Evaluation of infliximab-induced genotoxicity and possible action on BCL-2 and P53 genes.

Although the last pandemic created an urgency for development of vaccines, there was a continuous and concerted effort to search for therapeutic medications among existing drugs with different indications. One of the medications of interest that underwent this change was infliximab (IFM). This drug is used as an anti-inflammatory, predominantly in patients with Crohn 's disease, colitis ulcerative, and rheumatoid arthritis. In addition to these patients, individuals infected with Coronavirus Disease (COVID-19) were administered this chimeric monoclonal antibody (IMF) to act as an immunomodulator for patients in the absence of comprehensive research. Consequently, the present study aimed to examine the genotoxic effects attributed to IFM treatment employing different assays in vivo using mouse Mus musculus. Therefore, IFM was found to induce genotoxic effects as evidenced by the comet assay but did not demonstrate genotoxic potential utilizing mouse bone marrow MN test. The results of evaluating the expression of the P53 and BCL-2 genes using RT-qPCR showed stimulation of expression of these genes at 24 hr followed by a decline at 48 hr. Although the comet assay provided positive results, it is noteworthy that based upon negative findings in the micronucleus test, the data did not demonstrate significant changes in the genetic material that might affect the therapeutic use of IFM. The stimulation of expression of P53 and BCL-2 genes at 24 hr followed by a decline at 48 hr suggest a transient, if any, effect on genetic material. However, there is still a need for more research to more comprehensively understand the genotoxic profile of this medication.

Perfil molecular de cáncer de endometrio en mujeres de Bogotá DC, Colombia / Molecular profile of endometrial cancer in women from Bogota DC, Colombia

Introducción: El cáncer de endometrio ocupa el sexto lugar en incidencia del cáncer en mujeres. La caracterización molecular de este cáncer permite optimizar la estratificación de riesgo para mejorar el tratamiento de las pacientes. Objetivo: Determinar el perfil molecular TCGA de pacientes con cáncer de endometrio en Bogotá, D.C., Colombia. Método: Estudio descriptivo en una cohorte de pacientes con cáncer de endometrio. Las mutaciones en los exones 9 a 14 del gen POLE fueron identificadas mediante amplificación por reacción en cadena de la polimerasa, seguida de secuenciación Sanger y análisis bioinformático. La expresión de las proteínas MMR y p53 se identificó mediante inmunohistoquímica. Resultados: Se incluyeron 40 pacientes con una mediana de edad de 66 años. El 15% presentaron mutaciones en el dominio exonucleasa de POLE. El 32% de las pacientes que no presentaron mutaciones manifestaron deficiencia en el sistema MMR. El 43,47% de las pacientes sin mutaciones en POLE ni alteración del sistema MMR presentaron alteración de la proteína p53. Conclusiones: La población de cáncer de endometrio analizada presenta un perfil molecular TCGA similar a lo reportado para otras poblaciones.

Introduction: Endometrial cancer ranks sixth in cancer incidence among women. Its molecular characterization allows for a more precise risk stratification with the aim of improving patient treatment. Objective: To determine the TCGA molecular profile of patients with endometrial cancer in Bogota, Colombia. Method: A descriptive study of a cohort of patients with endometrial cancer. The expression of MMR proteins and p53 was identified through immunohistochemistry. Mutations in exons 9 to 14 of the POLE gene were identified through polymerase chain reaction amplification, followed by Sanger sequencing and bioinformatic analysis. Results: Forty patients were included in the study, with a median age of 66 years, 15% of them exhibited mutations in the exonuclease domain of POLE, while 32% of patients without mutations showed deficiency in the MMR system. Forty three percent of patients without mutations in POLE or MMR alterations showed aberrant p53 protein expression. Conclusions: The analyzed population of endometrial cancer presents a TCGA molecular profile similar to that reported for other populations.

