Résumé
Siendo el cáncer gástrico la 3ª causa de muerte por cáncer en Chile, y existiendo estrategias de tamizaje consistentes en pesquisa de lesiones preneoplásicas de la mucosa gástrica, es relevante conocer los aspectos genéticos y moleculares que puedan ser aplicados, en la optimización de dichas estrategias a grupos de mayor riesgo. El objetivo de este manuscrito fue revisar la evidencia actual en los aspectos señalados, y de la inmunohistoquímica de 4 marcadores (p53, CDX2, MUC2 y S100A9) en la mucosa gástrica normal y en las lesiones preneoplásicas de la misma.
SUMMARY: Since gastric cancer is the 3rd leading cause of death from cancer in Chile, and there are screening strategies consisting of screening for preneoplastic lesions of the gastric mucosa, it is important to know certain genetic and molecular aspects that can be applied in optimizing these strategies for higher risk groups. The aim of this manuscript was to review the current evidence on the aforementioned aspects, and on the immunohistochemistry of 4 markers (p53, CDX2, MUC2 and S100A9) in normal gastric mucosa and in its preneoplastic lesions.
Sujets)
Humains , États précancéreux/anatomopathologie , Tumeurs de l'estomac/anatomopathologie , Muqueuse gastrique/anatomopathologie , États précancéreux/génétique , États précancéreux/métabolisme , Tumeurs de l'estomac/génétique , Tumeurs de l'estomac/métabolisme , Immunohistochimie , Marqueurs biologiques tumoraux , Dépistage de masse , Facteurs de risque , Gènes p53 , Mucine-2 , Facteurs de transcription CDX2 , Muqueuse gastrique/métabolisme , MétaplasieRésumé
Objective: To investigate the clinicopathological, immunophenotypic, and genetic features of malignant peripheral nerve sheath tumor (MPNST). Methods: Twenty-three cases of MPNST were diagnosed at the Jiangsu Province Hospital (the First Affiliated Hospital of Nanjing Medical University), China, between January 2012 and December 2022 and thus included in the study. EnVision immunostaining and next-generation sequencing (NGS) were used to examine their immunophenotypical characteristics and genomic aberrations, respectively. Results: There were 10 males and 13 females, with an age range of 11 to 79 years (median 36 years), including 14 cases of neurofibromatosis type I-associated MPNST and 9 cases of sporadic MPNST. The tumors were located in extremities (7 cases), trunk (4 cases), neck and shoulder (3 cases), chest cavity (3 cases), paraspinal area (2 cases), abdominal cavity (2 cases), retroperitoneum (1 case), and pelvic cavity (1 case). Morphologically, the tumors were composed of dense spindle cells arranged in fascicles. Periphery neurofibroma-like pattern was found in 73.9% (17/23) of the cases. Under low magnification, alternating hypercellular and hypocellular areas resembled marbled appearance. Under high power, the tumor cell nuclei were irregular, presenting with oval, conical, comma-like, bullet-like or wavy contour. In 7 cases, the tumor cells demonstrated marked cytological pleomorphism and rare giant tumor cells. The mitotic figures were commonly not less than 3/10 HPF, and geographic necrosis was often noted. Immunohistochemically, tumor cells were positive for S-100 (14/23, 60.9%) and SOX10 (11/23, 47.8%). The loss of the CD34-positive fibroblastic network encountered in neurofibromas was observed in 14/17 of the MPNST cases. The loss of H3K27me3 expression was observed in 82.6% (19/23) of the cases. Moreover, SDHA and SDHB losses were presented in one case. NGS revealed that NF1 gene loss of function (germline or somatic) were found in all 5 cases tested. Furthermore, four cases accompanied with somatic mutations of SUZ12 gene and half of them had somatic mutations of TP53 gene, while one case with germline mutation in SDHA gene and somatic mutations in FAT1, BRAF, and KRAS genes. Available clinical follow-up was obtained in 19 cases and ranged from 1 to 67 months. Four patients died of the disease, all of whom had the clinical history of neurofibromatosis type Ⅰ. Conclusions: MPNST is difficult to be differentiated from a variety of spindle cell tumors due to its wide spectrum of histological morphology and complex genetic changes. H3K27me3 is a useful diagnostic marker, while the loss of CD34 positive fibroblastic network can also be a diagnostic feature of MPNST. NF1 gene inactivation mutations and complete loss of PRC2 activity are the common molecular diagnostic features, but other less commonly recurred genomic aberrations might also contribute to the MPNST pathogenesis.
Sujets)
Femelle , Mâle , Humains , Enfant , Adolescent , Jeune adulte , Adulte , Adulte d'âge moyen , Sujet âgé , Neurofibrosarcome , Neurofibromatose de type 1 , Histone , Gènes p53 , Tumeurs des gaines nerveusesRésumé
Introduction: Breast cancer is the most common cancer in women and incidence and mortality rates are increasing among young women worldwide, including Brazil. TP53 Arg72Pro polymorphism (rs1042522) has been associated with breast cancer, due to its important role in cell cycle that impacts the development of cancer. Objective: To determine the magnitude of the association between TP53 Arg72Pro polymorphism and breast cancer development in young Brazilian women. Method: Hospital-based case-control study conducted in Rio de Janeiro with 268 confirmed breast cancer cases and 277 controls with women enrolled among hospitalized patients without neoplastic diseases or their companions at three public hospitals. Results: The genotype frequency was 46.57% for Arg/Pro, 35.74% for Arg/Arg, and 17.69% for Pro/Pro among healthy controls and 41.04% for Arg/Pro, 46.64% for Arg/Arg, and 12.31% for Pro/Pro among breast cancer cases. The genotypes Pro/Pro (OR=0.46; 95% CI=0.27-0.80, in comparison with Arg/Arg genotype) and Pro allele in dominant model (OR=0.65; 95% CI=0.45-0.92, in comparison with Arg/Arg genotype) were statistically associated with a protective effect for breast cancer among young Brazilian women. Also, family history of breast or ovary cancer (OR=2.18; 95% CI=1.37-3.46) and tobacco use (OR=1.74; 95% CI=1.14-2.68) were statistically associated with breast cancer. Conclusion: Further studies are necessary to confirm that Arg72Pro polymorphism can be a protective factor for breast cancer development among young women, since ethnicity can influence genotypes frequencies and the risk of developing breast cancer
