraumeni-like syndromes (LFS/LFL), both of which are caused by TP53 germline mutations. Recent studies have shown that a specific TP53 mutation, known as p.R337H, is present in 1 in 300 newborns in Southern and Southeast Brazil. In addition, a significant percentage of children with LFS/LFL spectrum tumors in the region have a family history compatible with LFS/LFL. OBJECTIVE: to review clinical relevant aspects of LFS/LFL by our multidisciplinary team with focus on pediatric cancer. METHODS: the NCBI (PubMed) and SciELO databases were consulted using the keywords Li-Fraumeni syndrome, Li-Fraumeni-like syndrome and pediatric cancer; and all manuscripts published between 1990 and 2014 using these keywords were retrieved and reviewed. CONCLUSION: although LFS/LFL is considered a rare disease, it appears to be substantially more common in certain geographic regions. Recognition of population- specific risks for the syndrome is important for adequate management of hereditary cancer patients and families. In Southern and Southeastern Brazil, LFS/ LFL should be considered in the differential diagnosis of children with cancer, especially if within the spectrum of the syndrome. Due to the complexities of these syndromes, a multidisciplinary approach should be sought for the counseling, diagnosis and management of patients and families affected by these disorders. Pediatricians and pediatric oncologists in areas with high prevalence of hereditary cancer syndromes have a central role in the recognition and proper referral of patients and families to genetic cancer risk evaluation and management programs.
IMPORTANCE: Li-Fraumeni syndrome, usually characterized by germline TP53 mutations, is associated with markedly elevated lifetime risks of multiple cancers, and has been linked to an increased risk of early-onset colorectal cancer. OBJECTIVE: To examine the frequency of germline TP53 alterations in patients with early-onset colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter cross-sectional cohort study of individuals recruited to the Colon Cancer Family Registry (CCFR) from 1998 through 2007 (genetic testing data updated as of January 2015). Both population-based and clinic-based patients in the United States, Canada, Australia, and New Zealand were recruited to the CCFR. Demographic information, clinical history, and family history data were obtained at enrollment. Biospecimens were collected from consenting probands and families, including microsatellite instability and DNA mismatch repair immunohistochemistry results. A total of a 510 individuals diagnosed as having colorectal cancer at age 40 years or younger and lacking a known hereditary cancer syndrome were identified from the CCFR as being potentially eligible. Fifty-three participants were excluded owing to subsequent identification of germline mutations in DNA mismatch repair genes (n = 47) or biallelic MUTYH mutations (n = 6). INTERVENTIONS: Germline sequencing of the TP53 gene was performed. Identified TP53 alterations were assessed for pathogenicity using literature and international mutation database searches and in silico prediction models. MAIN OUTCOMES AND MEASURES: Frequency of nonsynonymous germline TP53 alterations. RESULTS: Among 457 eligible participants (314, population-based; 143, clinic-based; median age at diagnosis, 36 years [range, 15-40 years]), 6 (1.3%; 95% CI, 0.5%-2.8%) carried germline missense TP53 alterations, none of whom met clinical criteria for Li-Fraumeni syndrome. Four of the identified TP53 alterations have been previously described in the literature in probands with clinical features of Li-Fraumeni syndrome, and 2 were novel alterations. CONCLUSIONS AND RELEVANCE: In a large cohort of patients with early-onset colorectal cancer, germline TP53 mutations were detected at a frequency comparable with the published prevalence of germline APC mutations in colorectal cancer. With the increasing use of multigene next-generation sequencing panels in hereditary cancer risk assessment, clinicians will be faced with the challenge of interpreting the biologic and clinical significance of germline TP53 mutations in families whose phenotypes are atypical for Li-Fraumeni syndrome.
Ballinger ML, Mitchell G, Thomas DM Surveillance recommendations for patients with germline TP53 mutations. Curr Opin Oncol. 2015; 27(4):332-7 [PubMed] Related Publications
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.
Li-Fraumeni syndrome is a rare cancer predisposition syndrome classically associated with remarkably early onset of cancer in families with a typical spectrum of malignancies, including sarcoma, breast cancer, brain tumors, and adrenocortical carcinoma. Because the risks of cancer development are strikingly high for Li-Fraumeni syndrome, aggressive cancer surveillance is often pursued in these individuals. However, optimal screening methods and intervals for Li-Fraumeni syndrome have yet to be determined. In addition, there may be a significant psychosocial burden to intensive cancer surveillance and some prevention modalities. Here, we describe a case of a young woman with a de novo mutation in TP53 and multiple malignancies, with her most recent cancers found at early, curable stages due to aggressive cancer screening. The potential benefits and risks of intensive cancer surveillance in hereditary cancer syndromes is discussed.
Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol. 2015; 33(21):2345-52 [PubMed] Related Publications
PURPOSE: The aim of the study was to update the description of Li-Fraumeni syndrome (LFS), a remarkable cancer predisposition characterized by extensive clinical heterogeneity. PATIENTS AND METHODS: From 1,730 French patients suggestive of LFS, we identified 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations and updated their clinical presentation. RESULTS: The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. The TP53 mutation detection rate in children presenting with ACC or choroid plexus carcinomas, and in females with breast cancer before age 31 years, without additional features indicative of LFS, was 45%, 42% and 6%, respectively. The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations. CONCLUSION: The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation.
Kappel S, Janschek E, Wolf B, et al. TP53 germline mutation may affect response to anticancer treatments: analysis of an intensively treated Li-Fraumeni family. Breast Cancer Res Treat. 2015; 151(3):671-8 [PubMed] Related Publications
Li-Fraumeni syndrome (LFS) is a rare autosomal dominant inherited disorder associated with the occurrence of a wide spectrum of early-onset malignancies, the most prevalent being breast cancer and sarcoma. The presence of TP53 germline mutations in the majority of LFS patients suggests a genetic basis for the cancer predisposition. No special recommendations for the treatment of LFS patients have been made to date, except that of minimizing radiation. We hypothesized that TP53 germline mutations may be associated not only with cancer predisposition, but also with lack of response to chemo- and radiotherapy. Here, we present an Austrian LFS family whose members were intensively treated with chemo- and radiotherapy due to cancers that occurred at a predominantly young age, including eight breast cancers in six patients. Material from seven family members was screened for p53 mutation by Sanger sequencing and immunohistochemistry. A rare missense mutation in the tetramerization domain of exon 10 of the TP53 gene was found to segregate with malignant disease in this family. Lack of response to various chemotherapies and radiotherapy could be ascertained by histopathology of surgical specimens after neoadjuvant treatment, by cancer relapse occurring while receiving adjuvant systemic treatment and by the occurrence of second primaries in areas of adjuvant radiation. Our observations suggest that current standards of cancer treatment may not be valid for patients with LFS. In patients with TP53 germline mutation, cytotoxic treatment may bear not only the risk of tumor induction but also the risk of treatment failure.
Bahar M, Kordes U, Tekautz T, Wolff J Radiation therapy for choroid plexus carcinoma patients with Li-Fraumeni syndrome: advantageous or detrimental? Anticancer Res. 2015; 35(5):3013-7 [PubMed] Related Publications
BACKGROUND: Choroid plexus carcinomas (CPCs) are rare pediatric tumors often associated with Li-Fraumeni Syndrome (LFS), a germline mutation in the TP53 tumor-suppressor gene, predisposing to cancer. MATERIALS AND METHODS: We performed a systemic literature review from 1990-2013 to evaluate the hypothesis that radiation therapy should be avoided in patients with CPC and LFS. Overall survival (OS) was compared using Kaplan-Meier curves and log-rank tests. RESULTS: Twenty-eight patients were documented with CPC and LFS. Eleven out of 17 patients received radiation therapy. The survival of patients receiving radiation was inferior to that of those without radiation [median (±95% confidence interval) 2-year OS=0.18 ± 0.12% versus 0.58 ± 0.12%]. The log-rank tests suggested the difference to be marginally significant (p=0.056). CONCLUSION: This finding provides evidence for pursuing treatment approaches that do not include radiation therapy for patients with LFS.