Linfoma de Células do Manto, seus principais aspectos prognósticos, terapêuticos e perspectivas futuras / Mantle Cell Lymphoma, prognostics and therapeutics aspects. and future perspectives

O Linfoma de Células do Manto é uma doença hematológica considerada rara, conhecida por apresentar um desfecho heterogêneo, compreendendo diferentes mecanismos patológicos e envolvendo diversas vias de sinalização. No curso do diagnóstico deste linfoma, o subtipo histológico é fundamental assim como a análise de demais fatores para a estratificação do risco e avaliação prognóstica do paciente. Diversos estudos com o intuito de melhorar e padronizar a avaliação do paciente vem sendo desenvolvidos. Dito isto, atualmente a análise biomolecular da doença foi incorporada na calculadora de estimativa da sobrevida. O acúmulo de evidências científicas fundamenta os protocolos baseados na imunoterapia com Rituximabe e Citarabina para os pacientes que requerem tratamento. O transplante autólogo de medula óssea é utilizado para consolidar a resposta após a indução e, a manutenção do tratamento com Rituximabe confere benefício adicional aos pacientes. No cenário da doença recidivada e refratária, o tratamento foi modificado com o advento de inibidores de vias patogênicas envolvidas na patogenia da doença. Apesar disso, estudos seguem sendo feitos para o aprimoramento das respostas. Em 2020, o uso da modalidade terapêutica do CarT cell foi aprovado para esses casos.

Mantle cell lymphoma is a rare hematological disease well known for its heterogeneous outcomes, it encompasses various pathological mechanisms involving different signaling pathways. Histological subtype plays a fundamental role in diagnosis, alongside the analysis of other factors for risk stratification and prognostic estimation. Numerous studies aimed at improving and standardizing patient assessment have been conducted. Biomolecular analysis of the disease is now incorporated into survival estimation calculators. Scientific evidence data still supports immunotherapy- based regimens with Rituximab and Cytarabine as the preferred induction therapy for patients requiring treatment. Autologous bone marrow transplantation remains advocated for consolidating response, and maintenance therapy with Rituximab post- induction offers additional treatment benefits. In the case of relapsed and refractory disease, treatment has seen a modification with the introduction of inhibitors targeting pathogenic pathways involved in disease pathogenesis. Ongoing studies aim to enhance responses, with the utilization of CarT cell therapy, which gained approval in 2020 for treating such cases, being among the avenues of exploration.

Mutant p53 Gain-of-Function Induces Migration and Invasion through Overexpression of miR-182-5p in Cancer Cells.

The master-key TP53 gene is a tumor suppressor that is mutated in more than 50% of human cancers. Some p53 mutants lose their tumor suppressor activity and acquire new oncogenic functions, known as a gain of function (GOF). Recent studies have shown that p53 mutants can exert oncogenic effects through specific miRNAs. We identified the differentially expressed miRNA profiles of the three most frequent p53 mutants (p53R273C, p53R248Q, and p53R175H) after their transfection into the Saos-2 cell line (null p53) as compared with p53WT transfected cells. The associations between these miRNAs and the signaling pathways in which they might participate were identified with miRPath Software V3.0. QRT-PCR was employed to validate the miRNA profiles. We observed that p53 mutants have an overall negative effect on miRNA expression. In the global expression profile of the human miRNome regulated by the p53R273C mutant, 72 miRNAs were underexpressed and 35 overexpressed; in the p53R175H miRNAs profile, our results showed the downregulation of 93 and upregulation of 10 miRNAs; and in the miRNAs expression profile regulated by the p53R248Q mutant, we found 167 decreased and 6 increased miRNAs compared with p53WT. However, we found overexpression of some miRNAs, like miR-182-5p, in association with processes such as cell migration and invasion. In addition, we explored whether the induction of cell migration and invasion by the p53R48Q mutant was dependent on miR-182-5p because we found overexpression of miR-182-5p, which is associated with processes such as cell migration and invasion. Inhibition of mutant p53R248Q and miR-182-5p increased FOXF2-MTSS1 levels and decreased cell migration and invasion. In summary, our results suggest that p53 mutants increase the expression of miR-182-5p, and this miRNA is necessary for the p53R248Q mutant to induce cell migration and invasion in a cancer cell model.

Aspectos histológicos, genéticos y moleculares de las lesiones preneoplásicas de la mucosa gástrica / Histological, genetic and molecular aspects of preneoplastic lesions of the gastric mucosa

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.

Association between the Arg72Pro Genotypes in the TP53 Gene and Ile655Val in the HER2 Gene and the Risk of Developing Breast Cancer in the Population of Amapá, Northern Brazil.