Introdução: O câncer de mama é o mais comum em mulheres e as taxas de incidência e mortalidade estão aumentando entre mulheres jovens em todo o mundo, inclusive no Brasil. O polimorfismo TP53 Arg72Pro (rs1042522) tem sido associado ao câncer de mama em razão do seu importante papel no ciclo celular que pode impactar o desenvolvimento do câncer. Objetivo: Determinar a magnitude da associação entre o polimorfismo TP53 Arg72Pro e o desenvolvimento de câncer de mama em mulheres jovens brasileiras. Método: Estudo caso-controle de base hospitalar realizado no Rio de Janeiro com 268 casos confirmados de câncer de mama e 277 controles com mulheres cadastradas entre pacientes internados sem doenças neoplásicas ou seus acompanhantes em três hospitais públicos. Resultados: A frequência genotípica foi de 46,57% para Arg/Pro, 35,74% para Arg/Arg e 17,69% para Pro/Pro entre controles saudáveis e 41,04% para Arg/Pro, 46,64% para Arg/ Arg e 12,31% para Pro /Pro entre os casos de câncer de mama. Os genótipos Pro/Pro (OR=0,46; IC 95%=0,27-0,80, em comparação ao genótipo Arg/ Arg) e o alelo Pro no modelo dominante (OR=0,65; IC 95%=0,45-0,92, em comparação com o genótipo Arg/Arg) foram estatisticamente associados a um efeito protetor para o câncer de mama em mulheres jovens brasileiras. Além disso, história familiar de câncer de mama ou ovário (OR=2,18; IC 95%=1,37-3,46) e tabagismo (OR=1,74; IC 95%=1,14-2,68) foi estatisticamente associada ao câncer de mama. Conclusão: Novos estudos são necessários para confirmar que o polimorfismo Arg72Pro pode ser um fator de proteção para o desenvolvimento de câncer de mama em mulheres jovens, uma vez que a etnia pode influenciar tanto as frequências desses genótipos quanto o risco de desenvolver câncer de mama
Introducción: El cáncer de mama es el cáncer más común en la mujer y las tasas de incidencia y mortalidad están aumentando entre las mujeres jóvenes en todo el mundo, incluido Brasil. El polimorfismo TP53 Arg72Pro (rs1042522) se ha asociado con el cáncer de mama, debido a su importante papel en el ciclo celular que puede afectar el desarrollo del cáncer. Objetivo: Determinar la magnitud de la asociación entre el polimorfismo TP53 Arg72Pro y el desarrollo de cáncer de mama en mujeres jóvenes brasileñas. Método: Estudio de casos y controles de base hospitalaria realizado en Río de Janeiro con 268 casos confirmados de cáncer de mama y 277 controles con mujeres inscritas entre pacientes hospitalizadas sin enfermedades neoplásicas o sus acompañantes en tres hospitales públicos. Resultados: La frecuencia de genotipos fue del 46,57% para Arg/Pro, 35,74% para Arg/Arg y 17,69% para Pro/Pro entre controles sanos y 41,04% para Arg/Pro, 46,64% para Arg/Arg y 12,31% para Pro/Pro entre los casos de cáncer de mama. El genotipo Pro/Pro (OR=0,46; IC 95%=0,27-0,80, en comparación con el genotipo Arg/Arg) y el alelo Pro en el modelo dominante (OR=0,65; IC del 95 %=0,45-0,92, en comparación con el genotipo Arg/Arg) se asociaron estadísticamente con un efecto protector frente el cáncer de mama entre mujeres jóvenes brasileñas. Además, los antecedentes familiares de cáncer de mama o de ovario (OR=2,18; IC 95%=1,37-3,46) y el hábito del tabaquismo (OR=1,74; IC 95%=1,14-2,68) se asociaron estadísticamente con el cáncer de mama. Conclusión: Son necesarios nuevos estudios para confirmar que el polimorfismo Arg72Pro puede ser un factor de protección para el desarrollo del cáncer de mama en mujeres jóvenes, ya que la etnia puede influir r tanto en las frecuencias de estos genotipos como en el riesgo de desarrollar cáncer de mama
Sujets)
Humains , Mâle , Femelle , Adulte , Polymorphisme génétique , Tumeurs du sein , Gènes p53 , Jeune adulteRésumé
RESUMEN Las alteraciones genéticas en el gen TP53 están presentes entre el 5 al 8 % de los pacientes de leucemia linfocítica crónica (LLC) en el momento del diagnóstico. Estos casos se relacionan con un mal pronóstico debido a su resistencia al tratamiento estándar. Presentamos el caso de un paciente masculino de 52 años diagnosticado con LLC, expresión del marcador CD38 y una deleción en el gen TP53 (17p13.1). Tras la evaluación posterior del tratamiento, se observó enfermedad mínima residual lo que llevó a un trasplante haploidéntico de progenitores hematopoyéticos. Debido al alto riesgo de recaída, su edad y la ausencia de comorbilidades, era la única opción curativa hasta la fecha para la LLC. El objetivo de este trabajo es realizar una revisión de la literatura que sirva como base para analizar el caso clínico presentado, en el marco de las implicaciones clínicas, pronóstico y respuesta al tratamiento en los individuos con LLC que presentan alteraciones en el gen TP53.
SUMMARY Genetic alterations in the TP53 gene are present in 5 to 8% of chronic lymphocytic leukemia (CLL) cases at the time of diagnosis. These cases are typically associated with poor prognosis due to their resistance against standard CLL treatment. In our report a 52-yearold male patient was diagnosed with CLL, CD38 expression and a deletion in the TP53 gene (17p13.1). Upon evaluation post-treatment, minimal residual disease (MDR) was observed, and a haploidentical stem cell transplant was performed. Because of the high risk of relapse, his age, and the absence of comorbidities it was the only curative option to date for CLL. The purpose of this article is to complete a literature review that will give a basis to analyze the clinical case presented, within the framework of the clinical implications, prognosis, and response to treatment in patients with CLL who present with aberrations of the TP53 gene.