Li-Fraumeni syndrome (LFS) is a rare, autosomal dominant, hereditary cancer predisposition disorder. In Brazil, the p.R337H TP53 founder mutation causes the variant form of LFS, Li-Fraumeni-like syndrome. The occurrence of cancer and age of disease onset are known to vary, even in patients carrying the same mutation, and several mechanisms such as genetic and epigenetic alterations may be involved in this variability. However, the extent of involvement of such events has not been clarified. It is well established that p53 regulates several pathways, including the thymine DNA glycosylase (TDG) pathway, which regulates the DNA methylation of several genes. This study aimed to identify the DNA methylation pattern of genes potentially related to the TDG pathway (CDKN2A, FOXA1, HOXD8, OCT4, SOX2, and SOX17) in 30 patients with germline TP53 mutations, 10 patients with wild-type TP53, and 10 healthy individuals. We also evaluated TDG expression in patients with adrenocortical tumors (ADR) with and without the p.R337H TP53 mutation. Gene methylation patterns of peripheral blood DNA samples assessed by pyrosequencing revealed no significant differences between the three groups. However, increased TDG expression was observed by quantitative reverse transcription PCR in p.R337H carriers with ADR. Considering the rarity of this phenotype and the relevance of these findings, further studies using a larger sample set are necessary to confirm our results.
Basso TR, Villacis RA, Canto LM, et al. Genomic profile of a Li-Fraumeni-like syndrome patient with a 45,X/46,XX karyotype, presenting neither mutations in TP53 nor clinical stigmata of Turner syndrome. Cancer Genet. 2015; 208(6):341-4 [PubMed] Related Publications
Li-Fraumeni syndrome (LFS) is a hereditary disorder that predisposes patients to several types of cancer and is associated with TP53 germline mutations. Turner syndrome (TS) is one of the most common aneuploidies in women. Patients with TS have a higher risk of developing cancer, although multiple malignant tumors are extremely rare. Herein, we describe a patient with a 45,X/46,XX karyotype with no classic phenotype of TS. She presented with a clinical diagnosis of Li-Fraumeni-like syndrome (LFL), showing papillary thyroid carcinoma and fibrosarcoma of the left flank, and had no TP53 germline mutations. Genome-wide analysis of copy number variations (CNVs) was assessed in DNA from peripheral blood cells and saliva. A total of 109 rare CNVs in the blood cells, including mosaic loss of the X chromosome (76% of cells), were identified. In saliva, three rare CNVs were detected, all of them were also detected in the blood cells: loss of 8q24.11 (EXT1), gain of 16q24.3 (PRDM7 and GAS8), and the mosaic loss of the X chromosome (50% of cells). Results of conventional G-banding confirmed the 45,X/46,XX karyotype. Surprisingly, the patient presented with an apparently normal phenotype. The PRDM and GAS8 genes are potential candidates to be associated with the risk of developing cancer in this LFL/TS patient.
In vitro modeling of human disease has recently become feasible with induced pluripotent stem cell (iPSC) technology. Here, we established patient-derived iPSCs from a Li-Fraumeni syndrome (LFS) family and investigated the role of mutant p53 in the development of osteosarcoma (OS). LFS iPSC-derived osteoblasts (OBs) recapitulated OS features including defective osteoblastic differentiation as well as tumorigenic ability. Systematic analyses revealed that the expression of genes enriched in LFS-derived OBs strongly correlated with decreased time to tumor recurrence and poor patient survival. Furthermore, LFS OBs exhibited impaired upregulation of the imprinted gene H19 during osteogenesis. Restoration of H19 expression in LFS OBs facilitated osteoblastic differentiation and repressed tumorigenic potential. By integrating human imprinted gene network (IGN) into functional genomic analyses, we found that H19 mediates suppression of LFS-associated OS through the IGN component DECORIN (DCN). In summary, these findings demonstrate the feasibility of studying inherited human cancer syndromes with iPSCs.
Schlegelberger B, Kreipe H, Lehmann U, et al. A child with Li-Fraumeni syndrome: Modes to inactivate the second allele of TP53 in three different malignancies. Pediatr Blood Cancer. 2015; 62(8):1481-4 [PubMed] Related Publications
Here we report on a child with Li-Fraumeni syndrome with a de novo TP53 mutation c.818G>A, who developed three malignancies at the age of 4 months, 4 and 5 years, respectively. We show that (i) in the choroid plexus carcinoma, the germline mutation was detected in a homozygous state due to copy-neutral LOH/uniparental disomy, (ii) in the secondary AML, a complex karyotype led to loss of the wild-type TP53 allele, (iii) in the Wilms tumor, the somatic mutation c.814G>A led to compound heterozygosity. The findings show that the complete inactivation of TP53 by different mechanisms is an important step towards tumorigenesis.
