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1.
Nat Commun ; 11(1): 3945, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770028

RESUMO

TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1α, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading to enhanced vesicular trafficking and secretion. The mut-p53/HIF1α/miR-30d axis potentiates the release of soluble factors and the deposition and remodeling of the ECM, affecting mechano-signaling and stromal cells activation within the tumor microenvironment, thereby enhancing tumor growth and metastatic colonization.


Assuntos
Neoplasias da Mama/genética , Transformação Celular Neoplásica/genética , Complexo de Golgi/patologia , Síndrome de Li-Fraumeni/genética , MicroRNAs/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Biópsia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Feminino , Fibroblastos , Regulação Neoplásica da Expressão Gênica , Complexo de Golgi/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Síndrome de Li-Fraumeni/patologia , Camundongos , Microtúbulos/metabolismo , Microtúbulos/patologia , Mutação , Cultura Primária de Células , Vesículas Secretórias/metabolismo , Vesículas Secretórias/patologia , Transdução de Sinais/genética , Pele/citologia , Pele/patologia , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
PLoS One ; 15(6): e0234262, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32516327

RESUMO

p53 is one of the most extensively studied proteins in cancer research. Mutations in p53 generally abolish normal p53 function, and some mutants can gain new oncogenic functions. However, the mechanisms underlying p53 mutation-driven cancer remains to be elucidated. Our study investigated the function of a heterozygous p53 mutation (p.Asn268Glufs*4) in a Li-Fraumeni syndrome (LFS) patient. We used episomal technology to perform somatic reprogramming, and used molecular and cell biology methods to determine the p53 mutation levels in patient-originated induced pluripotent stem (iPS) cells at the RNA and protein levels. We found that p53 protein expression was not increased in this patient's somatic cells compared with those of a healthy control. p53 mutation facilitates the proliferation of tumor cells by inhibiting apoptosis and promoting cell division. It can inhibit the efficiency of somatic reprogramming by inhibiting OCT4 expression during reprogramming stage. Moreover, not all p53 mutant iPS cell lines have mutant p53 RNA sequences. A small percentage of mutant p53 mRNA is present in the somatic cells from the patient and his mother. In summary, this p53 mutation can promote tumor cell proliferation, inhibit somatic reprogramming, and exhibit random p53 allelic expression of heterozygous mutations in the patient and iPS cells which may be one of the reasons why the people with p53 mutations develop cancer at random. This finding suggested that mutant p53 allelic expression should be added to the risk forecasting of cancer.


Assuntos
Heterozigoto , Síndrome de Li-Fraumeni/genética , Mutação , Proteína Supressora de Tumor p53/genética , Alelos , Animais , Sequência de Bases , Células HEK293 , Humanos , Camundongos
3.
Jpn J Clin Oncol ; 50(10): 1214-1217, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32577752

RESUMO

Germline mutations of TP53 are responsible for Li-Fraumeni syndrome in its 60-80%. We found a novel germline mutation, TP53: c.997del:p.R333Vfs*12 (NM_000546.6, GRCh, 17:7670713..7670713). The proband is a 40-year-old female, who was suffered from osteosarcoma in her right forearm at her age of 11. She was also suffered from lung adenocarcinoma in her right upper lobe and bone metastasis in her right scapula at her age of 37. She was treated with gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) because of EGFR mutation (L747-S752 del). Her bone metastasis became resistant after 1-year treatment. Bone metastasis had an additional EGFR mutation (T790M). The secondary treatment with osimertinib, an another EGFR-TKI, can successfully control the tumors for over 2 years. This TP53 mutation (R333Vfs*12) was first found in lung adenocarcinomas. The therapeutic effect of osimertinib for this triple mutant lung adenocarcinoma is better than the previous report.