Sujets)
Humains , Leucémie chronique lymphocytaire à cellules B , Gènes p53 , Rapport de rechercheRésumé
Introducción: La displasia epitelial oral (DEO) es la presencia de alteraciones celulares y tisulares, lo que puede significar una etapa anterior al desarrollo del cáncer. Múltiples marcadores han sido considerados para estimar su potencial neoplásico y evolución a carcinoma, incluyendo a la molécula p53, se considera como participe de diversos fenómenos de la homeostasis celular. Objetivo: Determinar la relación entre la inmunoexpresión de p53 DO-7 y PAb 240 con el grado de severidad de la displasia epitelial oral. Material y métodos: Se analizaron nueve muestras de DEO (tres para cada grado de severidad). La inmunoexpresión de p53 tipo silvestre (DO-7) y forma mutada (PAb 240), fue determinada a través de ensayo de inmunohistoquímica por peroxidasa. Se obtuvieron la media y desviación estándar y se realizó la prueba χ2 (p < 0.05). Resultados: La edad media fue de 65.7 ± 11.4 años, la zona anatómica con mayor presencia de DEO es el borde lateral de la lengua. Ocho de nueve muestras fueron positivas para DO-7 y solo dos para PAb 240. Conclusiones: Nuestros resultados indican que, aunque la expresión de p53 DO-7 podría estar relacionada parcialmente con la patogénesis de la displasia epitelial, no todas las displasias presentaron la forma mutada de p53 (PAb 240). Lo cual coincide con el comportamiento biológico incierto de las displasias al poder permanecer sin cambios, involucionar o transformarse
Introduction: Oral epithelial dysplasia (OED) is the presence of cellular and tissue alterations, which may mean a stage prior to the development of cancer. Multiple markers have been considered to estimate its pathogenic potential and evolution to neoplasms, including the p53 molecule, considered as participating in various phenomena of cellular homeostasis. Objective: To determine the relationship between the immunoexpression of p53 DO-7 and PAb 240 with the degree of severity of oral epithelial dysplasia. Material and methods: Nine OED samples were analyzed (three for each degree of severity). The immunoexpression of wild-type p53 (DO-7) and mutated form (PAb 240) was determined through a peroxidase immunohistochemical assay. The mean and standard deviation were obtained, and χ2 test (p < 0.05) were performed. Results: The mean age was 65.7 ± 11.4 years, with a greater presence of OED in the anatomical area of the lateral side of the tongue. Eight out of nine samples were positive for DO-7 and only two for PAb 240. Conclusions: Our results indicate that, although the expression of p53 DO-7 could be partially related to the pathogenesis of epithelial dysplasia, not all dysplasias presented the mutated form of p53 (PAb 240), which coincides that not all dysplasias have a potential for malignant transformation and that could be related to other oncogenic mechanisms (AU)
Sujets)
Humains , Mâle , Femelle , Enfant , Adolescent , Adulte , Adulte d'âge moyen , Sujet âgé , États précancéreux , Immunohistochimie , Gènes p53 , Tumeur de la gencive , Tumeurs de la langue , Projets pilotes , Carcinogenèse , Étude d'observation , MexiqueRésumé
Objetivo: describir el caso de una paciente con Síndrome de Li-Fraumeni (SLF) y cáncer de mama, en quien se cuestionó el beneficio en la supervivencia de la mastectomía profiláctica contralateral (MPC); asimismo, se pretende hacer una discusión crítica acerca de la evidencia que soporta este procedimiento en esta población. Presentación del caso: mujer de 37 años con cáncer de mama y múltiples antecedentes familiares de cánceres de temprana aparición del espectro del SLF, en quien, durante la adyuvancia hormonal, se confirmó una variante patogénica en el gen TP53. La paciente fue presentada en la Junta Multidisciplinaria del Servicio de Mama de un Centro Oncológico de referencia en Colombia, con el fin de discutir el beneficio de la MPC. La decisión de la junta fue no realizar la MPC. Después de 30 meses de seguimiento la paciente se encuentra libre de enfermedad. Conclusión: no existe evidencia que analice, de forma particular, el impacto de la MPC en la supervivencia de las pacientes con SLF y cáncer de mama. Sin embargo, a la luz del conocimiento actual no es posible generalizar la conducta de omitir esta cirugía profiláctica. Es importante reportar los casos en los que se decida realizar u omitir este procedimiento con el fin de incrementar el cuerpo de la evidencia, dado que existen limitaciones para construir grandes cohortes o estudios experimentales exclusivos para esta alteración genética.
Objective: To describe the case of a patient with Li-Fraumeni syndrome (LFS) and breast cancer in whom the benefit of contralateral prophylactic mastectomy (CPM) was challenged; and to offer a critical discussion regarding the evidence supporting this procedure in this patient population. Case presentation: A 37-year-old woman with breast cancer and a family history of multiple early onset cancer of the LFS spectrum in whom a pathogenic variant of the TP53 gene was confirmed during adjuvant hormonal therapy. The case was presented during the multidisciplinary meeting of the Breast Service of a referral oncology center in Colombia, in order to discuss the benefit of CPM. The decision of the board meeting was not to perform CPM. After 30 months of follow-up, the patient is disease-free. Conclusion: There is no evidence on the impact of CPM on survival of patients with LFS and breast cancer in particular. However, in light of the current knowledge, it is not possible to generalize the approach of withholding this prophylactic surgery. It is important to report those cases in which the decision is made to either perform or omit this procedure in order to increase the body of evidence, considering the limitations that make it difficult to build large cohorts or conduct trials exclusively for this genetic disorder.
Sujets)
Femelle , Adulte , Tumeurs du sein , Syndrome de Li-Fraumeni , Gènes p53 , Mastectomie prophylactiqueRésumé
El cáncer en pediatría es una entidad infrecuente. Se estima que más de un 10-15 % de los tumores son secundarios a una variante patogénica en un gen de predisposición al cáncer.Se conocen más de 100 genes de predisposición al cáncer y su asociación con síndromes o tumores aislados. Uno de los más descritos es el síndrome de Li-Fraumeni.Los pacientes con este síndrome tienen alto riesgo de desarrollar uno o más tumores. Su conocimiento permite realizar un protocolo de seguimiento del paciente y de sus familiares afectos, con el que detectar precozmente nuevos tumores y disminuir la morbimortalidad del tumor y de su tratamiento.Esta revisión pretende ser una guía útil para el pediatra. Utilizando como caso guía a una familia, se revisarán los motivos de sospecha de un síndrome de Li-Fraumeni, su diagnóstico clínico y genético, y el protocolo de seguimiento de los familiares portadores de la misma mutación
Pediatric cancer is rare. It is estimated that more than 10-15 % of tumors are secondary to a pathogenic variant in a cancer predisposition gene.More than 100 cancer predisposition genes and their association with syndromes or isolated tumors have been identified. Li-Fraumeni syndrome is one of those who have been most widely described.Patients with this syndrome present a high risk of developing one or more tumors. Its knowledge allows to establish a follow-up protocol for the patient and affected family members, so as to detect new tumors in an early manner and reduce tumor- and treatment-related morbidity and mortality.The objective of this review is to offer useful guidelines for pediatricians. Based on a family case, reasons for Li-Fraumeni syndrome suspicion, clinical and genetic diagnosis, and the follow-up protocol of family members who carry the same mutation will be reviewed.