Somatic mutations of TP53 are among the most common in cancer and germline mutations of TP53 (usually missense) can cause Li-Fraumeni syndrome (LFS). Recently, recurrent genomic rearrangements in intron 1 of TP53 have been described in osteosarcoma (OS), a highly malignant neoplasm of bone belonging to the spectrum of LFS tumors. Using whole-genome sequencing of OS, we found features of TP53 intron 1 rearrangements suggesting a unique mechanism correlated with transcription. Screening of 288 OS and 1,090 tumors of other types revealed evidence for TP53 rearrangements in 46 (16%) OS, while none were detected in other tumor types, indicating this rearrangement to be highly specific to OS. We revisited a four-generation LFS family where no TP53 mutation had been identified and found a 445 kb inversion spanning from the TP53 intron 1 towards the centromere. The inversion segregated with tumors in the LFS family. Cancers in this family had loss of heterozygosity, retaining the rearranged allele and resulting in TP53 expression loss. In conclusion, intron 1 rearrangements cause p53-driven malignancies by both germline and somatic mechanisms and provide an important mechanism of TP53 inactivation in LFS, which might in part explain the diagnostic gap of formerly classified "TP53 wild-type" LFS.
Id Said B, Malkin D A functional variant in miR-605 modifies the age of onset in Li-Fraumeni syndrome. Cancer Genet. 2015 Jan-Feb; 208(1-2):47-51 [PubMed] Related Publications
Li-Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome, typically associated with germline mutations in the TP53 gene. Despite the high penetrance of TP53 mutations, LFS patients display striking phenotypic differences, suggesting the presence of secondary risk loci. To date, all genetic modifiers in LFS have been shown to map to either TP53 or its principal negative regulator, MDM2. Given this strong association, we set out to investigate the contribution of miR-605, a recently described microRNA (miRNA) regulator of the p53-MDM2 loop. We hypothesized that, if functional, the miR-605 gene and its variant (rs2043556) could impact the cancer risk profile of TP53 mutation carriers. Consistent with this proposition, the variant G-allele of miR-605 was associated with a 10-year acceleration in the mean age of LFS tumor onset (P = 0.04) and caused a 2.6-fold reduction in the processing levels of its host miRNA (P < 0.05). We also demonstrate that miR-605 overexpression leads to a decrease in cell proliferation, clonogenicity, and migration in two rhabdomyosarcoma cell lines carrying hotspot TP53 mutations. Together, our results implicate miR-605 as a novel modifier gene of the LFS phenotype and a promising therapeutic target in TP53 mutant cancers.
Ilić MP, Kiralj A, Markov B, et al. Li-Fraumeni syndrome: a case report. Vojnosanit Pregl. 2014; 71(12):1159-62 [PubMed] Related Publications
INTRODUCTION: Li-Fraumeni syndrome (LFS) is a very rare familial disease with the predisposition to the development of malignant tumors, such as osteosarcoma, breast cancer, brain neoplasm, leukemia, and adrenal tumors. Inheritance is autosomal dominant and is caused by heterozygous mutations in the p53 gene. The diagnosis is based on clinical criteria: a person under the age of 45 years suffering from sarcoma, the closest relative younger than 45 years diagnosed with cancer and a relative of the first or second degree, which is up to 45 years, was diagnosed with cancer and was diagnosed with sarcoma at any age. CASE REPORT: The presented family with three members diagnosed with malignant disease typical for LFS suggests the need to carefully follow those diagnosed with LFS related tumor. A 24-year-old man diagnosed and treated for osteosarcoma of the maxilla died in the first year. His younger brother was submitted to surgery due to osteosarcoma of the mandible three years later, and a year later in his 24 year he had no signs of locoregional recurrence. Their mother was operated in 1996 for glioblastoma multiform brain cancer and ductal carcinoma, and died two years later at the age of 33. CONCLUSION: The presented family highlights the need for careful examination, inspection and notification of the risks of family members diagnosed with LFS related tumors.