Assuntos
Adenocarcinoma de Pulmão/complicações , Adenocarcinoma de Pulmão/genética , Mutação em Linhagem Germinativa/genética , Síndrome de Li-Fraumeni/complicações , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/genética , Proteína Supressora de Tumor p53/genética , Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/patologia , Adulto , Compostos de Anilina/uso terapêutico , Neoplasias Ósseas/secundário , Feminino , Gefitinibe/uso terapêutico , Humanos , Síndrome de Li-Fraumeni/tratamento farmacológico , Síndrome de Li-Fraumeni/genética , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Masculino , Linhagem , Inibidores de Proteínas Quinases/uso terapêutico
4.
Nat Rev Cancer ; 20(8): 471-480, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32404993

RESUMO

The evolutionarily conserved p53 protein and its cellular pathways mediate tumour suppression through an informed, regulated and integrated set of responses to environmental perturbations resulting in either cellular death or the maintenance of cellular homeostasis. The p53 and MDM2 proteins form a central hub in this pathway that receives stressful inputs via MDM2 and respond via p53 by informing and altering a great many other pathways and functions in the cell. The MDM2-p53 hub is one of the hubs most highly connected to other signalling pathways in the cell, and this may be why TP53 is the most commonly mutated gene in human cancers. Initial or truncal TP53 gene mutations (the first mutations in a stem cell) are selected for early in cancer development inectodermal and mesodermal-derived tissue-specific stem and progenitor cells and then, following additional mutations, produce tumours from those tissue types. In endodermal-derived tissue-specific stem or progenitor cells, TP53 mutations are functionally selected as late mutations transitioning the mutated cell into a malignant tumour. The order in which oncogenes or tumour suppressor genes are functionally selected for in a stem cell impacts the timing and development of a tumour.


Assuntos
Evolução Molecular , Genes p53/genética , Mutação/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética , Animais , Evolução Biológica , Genes BRCA1/fisiologia , Genes p53/fisiologia , Genes ras/genética , Humanos , Síndrome de Li-Fraumeni/genética , Mutação/fisiologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/metabolismo , Estresse Fisiológico/genética , Estresse Fisiológico/fisiologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Vertebrados/genética , Vertebrados/metabolismo , Vertebrados/fisiologia
5.
PLoS One ; 15(1): e0227260, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978118

RESUMO

Sarcomas represent less than 1% of all solid neoplasms in adults and over 20% in children. Their etiology is unclear, but genetic susceptibility plays an important role in this scenario. Sarcoma is central in Li-Fraumeni Syndrome (LFS), a familial predisposition cancer syndrome. In Brazil, the high prevalence of p.Arg337His mutations in the TP53 gene brings about a unique condition: a cluster of LFS. In the present work, we studied 502 sarcoma patients not selected by age or family history in an attempt to assess the impact of the so-called "Brazilian germline TP53 mutation" (p.Arg337His) on this tumor type. We found that 8% of patients are carriers, with leiomyosarcoma being the main histologic type of sarcoma, corresponding to 52.5% of the patients with the mutated TP53 gene. These findings emphasize the importance of genetic counseling and can better guide the management of sarcoma patients.


Assuntos
Predisposição Genética para Doença , Síndrome de Li-Fraumeni/genética , Sarcoma/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Feminino , Efeito Fundador , Aconselhamento Genético , Mutação em Linhagem Germinativa , Humanos , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/epidemiologia , Síndrome de Li-Fraumeni/patologia , Masculino , Pessoa de Meia-Idade , Prevalência , Sarcoma/diagnóstico , Sarcoma/epidemiologia , Sarcoma/patologia , Adulto Jovem
6.
Cancer Genet ; 240: 54-58, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31778928