BACKGROUND: The polymorphisms Arg72Pro in the TP53 gene (rs1042522) and Ile655Val in the HER2 gene (rs1136201) have been related to susceptibility to several types of cancer. Different studies show the association of these polymorphisms with breast cancer, so our aim in this study was to investigate whether the Arg72Pro and Ile655Val polymorphisms have any influence on the risk of developing breast cancer in women from the city of Macapá, Amapá, located in the brazilian amazon region. METHODS AND RESULTS: We then analyzed 80 DNA samples from women with breast cancer and 83 DNA samples from women without the disease, by the Restriction Fragment Length Polymorphism - Polymerase Chain Reaction (PCR-RFLP) technique. The genotype frequencies for rs1042522 were Ar/Arg 23.7%, Arg/Pro 47.5% and Pro/Pro 28.5% in patients and in controls Ar/Arg 69.8%, Arg/Pro 19.2% and Pro/Pro 10.8%. For the HER-2 gene the frequency of Ile/Ile, Ile/Val and Val/Val genotypes was 82.5%, 17.5% and 0% in the patients and 75.9%, 20.4% and 3.6% in the controls. The presence of at least one altered allele in rs1042522 and rs1136201 polymorphisms was found in 91.25% of patient samples. CONCLUSION: This study found a significant association between the Arg/Pro and Pro/Pro genotypes in the TP53 gene and the Ile/Val genotype in the HER-2 gene and breast cancer risk, however, we emphasize that more studies need to be carried out in the investigated population to consolidate our results.

Alterations in APC, BECN1, and TP53 gene expression levels in colon cancer cells caused by monosodium glutamate / Alterações nos níveis de expressão gênica APC, BECN1 e TP53 em células de câncer de cólon causadas por glutamato monossódico

Colorectal cancer (CRC) is a disease with high incidence worldwide. As of 2018, it is the second leading cause of cancer deaths in the world. In Saudi Arabia, the incidence of this disease has been increasing in the younger population. Both genetic and lifestyle factors may have contributed to its increased incidence and pathogenesis. Monosodium glutamate (MSG) is a food flavor enhancer that can be found in many commercial foods, and it can sometimes be used as a substitute to table salt. MSG has been investigated for its possible genotoxicity, yielding controversial results. In the present study, the effect of MSG on cell viability and its effect on expression of APC, BECN1, and TP53 genes in SW620 and SW480 colon cancer cell lines were studied. TP53 is a tumor suppressor gene that functions in modifying DNA errors and/or inducing apoptosis of damaged cells, and both APC and BECN1 genes are involved in CRC and are of importance in cellular growth and metastasis. Cancer cell viability was analyzed using MTT assay, and the results showed a significant increase in the number of viable cells after 24h of treatment with MSG with different concentrations (0.5, 1.0, 10, 50, and 100mM). Moreover, gene expression results showed a significant increase in the expression levels of APC and BECN1 under specified conditions in both cell lines; conversely, TP53 showed a significant decrease in expression in SW620 cells. Thus, it can be concluded that MSG possibly confers a pro-proliferative effect on CRC cells.(AU)

O câncer colorretal (CCR) é uma doença com alta incidência mundial. Desde 2018, é a segunda principal causa de mortes por câncer no mundo. Na Arábia Saudita, a incidência dessa doença vem aumentando na população mais jovem. Tanto fatores genéticos quanto de estilo de vida podem ter contribuído para o aumento da sua incidência e patogênese. O glutamato monossódico (MSG) é um intensificador de sabor de alimentos que pode ser encontrado em muitos alimentos comerciais e às vezes pode ser usado como um substituto do sal de cozinha. O MSG tem sido investigado por sua possível genotoxicidade, produzindo resultados controversos. Neste estudo, foram estudados o efeito do MSG na viabilidade celular e seu efeito na expressão dos genes APC, BECN1 e TP53 em linhas de células de câncer de cólon SW620 e SW480. TP53 é um gene supressor de tumor que atua modificando erros de DNA e/ou induzindo apoptose de células danificadas, estando os genes APC e BECN1 envolvidos no CRC e sendo importantes no crescimento celular e metástase. A viabilidade das células cancerosas foi analisada por meio do ensaio MTT, e os resultados mostraram um aumento significativo no número de células viáveis após 24 h de tratamento com MSG em diferentes concentrações (0,5; 1,0; 10; 50 e 100mM). Além disso, os resultados da expressão gênica mostraram um aumento significativo nos níveis de expressão de APC e BECN1 sob condições especificadas em ambas as linhagens celulares. Por outro lado, TP53 mostrou uma diminuição significativa na expressão em células SW620. Assim, pode-se concluir que, possivelmente, o MSG confere um efeito pró-proliferativo às células CRC.(AU)