Sujets)
Humains , Nourrisson , Enfant d'âge préscolaire , Enfant , Syndrome de Li-Fraumeni/diagnostic , Pédiatrie , Syndromes néoplasiques héréditaires , Gènes p53 , Syndrome de Li-Fraumeni/épidémiologieRésumé
ABSTRACT Recent advances in chronic lymphocytic leukemia (CLL) includes description of disease genomic landscape, inclusion of prognostic relevant genetic tests in CLL workflow and evaluation of minimal residual disease (MRD)1 in parallel with the increase availability of novel therapy agents.In this review, the theoretical and practical aspects of response assessment have been discussed. These are based on updated recommendations of the European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) for genetic tests (TP53 mutation and IGHV status) and flow cytometry analysis for CLL. Methodological approaches and interpretation of results were also discussed.2,3
Sujets)
Leucémie chronique lymphocytaire à cellules B/diagnostic , Gènes p53 , Maladie résiduelle , Cytométrie en flux , MutationRésumé
ABSTRACT Chronic lymphocytic leukemia is the most common hematologic malignancy among adults in Western countries. Several studies show that somatic mutations in the TP53 gene are present in up to 50% of patients with relapsed or refractory chronic lymphocytic leukemia. This study aims to review and compare the methods used to detect somatic TP53 mutations and/or 17p deletions and analyze their importance in the chronic lymphocytic leukemia diagnosis and follow-up. In chronic lymphocytic leukemia patients with refractory or recurrent disease, the probability of clonal expansion of cells with the TP53 mutation and/or 17p deletion is very high. The studies assessed showed several methodologies able to detect these changes. For the 17p deletion, the chromosome G-banding (karyotype) and interphase fluorescence in situ hybridization are the most sensitive. For somatic mutations involving the TP53 gene, moderate or high-coverage read next-generation sequencing and Sanger sequencing are the most recommended ones. The TP53 gene mutations represent a strong adverse prognostic factor for patient survival and treatment resistance in chronic lymphocytic leukemia. Patients carrying low-proportion TP53 mutation (less than 20-25% of all alleles) remain a challenge to these tests. Thus, for any of the methods employed, it is essential that the laboratory conduct its analytical validation, documenting its accuracy, precision and sensitivity/limit of detection.
Sujets)
Humains , Leucémie chronique lymphocytaire à cellules B , Gènes p53 , Délétion de segment de chromosome , MutationSujets)
Humains , Mâle , Femelle , Nouveau-né , Enfant , Gènes p53/génétique , Dépistage précoce du cancer/méthodes , Pronostic , Brésil , Cortex surrénal/anatomopathologie , Cortex surrénal/imagerie diagnostique , Tumeurs corticosurrénaliennes/chirurgie , Tumeurs corticosurrénaliennes/diagnostic , Tumeurs corticosurrénaliennes/génétique , Tumeurs corticosurrénaliennes/épidémiologie , Carcinome corticosurrénalien , Carcinome corticosurrénalien/chirurgie , Carcinome corticosurrénalien/diagnostic , Carcinome corticosurrénalien/génétique , Âge de début , Surrénalectomie/méthodes , Diagnostic différentiel , Évaluation des symptômes , MutationRésumé
Objective: To explore the clinical implications and prognostic value of TP53 gene mutation and deletion in patients with myelodysplastic syndromes (MDS) . Methods: 112-gene targeted sequencing and interphase fluorescence in situ hybridization (FISH) were used to detect TP53 mutation and deletion in 584 patients with newly diagnosed primary MDS who were admitted from October 2009 to December 2017. The association of TP53 mutation and deletion with several clinical features and their prognostic significance were analyzed. Results: Alterations in TP53 were found in 42 (7.2%) cases. Of these, 31 (5.3%) cases showed TP53 mutation only, 8 (1.4%) cases in TP53 deletion only, 3 (0.5%) cases harboring both mutation and deletion. A total of 37 mutations were detected in 34 patients, most of them (94.6%) were located in the DNA binding domain (exon5-8) , the remaining 2 were located in exon 10 and splice site respectively. Patients with TP53 alterations harbored significantly more mutations than whom without alterations (z=-2.418, P=0.016) . The median age of patients with TP53 alterations was higher than their counterparts[60 (21-78) years old vs 52 (14-83) years old, z=-2.188, P=0.029]. TP53 alterations correlated with complex karyotype and International prognostic scoring system intermediate-2/high significantly (P<0.001) . Median overall survival of patients with TP53 alterations was shorter than the others[13 (95%CI 7.57-18.43) months vs not reached, χ(2)=12.342, P<0.001], while the significance was lost during complex karyotype adjusted analysis in multivariable model. Conclusion: TP53 mutation was more common than deletion in MDS patients. The majority of mutations were located in the DNA binding domain. TP53 alterations were strongly associated with complex karyotype and always coexisted with other gene mutations. TP53 alteration was no longer an independent prognostic factor when complex karyotype were occurred in MDS.