RESUMO

Li-Fraumeni and Li-Fraumeni-like (LFS/LFL) Syndrome are cancer predisposition syndromes caused by germline pathogenic variants in TP53 and are associated with an increased risk of multiple early-onset cancers. In Southern and Southeastern Brazil, a germline founder variant with partial penetrance located in the oligomerization domain of TP53, c.1010G>A p.(Arg337His, commonly known as R337H), has been detected in 0.3% of the general population. Recently, the functional MIR605 variant rs2043556 (A>G) has been identified as a novel LFS phenotype modifier in families with germline TP53 DNA binding variants. In this study, our goal was to verify MIR605 rs2043556 allele frequencies and further explore its possible effects on the phenotype of 238 Brazilian individuals carrying TP53 p.(Arg337His). The MIR605 rs2043556 G allele was detected in 136 (57.1%) individuals, including 25 homozygotes (10.5%), and although it had been previously associated with an earlier mean age of tumor onset, this effect was not observed in this study (p = 0.8). However, in p.(Arg337His) mutation carriers, the GG genotype was significantly associated with the occurrence of multiple primary tumors (p = 0.005). We provide further evidence of MIR605 rs2043556 G allele's effect as a phenotype modulator in carriers of germline TP53 pathogenic variants.


Assuntos
Predisposição Genética para Doença , Síndrome de Li-Fraumeni/genética , MicroRNAs/genética , Neoplasias Primárias Múltiplas/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idade de Início , Brasil/epidemiologia , Feminino , Efeito Fundador , Mutação em Linhagem Germinativa , Humanos , Síndrome de Li-Fraumeni/epidemiologia , Masculino , Neoplasias Primárias Múltiplas/epidemiologia , Polimorfismo de Nucleotídeo Único
7.
Cancer Res ; 80(2): 347-353, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31719099

RESUMO

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder associated with TP53 germline mutations and an increased lifetime risk of multiple primary cancers (MPC). Penetrance estimation of time to first and second primary cancer within LFS remains challenging because of limited data and the difficulty of characterizing the effects of a primary cancer on the penetrance of a second primary cancer. Using a recurrent events survival modeling approach that incorporates a family-wise likelihood to efficiently integrate the pedigree structure, we estimated the penetrance for both first and second primary cancer diagnosis from a pediatric sarcoma cohort at MD Anderson Cancer Center [MDACC, Houston, TX; number of families = 189; single primary cancer (SPC) = 771; and MPC = 87]. Validation of the risk prediction performance was performed using an independent MDACC clinical cohort of TP53 tested individuals (SPC = 102 and MPC = 58). These findings showed that an individual diagnosed at a later age was more likely to be diagnosed with a second primary cancer. In addition, TP53 mutation carriers had a HR of 1.65 (95% confidence interval, 1.1-2.5) for developing a second primary cancer versus SPC. The area under the ROC (AUC) curve for predicting individual outcomes of MPC versus SPC was 0.77. In summary, we provide the first set of penetrance estimates for first and second primary cancer for TP53 germline mutation carriers and demonstrate its accuracy for cancer risk assessment. SIGNIFICANCE: These findings present an open-source R package LFSPRO that could be used for genetic counseling and health management of individuals with LFS as it estimates the risk of both first and second primary cancer diagnosis.See related article by Shin et al., p. 354.


Assuntos
Predisposição Genética para Doença , Síndrome de Li-Fraumeni/genética , Modelos Genéticos , Segunda Neoplasia Primária/genética , Penetrância , Adolescente , Adulto , Criança , Pré-Escolar , Biologia Computacional , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Aconselhamento Genético/métodos , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Lactente , Recém-Nascido , Síndrome de Li-Fraumeni/diagnóstico , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/epidemiologia , Valor Preditivo dos Testes , Medição de Risco/métodos , Software , Fatores de Tempo , Proteína Supressora de Tumor p53/genética , Adulto Jovem
8.
Nat Commun ; 10(1): 5061, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699989