Polimorfismo Genético TP53 Arg72Pro e Câncer de Mama em Mulheres Jovens: Estudo Caso-Controle no Brasil / TP53 Arg72Pro Genetic Polymorphism and Young Women with Breast Cancer: Case-Control Study in Brazil / Polimorfismo Genético TP53 Arg72Pro y Cáncer de Mama en Mujeres Jóvenes: Estudio de Casos y Controles en el Brasil

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

p53 gene delivery via a recombinant Salmonella enterica Typhimurium leads to human bladder carcinoma cell death in vitro.

Numerous studies have attempted to restore the function of the tumour suppressor p53 as an anti-cancer strategy through gene delivery. However, most studies employed non-bacterial vectors to deliver p53. Various facultative and obligate anaerobic bacteria have been proposed as vectors because of their intrinsic tumour targeting ability and anti-tumour activity. Salmonella enterica Typhimurium is the most studied bacterial vector in anti-cancer therapy. We used the previously designed χ11218 strain of S. enterica Typhimurium, displaying regulated delayed lysis, as a vector for delivering p53 to human bladder carcinoma cells, restoring wild-type p53 protein function. We cloned p53 into pYA4545 (containing a eukaryotic expression system) to generate the χ11218 pYA4545p53 strain. Cloning of p53 did not affect the growth or interfere with the invasive and replicative capacity of χ11218 bacteria in tumour cells. Human bladder carcinoma cells (expressing mutated p53) transfected with pYA4545p53 showed a significant increase in the expression of p53 protein. We demonstrated that p53 supplied by χ11218 significantly decreased the viability of human bladder cancer cells in a dose-dependent manner. This study demonstrates the applicability of the attenuated χ11218 strain as a vector for DNA plasmids expressing tumour suppressor genes.

Arsenic concentration in topsoil of central Chile is associated with aberrant methylation of P53 gene in human blood cells: a cross-sectional study.

Gene expression can be modified in people who are chronically exposed to high concentrations of heavy metals. The soil surrounding the Ventanas Industrial Complex, located on the coastal zone of Puchuncaví and Quintero townships (Chile), contain heavy metal concentrations (As, Cu, Pb, Zn, among others) that far exceed international standards. The aim of this study was to determine the potential association of the heavy metals in soils, especially arsenic, with the status of methylation of four tumor suppressor genes in permanent residents in those townships. To study the methylation status in genes p53, p16, APC, and RASSF1A, we took blood samples from adults living in areas near the industrial complex for at least 5 years and compared it to blood samples from adults living in areas with normal heavy metal concentrations of soils. Results indicated that inhabitants of an area with high levels of heavy metals in soil have a significantly higher proportion of methylation in the promoter region of the p53 tumor suppressor gene compared with control areas (p-value: 0.0035). This is the first study to consider associations between heavy metal exposure in humans and aberrant DNA methylation in Chile. Our results suggest more research to support consistent decision-making on processes of environmental remediation or prevention of exposure.

Alterations in APC, BECN1, and TP53 gene expression levels in colon cancer cells caused by monosodium glutamate.