Sujets)
Adolescent , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Humains , Adulte d'âge moyen , Jeune adulte , Gènes p53 , Hybridation fluorescente in situ , Mutation , Syndromes myélodysplasiques/génétique , Pronostic , Protéine p53 suppresseur de tumeurRésumé
Objective: To analyze the survival and first-line immune-chemotherapy (CIT) of chronic lymphocytic leukemia (CLL) with abnormal TP53 gene in the era of traditional CIT. Methods: The clinical data of 118 CLL patients diagnosed from January 2003 to August 2017 were collected. Survival was analyzed according to indicators including sex, age, Binet risk stratification, B symptoms, β(2)-microglobulin (β(2)-MG) , immunoglobulin heavy chain variable region gene (IGHV) mutation status, chromosome karyotype and TP53 gene deletion/mutation. The efficacy of first-line CIT of 101 CLL patients was further analyzed. Results: Among 118 patients, median progression-free survival (PFS) was 12 (95%CI 10.148-13.852) months and median overall survival (OS) was 53 (95%CI 41.822-64.178) months, only 30.5% patients survived over 5 years. Low β(2)-MG<3.5 mg/L indicated longer PFS (P=0.027) , female and Binet A patients had longer OS (P=0.011 and 0.013, respectively) . Of 118 patients, 17 (14.4%) didn't receive any therapy until follow-up time or the dead time. Among the 101 patients who received ≥1 CIT, median time to first treatment (TTFT) was 1 (0-62) months, patients in Binet A had longer TTFT (P<0.001) compared to the patients in Binet B/C. According to statistical needs, we divided those first-line CIT into four groups: there were 30 cases (29.7%) in mild chemotherapy group (mainly treated with nitrogen mustard phenylbutyrate or rituximab alone) , 32 cases (31.7%) in the fludarabine-containing group, 23 cases (22.8%) in high-dose methyprednisolone (HDMP) containing group and 16 cases (15.8%) in the other chemotherapy group. The first regimen contained HDMP can bring longer PFS (P<0.001) , however the OS between four groups had no statistical differences. Conclusion: CLL patients with abnormal TP53 gene had poor response to immunotherapy, rapid clinical progressing, first-line immunotherapy containing HDMP can prolong PFS and will create an opportunity for patients to participate in clinical trials of novel drugs.
Sujets)
Femelle , Humains , Protocoles de polychimiothérapie antinéoplasique , Gènes p53 , Immunothérapie , Leucémie chronique lymphocytaire à cellules B/génétique , Analyse de survie , Protéine p53 suppresseur de tumeur/génétiqueRésumé
PURPOSE: Tumor protein p53-regulated apoptosis-inducing protein 1 (TP53AIP1) functions in various cancers. We studied the effect and molecular mechanism of TP53AIP1 in breast cancer. METHODS: The degree of correlation between TP53AIP1 expression and overall survival in patients with breast cancer was obtained from the online The Cancer Genome Atlas database. Six of the TP53AIP1 levels in the tumor and adjacent non-tumor tissues randomly selected from 38 breast cancer patients were determined. Transgenic technology was used to enhance the expression of TP53AIP1 in breast cancer cell lines, MDA-MB-415 and MDA-MB-468, and to observe the effects of gene overexpression on the proliferation, cell cycle, and apoptosis of breast cancer cells. The molecular mechanism of association between cell cycle- and apoptosis-related factors and the phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) pathway was also studied. RESULTS: The messenger RNA and protein expression levels of TP53AIP1 in cancer tissues were significantly lower than those in the control group. TP53AIP1 overexpression inhibits cell viability. The mechanism of TP53AIP1 inhibition of proliferation and growth of breast cancer cells includes cell cycle arrest, apoptosis promotion (p < 0.01), promotion of the expression of cleaved-caspase-3 (p < 0.01), cleaved-caspase-9 (p < 0.01), B cell lymphoma/leukemia-2 (Bcl-2)-associated X protein, and p53 (p < 0.01), and the inhibition of Bcl-2, Ki67, and PI3K/Akt pathways (p < 0.01). CONCLUSION: TP53AIP1 may be a novel tumor suppressor gene in breast cancer and can potentially be used as an effective target gene for the treatment of breast cancer.
Sujets)
Humains , Apoptose , Tumeurs du sein , Région mammaire , Points de contrôle du cycle cellulaire , Lignée cellulaire , Prolifération cellulaire , Survie cellulaire , Gènes p53 , Gènes suppresseurs de tumeur , Génome , Phosphotransferases , ARN messagerRésumé
Introducción: la mutación en el gen TP53 se ha asociado con la oncogénesis de los tumores de ovario tipo II. Se ha propuesto que las mutaciones de p53 se inician en las células de la trompa uterina y después migran al ovario. El objetivo de este estudio es establecer la frecuencia de la expresión de p53 en ovario y trompa uterina en carcinoma epitelial primario de ovario. Materiales y métodos: estudio de corte transversal en tumores primarios epiteliales de ovario. Se evaluó la expresión de p53 por inmunohistoquímica en el ovario y en las trompas uterinas. Resultados: se incluyeron 45 pacientes con edad media de 55 años. Se estudiaron 24 casos de carcinomas serosos, 6 endometrioides, 5 mixtos, 3 de células claras, 3 carcinosarcomas, 2 carcinomas mucinosos y 2 indiferenciados. Se observó positividad fuerte y difusa en 68% de los tumores tipo II. En 52 hubo positividad en trompa uterina y ovario, 92% con compromiso bilateral. En 3 de estos casos se reconoció carcinoma intraepitelial tubárico con positividad de p53 en el área tumoral, no tumoral y en el carcinoma seroso. Conclusión: como se ha observado en estudios previos, el gen TP53 está involucrado en la oncogénesis de los tumores tipo II y se ha demostrado que existe una relación entre una mutación inicial de p53, seguida por STIL, STIC, evolucionando a un carcinoma seroso de ovario.
Introduction: a TP53 gene mutation has been associated with the oncogenesis of type II ovary tumors. Mutations of the p53 gene in the fallopian tube cells which migrate to the ovary have been proposed as an alternative origin. This study focuses on establishing the frequency of p53 ovary and uterine tube expression in primary epithelial ovarian cancer. Materials and Methods: a cross-sectional study on primary epithelial ovarian tumors. Expression of p53 in the ovary and uterine tubes was assessed using immunohistochemistry. Results: 45 patients, median age 55 years, were included. Twenty-four (24) cases of serous carcinomas, 6 endometrioid carcinomas, 5 mixed carcinomas, 3 clear-cell carcinomas, 3 carcinosarcomas, 2 mucinous carcinomas and 2 undifferenciated tumors were studied. Positivity was strong and diffuse in 68% of type II tumors. Positivity was detected in the tubes and ovaries in 52 cases, 92% with bilateral compromise. Intraepithelial tube carcinoma was recognized in 3 cases with p53 positivity in the tumor, outside the tumor and in the serous carcinoma. Conclusion: as observed in previous studies, TP53 gene is involved in the oncogenesis of type II tumors and a correlation between the initial p53 mutations followed by STIL, STIC progressing to an ovary serous carcinoma has been demonstrated.