RESUMO

A noncoding polymorphism (rs78378222) in TP53, carried by scores of millions of people, was previously associated with moderate risk of brain tumors and other neoplasms. We find a positive association between this variant and soft tissue sarcoma. In sharp contrast, it is protective against breast cancer. We generated a mouse line carrying this variant and found that it accelerates spontaneous tumorigenesis and glioma development, but strikingly, delays mammary tumorigenesis. The variant creates a miR-382-5p targeting site and compromises a miR-325-3p site. Their differential expression results in p53 downregulation in the brain, but p53 upregulation in the mammary gland of polymorphic mice compared to that of wild-type littermates. Thus, this variant is at odds with Li-Fraumeni Syndrome mutants in breast cancer predisposition yet consistent in glioma predisposition. Our findings elucidate an underlying mechanism of cancer susceptibility that is conferred by genetic variation and yet altered by microRNA expression.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias da Mama/genética , Glioma/genética , Neoplasias Mamárias Experimentais/genética , Sarcoma/genética , Proteína Supressora de Tumor p53/genética , Animais , Encéfalo/metabolismo , Carcinogênese/genética , Regulação para Baixo , Feminino , Predisposição Genética para Doença , Humanos , Síndrome de Li-Fraumeni/genética , Glândulas Mamárias Humanas/metabolismo , Camundongos , MicroRNAs/metabolismo , Proteína Supressora de Tumor p53/metabolismo
9.
Presse Med ; 48(10): 1092-1100, 2019 Oct.
Artigo em Francês | MEDLINE | ID: mdl-31706893

RESUMO

In France, breast cancer is the most common cancer among women and the leading cause of cancer deaths. Identifying women with a "high" or "very high" breast cancer risk, according the terminology of the Haute Autorité de Santé 2014 guidelines, is essential to offer them special cares in term of screening and prevention. Women genetically predisposed have a very high risk of breast cancer. During the oncogenetic specialist consultation, familial and personal history of cancer is taken into account to evaluate the risk of hereditary Breast/Ovarian syndrome and thus the need of a genetic screening. In 2017, a list of 13 genes involved in hereditary ovarian or breast cancer has been established in France (Genetic and Cancer Group - Unicancer). Women carrying a BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN mutation have a higher risk of breast cancer and are considered as "high risk". Therefore, medical breast surveillance similar to carriers of BRCA1/BRCA2 mutation is recommended for these patients (INCa guidelines 2017). However a mutation in one of those genes is only identified in approximatively 10 % of the screened families. The oncogenetic specialist's assessment distinguishes families in which women remain at a "high" risk of breast cancer (HAS 2014 for screening) from those where women have a "very high" risk (INCa guidelines 2017 for screening and prevention).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação , Fatores Etários , Antígenos CD/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Neoplasias da Mama Masculina/genética , Caderinas/genética , Saúde da Família , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , França , Genes BRCA1 , Genes BRCA2 , Genes p53 , Testes Genéticos , Síndrome do Hamartoma Múltiplo/genética , Humanos , Síndrome de Li-Fraumeni/genética , Masculino , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Gravidez , Mastectomia Profilática , Fatores de Risco , Nanomedicina Teranóstica , Neoplasias de Mama Triplo Negativas/genética
10.
Exp Suppl ; 111: 149-169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588532

RESUMO

Adrenocortical malignancies can occur in the context of several tumor predisposition syndromes.The Carney complex (CNC) is responsible for the majority of primary pigmented nodular adrenal diseases and is more rarely associated with adrenocortical carcinoma (ACC). Other core manifestations of CNC include cardiac and cutaneous myxomas, lentiginosis, somatotroph pituitary adenomas, Sertoli tumors, melanocytic schwannoma, and thyroid, breast, and bone tumors. CNC is mostly due to germline inactivating mutations of PRKAR1A.The majority of childhood ACC are related to genetic predisposition. The Beckwith-Wiedemann syndrome (BWS) is an overgrowth and tumor predisposition syndrome due to genetic or epigenetic alterations at the 11p15 locus. Classical tumor spectrum of BWS includes embryonal tumors and childhood ACC. The Li-Fraumeni syndrome (LFS) is a devastating tumor predisposition syndrome, due to germline inactivating mutations of TP53, and characterized by a high, various, and early-onset cancer risk. LFS spectrum includes premenopausal breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumor, and ACC, accounting for 50-80% of pediatric cases. Finally, germline predisposition affects up to 10% of adult ACC patients, mostly in part of LFS and Lynch syndrome.This chapter focuses on the diagnosis, screening, and management of adrenal tumors in part of these tumor predisposition syndromes.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Síndrome de Beckwith-Wiedemann/genética , Complexo de Carney/genética , Síndrome de Li-Fraumeni/genética , Predisposição Genética para Doença , Humanos
11.
Pathologe ; 40(6): 592-599, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31511974