BACKGROUND: Endometrial cancer that occurs concurrently with peritoneal malignant mesothelioma (PMM) is difficult to diagnose preoperatively. CASE PRESENTATION: A postmenopausal woman had endometrial cancer extending to the cervix, vagina and pelvic lymph nodes, and PMM in bilateral ovaries, cul-de-sac, and multiple peritoneal sites. Adjuvant therapies included chemotherapy and radiotherapy. Targeted, massively parallel DNA sequencing and molecular inversion probe microarray analysis revealed a germline TP53 mutation compatible with Li-Fraumeni-like syndrome, somatic mutations of PIK3CA in the endometrial cancer, and a somatic mutation of GNA11 and JAK3 in the PMM. Large-scale genomic amplifications and some deletions were found in the endometrial cancer. The patient has been stable for 24 months after therapy. One of her four children was also found to carry the germline TP53 mutation. CONCLUSIONS: Molecular characterization of the coexistent tumors not only helps us make the definite diagnosis, but also provides information to select targeted therapies if needed in the future. Identification of germline TP53 mutation further urged us to monitor future development of malignancies in this patient and encourage cancer screening in her family.
Agarwal R, Liebe S, Turski ML, et al. Targeted therapy for hereditary cancer syndromes: hereditary breast and ovarian cancer syndrome, Lynch syndrome, familial adenomatous polyposis, and Li-Fraumeni syndrome. Discov Med. 2014; 18(101):331-9 [PubMed] Related Publications
Cancer genetics has rapidly evolved in the last two decades. Understanding and exploring the several genetic pathways in the cancer cell is the foundation of targeted therapy. Several genomic aberrations have been identified and their role in carcinogenesis is being explored. In contrast to most cancers where these mutations are acquired, patients with hereditary cancer syndromes have inherited genomic aberrations. The understanding of the molecular pathobiology in hereditary cancer syndromes has advanced dramatically. In addition, many molecularly targeted therapies have been developed that could have potential roles in the treatment of patients with hereditary cancer syndromes. In this review, we outline the presentation, molecular biology, and possible targeted therapies for two of the most widely recognized hereditary cancer syndromes -- hereditary breast and ovarian cancer syndrome and hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome). We will also discuss other syndromes such as familial adenomatous polyposis and Li-Fraumeni syndrome (TP53).
Ricordel C, Labalette-Tiercin M, Lespagnol A, et al. EFGR-mutant lung adenocarcinoma and Li-Fraumeni syndrome: report of two cases and review of the literature. Lung Cancer. 2015; 87(1):80-4 [PubMed] Related Publications
We report two cases of non-smoker patients diagnosed with EGFR-mutated lung adenocarcinoma and bearing germinal TP53 gene mutation, also known as Li-Fraumeni syndrome (LFS). We describe for the first time an EGFR-TKI resistance mutation in this population. Finally, we provide an analysis of discerning epidemiological data obtained from the IARC database and from all the published cases of EGFR-mutated lung cancer in TP53 germline mutation carriers.
Courtney R, Ranganathan S Simultaneous Adrenocortical Carcinoma and Neuroblastoma in an Infant With a Novel Germline p53 Mutation. J Pediatr Hematol Oncol. 2015; 37(3):215-8 [PubMed] Related Publications
We present an infant with 2 simultaneous, but histologically distinct tumors with a novel germline p53 mutation. The child was found to have a paraspinal neuroblastoma, a concurrent adrenal cortical carcinoma, and an I162F p53 gene mutation. We review the associations of germline p53 mutations (or Li-Fraumeni syndrome) with both tumor types and the current research in similar germline p53 mutations. Finally, we discuss the multiple ways in which our patient is unique including the paucity of cases with simultaneous but histologically unrelated tumors and the fact that our patient is the first reported case of an I162F germline p53 mutation.
Ariffin H, Chan AS, Oh L, et al. Frequent occurrence of gastric cancer in Asian kindreds with Li-Fraumeni syndrome. Clin Genet. 2015; 88(5):450-5 [PubMed] Related Publications
Type of cancer and age of onset in individuals with inherited aberrations in the tumour suppressor gene TP53 are variable, possibly influenced by genetic modifiers and different environmental exposure. Since 2009, the modified Chompret criteria (MCC) have been used to identify individuals for TP53 mutation screening. Using the TP53 mutation database maintained by the International Agency for Research on Cancer (IARC), we investigated if the MCC, mainly developed for a Caucasian population, was also applicable in Asia. We identified several differences in Asian families compared with similar Caucasian cohorts, suggesting that identification and management of Li-Fraumeni syndrome in Asia do not completely mirror that of North America and Western Europe. Early gastric cancer (<40 years) may be considered a new addition to the MCC especially for Asian families.