Sujets)
Humains , Femelle , Adulte d'âge moyen , Carcinome épithélial de l'ovaire , Gènes p53 , Trompes utérines , TumeursRésumé
Abstract Objective: To evaluate the clinical features associated with adrenocortical hormone overexpression and familial cancer profiling as potential markers for early detection of adrenocortical tumors in children from South and Southeast Brazil. Methods: The clinical manifestations and anthropometric measurements of 103 children diagnosed with adrenocortical tumors were analyzed. Results: Between 1982 and 2011, 69 girls and 34 boys diagnosed with adrenocortical tumors were followed-up for a median time of 9.0 years (0-34 years). Signs of androgen overproduction alone (n = 75) or associated with cortisol (n = 18) were present in 90.3%. TP53 p.R337H mutation was found in 90.5% of patients. Stages I, II, III, and IV were observed in 45.6%, 27.2%, 19.4%, and 7.8% of patients, respectively. At diagnosis, there were no significant differences in height (p = 0.92) and weight (p = 0.22) among children with adrenocortical tumors, but children with virilization alone had significantly higher height-for-age Z-scores (0.92 ± 1.4) than children with hypercortisolism alone or combined (−0.32 ± 1,8; p = 0.03). The five-year overall survival was 76.7% (SD ± 4.2). Patients with advanced-stage disease had a significantly worse prognosis than those with limited disease (p < 0.001). During follow-up, ten of 55 p.R337H carrier parents developed cancer, whereas none of the 55 non-carriers did. Conclusions: Signs of adrenocortical hormone overproduction appear early, even in cases with early-stage. These signs can be identified at the physical examination and anthropometric measurements. In southern Brazil, pediatric adrenocortical tumor is a sentinel cancer for detecting families with germline p.R337H mutation in TP53 gene.
Resumo Objetivo: Avaliar as manifestações clínicas da hiperexpressão de hormônios do córtex da adrenal e câncer familiar como marcadores para a detecção precoce de tumores adrenocorticais em crianças do Sul e Sudeste do Brasil. Pacientes e métodos: Foram analisadas as manifestações clínicas e antropométricas de 103 crianças diagnosticadas com tumores adrenocorticais. Resultados: Entre 1982 e 2011, 69 meninas e 34 meninos diagnosticados com tumores adrenocorticais foram acompanhados por um tempo mediano de nove anos (0-34). Ao diagnóstico, sinais de virilização isolada (n = 75) ou associada ao cortisol (n = 18) estavam presentes em 90,3% dos pacientes; a mutação do gene TP53 p.R337H foi identificada em 90,5% dos pacientes. Os pacientes foram classificados em estádio I (45,6%), II (27,2%), III (19,4%) e IV (7,8%). Ao diagnóstico, não houve diferença significativa para as medidas de altura (p = 0,92) e de peso (p = 0,22) entre as crianças com tumores adrenocorticais, mas crianças com virilização tiveram escore-Z mais elevado para a idade (0,92 ± 1,4) do que aquelas com hipercortisolismo isolado ou combinado (−0,32 ± 1,8; p = 0,03). A sobrevida global de cinco anos foi de 76,7% (DP ± 4,2). Pacientes com estádios avançados tiveram pior prognóstico (p < 0,001). Durante o seguimento, 10 dos 55 genitores portadores da p.R337H desenvolveram câncer, enquanto que nenhum caso ocorreu entre os 55 não portadores. Conclusões: Os sinais de hiperprodução de hormônios adrenocorticais aparecem precocemente no desenvolvimento do tumor e podem ser identificados pelo exame físico e pelas medidas antropométricas na consulta pediátrica de rotina. O tumor adrenocortical pediátrico é sentinela para a detecção de câncer em famílias que segregam a mutação germinativa p.R337H do gene TP53.
Sujets)
Humains , Mâle , Femelle , Nourrisson , Enfant d'âge préscolaire , Enfant , Gènes p53/génétique , Protéine p53 suppresseur de tumeur/génétique , Tumeurs corticosurrénaliennes/diagnostic , Tumeurs corticosurrénaliennes/génétique , Mutation germinale/génétique , Prédisposition génétique à une maladie/génétique , Pedigree , Études longitudinales , Stadification tumoraleRésumé
Cervical cancer is a public health problem and the molecular mechanisms underlying radioresistance are still poorly understood. Here, we evaluated the modulation of key molecules involved in cell proliferation, cell cycle and DNA repair in cervical cancer cell lines (CASKI and C33A) and in malignant tissues biopsied from 10 patients before and after radiotherapy. The expression patterns of epidermal growth factor receptor (EGFR), excision repair cross-complementation group 1 (ERCC1) and p53 were evaluated in cancer cell lines by quantitative PCR and western blotting, and in human malignant tissues by immunohistochemistry. The mutation status of TP53 gene was evaluated by direct sequencing. Among cell lines, absent or weak modulations of EGFR, ERCC1 and p53 were observed after exposure to 1.8 Gy. Conversely, increased expressions of p53 (5/10 patients; P=0.0239), ERCC1 (5/10 patients; P=0.0294) and EGFR (4/10 patients; P=0.1773) were observed in malignant tissues after radiotherapy with the same radiation dose. TP53 mutations were found only in one patient. Here we show that a single dose of radiotherapy induced EGFR, ERCC1 and p53 expression in malignant tissues from cervical cancer patients but not in cancer cell lines, highlighting the gap between in vitro and in vivo experimental models. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of p53, EGFR and ERCC1 may be part of a radioresistance mechanism.