RESUMO

The Li-Fraumeni syndrome (LFS, online Mendelian inheritance in man, OMIM #151623) is considered to be one of the currently known most aggressive cancer predisposition syndromes. The heterogeneous spectrum of tumors is dominated by bone and soft tissue sarcomas, various brain tumors, premenopausal breast cancer and adrenocortical carcinoma (ACC). Even in childhood the cancer risk is very strongly increased and it is not uncommon for people with LFS to develop synchronous and metachronous tumors. Typical histopathological findings and molecular genetic signatures can help towards the diagnosis. Inheritance is autosomal dominant and the penetrance appears to be more variable than previously thought. The prevalence of LFS is approximately 1:5000 with a high interregional variance. The LFS is caused by germline mutations in the TP53 gene coding for the protein p53, an essential cellular transcription factor that initiates antitumor responses to cellular stress, such as DNA damage. In people with LFS, due to the loss of functional p53, the protective mechanism of the cells is weakened resulting in a significantly increased cancer risk. In order to improve the survival of people with LFS, structured tumor early recognition and surveillance strategies are recommended; however, national and international longitudinal observational studies are needed to evaluate the cost-effort-benefit balance. For this reason, the authors have established the LFS cancer predisposition registry in which all patients with LFS and other syndromes predisposing to cancer can be registered. Detailed information can be found at www.cancer-predisposition.org .


Assuntos
Predisposição Genética para Doença , Síndrome de Li-Fraumeni , Genes p53/genética , Humanos , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/mortalidade , Síndrome de Li-Fraumeni/patologia
12.
Breast Cancer Res ; 21(1): 107, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533767

RESUMO

The introduction of next-generation sequencing has resulted in testing multiple genes simultaneously to identify inherited pathogenic variants (PVs) in cancer susceptibility genes. PVs with low minor allele frequencies (MAFs) (< 25-35%) are highlighted on germline genetic test reports. In this review, we focus on the challenges of interpreting PVs with low MAF in breast cancer patients undergoing germline testing and the implications for management.The clinical implications of a germline PV are substantial. For PV carriers in high-penetrance genes like BRCA1, BRCA2, and TP53, prophylactic mastectomy is often recommended and radiation therapy avoided when possible for those with Li-Fraumeni syndrome (LFS). For germline PV carriers in more moderate-risk genes such as PALB2, ATM, and CHEK2, annual breast MRI is recommended and prophylactic mastectomies considered for those with significant family histories. Detection of PVs in cancer susceptibility genes can also lead to recommendations for other prophylactic surgeries (e.g., salpingo-oophorectomy) and increased surveillance for other cancers. Therefore, recognizing when a PV is somatic rather than germline and distinguishing somatic mosaicism from clonal hematopoiesis (CH) is essential. Mutational events that occur at a post-zygotic stage are somatic and will only be present in tissues derived from the mutated cell, characterizing classic mosaicism. Clonal hematopoiesis is a form of mosaicism restricted to the hematopoietic compartment.Among the genes in multi-gene panels used for germline testing of breast cancer patients, the detection of a PV with low MAF occurs most often in TP53, though has been reported in other breast cancer susceptibility genes. Distinguishing a germline TP53 PV (LFS) from a somatic PV (TP53 mosaicism or CH) has enormous implications for breast cancer patients and their relatives.We review how to evaluate a PV with low MAF. The identification of the PV in another tissue confirms mosaicism. Older age, exposure to chemotherapy, radiation, and tobacco are known risk factors for CH, as is the absence of a LFS-related cancer in the setting of a TP53 PV with low MAF. The ability to recognize and understand the implications of somatic PVs, including somatic mosaicism and CH, enables optimal personalized care of breast cancer patients.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/genética , Diagnóstico Diferencial , Frequência do Gene , Genes p53/genética , Testes Genéticos , Hematopoese , Humanos , Mosaicismo , Mutação
13.
Cancer Genet ; 235-236: 21-27, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31296311