Sujets)
Humains , Femelle , Adulte , Adulte d'âge moyen , Sujet âgé , Carcinome épidermoïde/radiothérapie , Tumeurs du col de l'utérus/radiothérapie , Gènes p53/effets des radiations , Gènes erbB-1/effets des radiations , Protéines de liaison à l'ADN/effets des radiations , Endonucleases/effets des radiations , Immunohistochimie , Carcinome épidermoïde/génétique , Carcinome épidermoïde/anatomopathologie , Test clonogénique de cellules souches tumorales , Technique de Western , Études prospectives , Lignée cellulaire tumorale , MutationRésumé
A ausência de XPC, uma proteína canonicamente envolvida em reparo de DNA por excisão de nucleotídeos, está associada a vários fenótipos característicos de disfunção mitocondrial como o desequilíbrio entre os complexos da cadeia transportadora de elétrons (CTE), redução no consumo de oxigênio, maior produção de peróxido de hidrogênio, e maior sensibilidade a agentes que causam estresse mitocondrial. Contudo, uma descrição mecanística da relação entre deficiência de XPC e disfunção mitocondrial ainda não está bem estabelecida. Aqui mostramos que a deficiência de XPC está associada ao aumento na expressão do supressor de tumor p53. Essa alteração é acompanhada pelo aumento da expressão de diversas proteínas que participam em importantes funções mitocondriais. A inibição de p53 reverte a superexpressão de algumas dessas proteínas. O tratamento com o inibidor do Complexo III da CTE antimicina A induz aumento da expressão de p53 de forma mais acentuada na linhagem Xpc-/-, enquanto o tratamento com o antioxidante N-acetilcisteína diminue a produção basal de H2O2, expressão de p53 e sensibilidade aumentada ao tratamento com antimicina A. Em conjunto, nossos resultados suportam a hipótese de que o aumento da produção de H2O2 em células Xpc-/- tem um papel causal na regulação da expressão de p53 e na disfunção mitocondrial
Although XPC has been initially implicated in the nucleotide excision DNA repair pathway, its deficiency is associated with mitochondrial dysfunction, including unbalanced electron transport chain (ETC) activity, lower oxygen consumption, increased hydrogen peroxide production, and greater sensitivity to mitochondrial stress. However, a mechanistic understanding of the role of XPC in regulating mitochondrial function is still not well established. Here we show that XPC deficiency is associated with increased expression of the tumor suppressor p53, which is accompanied by increased expression of several proteins that participate in important mitochondrial functions. Inhibition of p53 reverses the overexpression of some of these proteins. In addition, treatment with the ETC inhibitor antimycin A induces p53 expression more robustly in the Xpc-/- cells, while treatment with the antioxidant N-acetylcysteine decreases basal H2O2 production, p53 expression and sensitivity to antimycin A treatment. Together, our results support a model in which increased H2O2 production in Xpc-/- causes upregulation of p53 expression and mitochondrial dysfunction
Sujets)
Xeroderma pigmentosum/classification , Protéine p53 suppresseur de tumeur/pharmacocinétique , Protéines mitochondriales , Peroxyde d'hydrogène/analyse , Gènes p53/physiologie , Antimycine A/effets indésirablesRésumé
O carcinoma epidermóide do pênis tem incidência significativa em países em desenvolvimento como o Brasil. O tratamento dos tumores invasivos consiste na ressecção da lesão primária e linfadenectomia bilateral, procedimento associado a alta taxa de morbidade. O estudo de fatores prognósticos do tumor primário pode ajudar na seleção dos pacientes candidatos às linfadenectomias. A expressão imunoistoquímica do ki-67, do p53 e da nucleofosmina (NPM) se associam a pior prognóstico em diversas neoplasias. Estudamos retrospectivamente 112 pacientes portadores de carcinoma epidermóide do pênis, submetidos a cirurgia do tumor primário no Departamento de Cirurgia Pélvica do AC Camargo Cancer Center. Os blocos de parafina foram revisados e submetidos a coloração imunoistoquímica para NPM, ki-67 e p53. A leitura foi realizada no dispositivo Aperio®. A imunorreatividade da NPM, Ki67 e p53 foi relacionada a fatores clínicos e patológicos: idade, estado civil, raça, tempo de evolução da doença, antecedentes venéreos, estadiamento clínico, espessura do tumor, grau de diferenciação, embolização linfovascular, estadiamento patológico, tipo de invasão. Analisamos quais fatores influenciaram o risco de metástases linfonodais e sobrevida global (SG) e livre de doença (SLD). Os testes estatísticos de associação utilizados foram o Qui-quadrado, teste de Fischer, a regressão logística múltipla. Na análise de sobrevida utilizamos o Kaplan e Meier, o Log-rank e o modelo de riscos proporcionais de cox. A imunorreatividade do p53 estava alta em 42,3% dos casos e se associou a maior ocorrência de recidivas, mas não a outras variáveis. A imunorreatividade do Ki67 estava alta em 89,1% dos casos e não se associou a nenhuma variável. A NPM apresentou imunoexpressão baixa em 50% dos casos e se associou a maiores estadios clínicos T e N e invasão de corpo cavernoso. A imunorreatividade do p53, da NPM e do Ki67 não se associaram a metástases linfonodais. A ocorrência de metástases linfonodais foi influenciada pelo estadiamento clínico N (p=0,001), grau de diferenciação (p=0,007), invasão vascular (p=0,004), invasão perineural (p<0,001), infiltração de corpos cavernosos (p=0,004), infiltração da uretra (p=0,013) e espessura tumoral (p=0,008). No modelo multivariado, estadiamento clínico N (RR=5,5); IC [1,4-20,8], infiltração de corpos cavernosos (RR=3,9); IC [1,2-12,3] e invasão perineural (RR=4,9); IC [1,5-16,2] foram fatores independentes de risco de metástases linfonodais. A SG ao final de 120 meses foi de 47,3% e foi influenciada por raça (p=0,009), recidivas (p=0,018), grau moderado e alto (p=0,031), infiltração de corpos cavernosos (p=0,037), invasão vascular (p=0,02), invasão perineural (p=0,030), espessura tumoral >5 mm (p=0,015) e metástases linfonodais (p=0,003). A imunoexpressão da NPM, do Ki67 e do p53 não influenciou a SG. Na análise multivariada, a invasão vascular (RR=1,9; IC [1,0-3,6]) se associou a menor SG. A SLD foi influenciada por infiltração de corpo cavernoso (p<0,001), infiltração da uretra (p=0,032), infiltração vascular (p<0,001), metástases linfonodais (p<0,001) e alta imunoexpressão do p53 (p=0,008). A imunorreatividade do Ki67 e da NPM não influenciaram a SLD. Na análise multivariada apenas a invasão de corpo cavernoso (RR=4,0; IC [1,4-11,3]) e a ocorrência de metástases linfonodais (RR=4,2;IC[1,4-13,1]) se associaram a menor SLD. Os resultados permitem concluir que a alta expressão do p53 se associou a pior SLD na análise univariada e a perda de expressão da NPM se associou a maiores estadios clínico e patológico
Penile carcinoma still has relevant incidence in developing countries like Brazil. The gold standard for the treatment of invasive lesions remains amputation followed by bilateral lymphadenectomy, procedures associated with high morbidity. The identification of prognostic factors could help to select the best candidates to lymphadenectomies. The immunoreactivity of p53, nucleophosmin (NPM) and ki67 has been associated with the prognosis of many tumors. A retrospective study of 112 patients with penile carcinoma submitted to amputation and lymphadenectomy at the Division of Urology of A.C.Camargo Cancer Center was undertaken to evaluate the prognostic value of immunoreactivity of p53, NPM and Ki67 in the primary tumor. The immunoreactivity of these proteins were correlated with the followed factors: age, race, marital status, time to diagnosis, venereal history, clinical stage, tumor thickness, histological grade, lymphovascular embolization, corpora cavernosa and urethra infiltration, pattern of invasion, lymph node metastasis, overall survival (OS) and disease free survival (DFS). The association among variables was done by the chi-square test and the survival analysis were performed with the Kaplan & Meier technique and the multi-factorial analysis by the Cox regression technique. The p53 immunoreactivity was high in 42,3% of the cases and was associated with high recurrence rates, but not with other variables. Ki67 immunoreactivity was high in 89,1% of the cases and was not associated with any variable. NPM immunostaining was considered low in 50% of the cases and was associated with higher clinical stages N and T and corpora cavernosa invasion, but not with other variables. There was no association between NPM, p53 and Ki67 immunostaining and lymph node metastasis. Clinical stage N (p=0,001), grade of differentiation (p=0,007), vascular invasion (p=0,004), perineural invasion (p<0,001), corpora cavernosa infiltration (p=0,004), urethral infiltration (p=0,013) and tumor thickness (p=0,008) were significant for the incidence of lymph node metastasis. The multivariate analysis revealed that clinical stage N (RR=5,5; CI [1,4-20,8]), corpora cavernosa infiltration (RR=3,9; CI [1,2-12,3]) and perineural invasion (RR=4,9; CI [1,5-16,2]) were significant for the incidence of lymph node metastasis. The OS at the end of 120 months was 47,3% and was influenced by race (p=0,009), recurrences (p=0,018), moderate or high pathologic grade (p=0,031), corpora cavernosa infiltration (p=0,037), lymphovascular embolization (p=0,02), perineural invasion (p=0,030), tumor thickness (p=0,015) and lymph node metastasis (p=0,03). There was no association between p53, NPM and Ki67 immunoreactivity and OS. Multivariate analysis revealed that vascular invasion (RR=1,9; CI [1,0-3,6]) influenced OS. DFS was influenced by corpora cavernosa infiltration (p<0,001), urethra infiltration (p=0,032), lymphovascular embolization (p<0,001), lymph node metastasis (p<0,001) and p53 immunostaining (p=0,008). NPM and Ki67 immunoreactivity did not influence DFS. Multivariate analysis revealed that corpora cavernosa infiltration (RR=4,0; CI [1,4-11,3]) and lymph node metastasis (RR=4,2; CI [1,4-13,1]) influenced DFS. These results showed that higher p53 expression was associated with a worst DFS at univariate analysis and the low NPM imunoexpression was associated with higher clinical and pathological stages
Sujets)
Humains , Mâle , Adulte , Adulte d'âge moyen , Sujet âgé , Sujet âgé de 80 ans ou plus , Tumeurs du pénis , Pronostic , Immunohistochimie , Gènes p53 , Métastase lymphatique , Survie , Antigène KI-67 , Kinase du lymphome anaplasiqueRésumé
Recentes indicações de um fenótipo mais variável e uma menor penetrância de câncer na síndrome de Li-Fraumeni (LFS) levantaram questões a respeito da verdadeira prevalência populacional da síndrome. Investigações anteriores, baseadas em contextos clínicos, propuseram que as estimativas de prevalência populacional de LFS poderiam variar entre um portador a cada 5.000 a 20.000 indivíduos. O primeiro artigo demonstrou que a prevalência populacional de variantes patogênicas e provavelmente patogênicas no gene TP53, as principais causas de LFS, é mais alta do que a esperada em uma população não selecionada pelo histórico de câncer. Nós sugerimos que a prevalência populacional poderia ser de até 10x mais alta do que previamente descrita. O segundo artigo teve como objetivo avaliar e validar as estimativas de prevalência de variantes germinativas em TP53 no banco de dados do gnomAD, que inclui variações genéticas de mais de 130.000 individuos. Variantes em TP53 foram selecionadas e classificadas com base em nosso algoritmo previamente descrito. Além disso, nós fornecemos estimativas de prevalência alternativas com base na classificação de três bancos de dados, ClinVar, HGMD e o portal UMD_TP53. Com base nessa nova análise, nós observamos que a prevalência populacional de variantes germinativas patogênicas e provavelmente patogênicas no gene TP53 é, de fato, maior do que previamente descrita. Contudo, as estimativas podem variar drasticamente (0,02-0,25%) devido a diferentes classificações e a algumas variantes específicas em TP53 que podem estar associadas a um risco inflacionado (p.N235S, p.V31I e p.R290H). Abordagens interdisciplinares são necessárias para melhor entender a interação entre classificação de variantes em TP53, estimativas de prevalência, penetrância de câncer e fenótipo em LFS
Recent suggestions of a variable Li-Fraumeni syndrome (LFS) phenotype and a lower LFS-associated cancer penetrance have raised questions regarding the true disease population prevalence. Earlier investigations, based on clinical contexts, had proposed that the estimated population prevalence of LFS could be between the range of one carrier in every 5,000-20,000 individuals. The first article reported a higher-than-expected population prevalence of pathogenic and likely pathogenic germline TP53 variants in a population unselected for cancer history. We suggested that the population prevalence could be up to 10x higher than previously described in clinically-based studies. The second article aimed to further evaluate germline TP53 variant prevalence estimates in the gnomAD database, which includes germline variation from over 130,000 individuals. Variants were selected and classified based on our previously published algorithm. In addition, we provided alternative prevalence estimates based on three other classifications databases, ClinVar, HGMD, and the UMD_TP53 website. Based on the new analysis, we observed that the population prevalence of pathogenic and likely pathogenic TP53 variants is indeed higher than previously described. However, the estimates can vary widely (0.02-0.25%) due to differences in variant classifications and due to some specific TP53 variants that may be associated with inflated risk (p.N235S, p.V31I, and p.R290H). Comprehensive approaches are needed to better understand the interplay of germline TP53 variant classification, prevalence estimates, cancer penetrance and phenotype of LFS