RESUMO

TP53 pathogenic germline variation is associated with the multi-cancer predisposition Li-Fraumeni syndrome (LFS). Next-generation sequencing and multigene panel testing are highlighting variability in the clinical presentation of patients with TP53 positive results. We aimed to investigate if the p53 variants considered as major hotspots at both germline and somatic levels (p.Arg175His, p.Gly245Asp, p.Gly245Ser, p.Arg248Gln, p.Arg248Trp, p.Arg273Cys, p.Arg273His, and p.Arg282Trp) were associated with poorer prognostic features compared to other pathogenic missense variants in the DNA-binding domain. To do so, we assessed clinical features from 1025 carriers of germline TP53 pathogenic variants (749 probands and 276 relatives) from three independent datasets (IARC TP53 Database, Ambry Single Gene Testing, and Ambry Multigene Panel Testing). We observed that, compared to carriers of non-hotspot germline variants, individuals that carried a hotspot germline variant were more likely to present with a Classic LFS phenotype, earlier age of first breast cancer onset, and shorter time to diagnosis to any cancer. Further studies with larger datasets addressing differences in cancer phenotypes by genotype are thus needed to replicate our findings and consider variant effect and position, towards future personalized clinical management of pathogenic variant carriers.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Variação Genética/genética , Genótipo , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fenótipo , Prognóstico
14.
Fam Cancer ; 18(4): 451-456, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31321604

RESUMO

Li-Fraumeni syndrome (LFS) and Li-Fraumeni Like (LFL) are autosomal dominant cancer predisposition syndromes caused by pathogenic germline variants in the TP53 gene. Recent studies have shown that the incorporation of next-generation sequencing by using multigene panels in clinical practice has resulted in the frequent identification of variants of uncertain significance (VUS). Given that there is no established medical management for VUS carriers, the identification of these variants may cause confusion and anxiety for both patients and practitioners. Herein, we aimed to verify VUS frequency and review VUS classification and interpretation in 1844 patients submitted for comprehensive germline TP53 testing independent of clinical criteria. Variant characterization was done assessing clinical information whenever available, variant frequency in population databases, pathogenicity predictions using in silico tools and previous functional studies. All variants were classified based on the guidelines proposed by the American College of Medical Genetics and Genomics (2015) and by the Sherloc framework (2017). Of the twelve VUS (0.65%) identified in TP53, two were classified as likely pathogenic and two were classified as likely benign after re-evaluation, potentially resulting in significant management modification for the proband and relatives. This report cases highlights the challenges and impact of TP53 variant interpretation especially when there is no clear LFS/LFL phenotype.


Assuntos
Aconselhamento Genético , Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Feminino , Frequência do Gene , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade
16.
Clin Genet ; 96(3): 216-225, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31081129

RESUMO

Pathogenic germline TP53 variants predispose to a wide range of early onset cancers, often recognized as the Li-Fraumeni syndrome (LFS). They are also identified in 1% of families with hereditary breast cancer (HrBC) that do not fulfill the criteria for LFS. In this study, we present a total of 24 different TP53 variants identified in 31 Swedish families with LFS or HrBC. Ten of these variants, nine exonic and one splice, have previously not been described as germline pathogenic variants. The nine exonic variants were functionally characterized and demonstrated partial transactivation activity compared to wild-type p53. Some show nuclear localization similar to wild-type p53 while others possess cytoplasmic or perinuclear localization. The four frameshift variants (W91Gfs*32, L111 Wfs*12, S227 Lfs*20 and S240Kfs*25) had negligible, while F134 L and T231del had low level of p53 activity. The L111 Wfs*12 and T231del variants are also deficient for induction of apoptosis. The missense variant R110C retain p53 effects and the nonsense E349* shows at least partial transcription factor activity but has reduced ability to trigger apoptosis. This is the first functional characterization of novel germline TP53 pathogenic or likely pathogenic variants in the Swedish cohort as an attempt to understand its association with LFS and HrBC, respectively.


Assuntos
Variação Genética , Mutação em Linhagem Germinativa , Proteína Supressora de Tumor p53/genética , Alelos , Substituição de Aminoácidos , Apoptose , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Estudos de Associação Genética , Loci Gênicos , Predisposição Genética para Doença , Genótipo , Humanos , Síndrome de Li-Fraumeni/genética , Transporte Proteico , Análise de Sequência de DNA , Suécia
17.
Genet Med ; 21(11): 2478-2484, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31105275

RESUMO

PURPOSE: Panel testing has led to the identification of TP53 pathogenic/likely pathogenic (P/LP) variant carriers (TP53+) who exhibit a broad range of phenotypes. We sought to evaluate and compare genotype-phenotype associations among TP53+ panel-ascertained subjects. METHODS: Between 2012 and 2017, 317 TP53+ subjects (279 females and 38 males) identified through panel testing at one testing laboratory were found to have evaluable clinical histories and molecular results. Subject cancer histories were obtained from test requisition forms. P/LP variants were categorized by type and were examined in relation to phenotype. RESULTS: Loss-of-function (LOF) variants were associated with the earliest age at first cancer, with a median age of 30.5 years (P = 0.014); increased frequency of a sarcoma diagnosis (P = 0.016); and more often meeting classic LFS testing and Chompret 2015 criteria (P = 0.004 and 0.002 respectively), as compared with dominant-negative missense, other missense, or miscellaneous (splice or in-frame deletion) P/LP variant categories. CONCLUSION: Loss-of-function variants were more often associated with characteristic LFS cancer histories than other variant categories in TP53+ carriers ascertained through multigene panel testing. These findings require validation in other TP53+ cohorts. Genetic counseling for panel-ascertained TP53+ individuals should reflect the dynamic expansion of the Li-Fraumeni syndrome phenotype.


Assuntos
Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Adulto , Estudos de Coortes , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Síndrome de Li-Fraumeni/diagnóstico , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade , Proteína Supressora de Tumor p53/metabolismo
18.
J Steroid Biochem Mol Biol ; 190: 250-255, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30974190

RESUMO

BACKGROUND: The TP53 p.R337H germline mutation is highly prevalent among children with adrenocortical tumors (ACTs) from South and Southeast Brazil. However, the prevalence of other tumors of the Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL) spectrum, the clinical outcomes and the potential tumor occurrence in relatives carrying this distinct TP53 mutation were not fully investigated. PATIENTS AND METHODS: We investigated tumor profile data and outcomes of individuals and their close relatives with the TP53 p.R337H germline mutation. A questionnaire and the Toronto protocol were used for evaluation of asymptomatic carriers of this TP53 mutation. RESULTS: The cohort of this study comprised 51 patients from 46 different families; 67% were female. All but one harbored the TP53 p.R337H mutation in heterozygous state; only one child was homozygous for this variant. Maternal allele inheritance occurred in 72% of the cases (p= 0,002). In pediatric group, ACT was the most common primary tumor at the diagnosis (55%; median age= 2 years). No patient of the pediatric group who initially presented with ACT developed a second primary tumor and 11% (n= 3) died due to complications related to the primary tumor (median follow-up time of 81.5 months, range= 3-378 months). In adult group, the main tumors at diagnosis were: adrenocortical carcinoma (ACC) (23%; median age= 29.5 years), breast cancer (12%; median age= 38.5 years), soft tissue sarcoma (8%; median age= 50.3 years) and choroid plexus carcinoma (CPC) (2%; median age= 18 years). Among adult patients who were diagnosed with ACC as the first primary tumor, all presented with aggressive disease as per histologic and clinical criteria at diagnosis, and 75% of patients died (median follow-up time of 19 months, range= 1-69 months). Five adult patients (22%) had a second primary tumor, including bronchoalveolar lung cancer (2 cases), ACC, uterine cervical carcinoma and fibrosarcoma. The diagnosis of these tumors was established from 8 to 36 months after the first primary tumor. Three families presented more than one case of ACT. Nine malignant neoplasms were diagnosed in asymptomatic carriers using Toronto protocol. CONCLUSIONS: This study confirms a high frequency of TP53 p.R337H mutation in pediatric group with ACT. In addition, we observed the occurrence of other tumors of LFS/LFL spectrum and a difference in the aggressiveness of ACTs depending on the age group in which they were diagnosed. The predominance of maternal mutated allele inheritance was first demonstrated in the affected Brazilian's families.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Neoplasias do Córtex Suprarrenal/epidemiologia , Adulto , Brasil/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Mutação em Linhagem Germinativa , Humanos , Lactente , Síndrome de Li-Fraumeni/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Adulto Jovem
19.
Artigo em Inglês | MEDLINE | ID: mdl-30886117

RESUMO

Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome caused by heterozygous germline mutations in the TP53 gene. Although more than 200 missense and null TP53 mutations are well established as disease-causing, little is known about the pathogenicity and cancer risks associated with small in-frame deletions. This leads to challenges in variant classification and subsequent difficulty making a molecular diagnosis. We report the genetic testing process for a pediatric patient diagnosed with an undifferentiated high-grade brain tumor following his mother's diagnosis of early-onset bilateral breast cancer. Sequential testing revealed that both harbored a heterozygous three-nucleotide deletion in exon 7 of TP53 (c.764_766delTCA; I255del), which was classified as a variant of uncertain significance. Because the maternal family history was void of any other LFS spectrum tumors, additional information was needed to effectively classify the variant. Targeted TP53 testing of the patient's maternal grandparents confirmed that neither carried the variant; this new de novo data upgraded the variant classification to likely pathogenic. To assess the impact of this mutation on the encoded p53 protein, additional in vitro analyses were performed. Structural modeling predicted that the deletion of isoleucine at codon 255 would disrupt the architecture of the DNA-binding domain, suggesting that it might negatively impact p53 function. Consistent with this notion, the I255del mutant protein exhibited significantly impaired transcriptional activity and greatly reduced growth suppressive properties, similar to more well-characterized LFS-associated p53 mutants. This report illustrates the importance of seeking additional evidence to assign proper pathogenicity classification, which enables optimal genetic counseling and medical management of individuals with LFS and their at-risk relatives.


Assuntos
Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Adulto , Neoplasias da Mama/genética , Pré-Escolar , Feminino , Predisposição Genética para Doença , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Deleção de Sequência/genética , Proteína Supressora de Tumor p53/metabolismo
20.
Hum Mutat ; 40(6): 788-800, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30840781

RESUMO

Germline pathogenic variants in the TP53 gene cause Li-Fraumeni syndrome, a condition that predisposes individuals to a wide range of cancer types. Identification of individuals carrying a TP53 pathogenic variant is linked to clinical management decisions, such as the avoidance of radiotherapy and use of high-intensity screening programs. The aim of this study was to develop an evidence-based quantitative model that integrates independent in silico data (Align-GVGD and BayesDel) and somatic to germline ratio (SGR), to assign pathogenicity to every possible missense variant in the TP53 gene. To do this, a likelihood ratio for pathogenicity (LR) was derived from each component calibrated using reference sets of assumed pathogenic and benign missense variants. A posterior probability of pathogenicity was generated by combining LRs, and algorithm outputs were validated using different approaches. A total of 730 TP53 missense variants could be assigned to a clinically interpretable class. The outputs of the model correlated well with existing clinical information, functional data, and ClinVar classifications. In conclusion, these quantitative outputs provide the basis for individualized assessment of cancer risk useful for clinical interpretation. In addition, we propose the value of the novel SGR approach for use within the ACMG/AMP guidelines for variant classification.


Assuntos
Biologia Computacional/métodos , Síndrome de Li-Fraumeni/genética , Mutação de Sentido Incorreto , Proteína Supressora de Tumor p53/genética , Algoritmos , Simulação por Computador , Predisposição Genética para Doença , Humanos , Modelos Genéticos
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