Colorectal cancer (CRC) is a disease with high incidence worldwide. As of 2018, it is the second leading cause of cancer deaths in the world. In Saudi Arabia, the incidence of this disease has been increasing in the younger population. Both genetic and lifestyle factors may have contributed to its increased incidence and pathogenesis. Monosodium glutamate (MSG) is a food flavor enhancer that can be found in many commercial foods, and it can sometimes be used as a substitute to table salt. MSG has been investigated for its possible genotoxicity, yielding controversial results. In the present study, the effect of MSG on cell viability and its effect on expression of APC, BECN1, and TP53 genes in SW620 and SW480 colon cancer cell lines were studied. TP53 is a tumor suppressor gene that functions in modifying DNA errors and/or inducing apoptosis of damaged cells, and both APC and BECN1 genes are involved in CRC and are of importance in cellular growth and metastasis. Cancer cell viability was analyzed using MTT assay, and the results showed a significant increase in the number of viable cells after 24 h of treatment with MSG with different concentrations (0.5, 1.0, 10, 50, and 100mM). Moreover, gene expression results showed a significant increase in the expression levels of APC and BECN1 under specified conditions in both cell lines; conversely, TP53 showed a significant decrease in expression in SW620 cells. Thus, it can be concluded that MSG possibly confers a pro-proliferative effect on CRC cells.

Revisiting the indication for prophylactic contralateral mastectomy in patients with Li-Fraumeni syndrome and breast cancer. Case report / Revisitando la indicación de la mastectomía profiláctica contralateral en pacientes con Síndrome de Li-Fraumeni y cáncer de mama. Reporte de un caso

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.

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.

Leucemia linfocítica crónica y deleción del gen TP53: reporte de un caso y revisión de la literatura / Chronic lymphocytic Leukemia and deletion of the TP53 gene: Case report and literature review

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.

Inmunoexpresión de p53 y su relación con el grado de severidad en displasia epitelial oral / Immunoexpression of p53 and its relationship with the degree of severity in oral epithelial dysplasia

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)

A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer.

BACKGROUND: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3-4 toxicity. METHODS: Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. RESULTS: Reported grade ≤ 2 and 3-4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70-10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19-1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. CONCLUSION: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.

Revisitando la indicación de la mastectomía profiláctica contralateral en pacientes con Síndrome de Li-Fraumeni y cáncer de mama. Reporte de un caso / Revisiting the indication for prophylactic contralateral mastectomy in patients with Li-Fraumeni syndrome and breast cáncer. Case report

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.

Comparative genomic characterization of melanoma of known and unknown primary.

BACKGROUND: This study aims to genomically characterize melanoma of unknown primary (MUP) in comparison to melanomas of cutaneous primary (MCP). METHODS: Eligible cases were collected from the MSK-IMPACT™ Clinical Sequencing Cohort published in the cBioPortal database. Genomic analysis was performed using a hybridization-capture-based next-generation sequencing assay designed to detect mutations, small insertions and deletions, copy number alterations, and genomic rearrangements. RESULTS: Among 462 patients of whom 18.4% had MUP, brain metastasis was more common among patients with MUP (23% vs 7.1%). The differences in genomic profiling between MCP and MUP did not reach statistical significance. The 187 MCP and 44 MUP patients treated with immune checkpoint inhibitors had a median overall survival of 49 and 44 months, respectively (p = 0.705). CONCLUSIONS: The differences in somatic mutation patterns and survival outcomes were not statistically significant. These findings may allude to similar carcinogenic processes but should be considered exploratory and interpreted with caution.

Importancia del síndrome de Li-Fraumeni, un síndrome genético de predisposición al cáncer / The importance of Li-Fraumeni syndrome, a hereditary cancer predisposition disorder

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.

Ingenol mebutate treatment for actinic cheilitis: clinical, histopathological and p53 profile of 14 cases.

INTRODUCTION: Actinic cheilitis (AC) is part of a spectral disease of keratinocyte carcinomas considered by some authors an early stage of in situ squamous cell carcinoma. Treatment options for AC can be lesion and field-directed therapies. Ingenol mebutate (IM) induces rapid and direct cell death and immune responses being able to destruct dysplastic cells. MATERIALS AND METHODS: This study enrolled patients with AC to receive IM gel 0.015% for self-application on the lower lip for 3 consecutive days. A biopsy was performed before and after treatment for histopathological and immunohistochemical evaluation. Local skin reactions (LSR) were evaluated. The level of significance considered was 5%. RESULTS: Fourteen patients were enrolled. All LSR had a complete resolution for up to 2 weeks. The most common adverse events were burning sensation, angular cheilitis, and pain. There was an improvement of more than 80% in patients' subjective evaluation. There was no statistically significant histopathological response since all patients remained with mild dysplasia. No reduction in the P53 expression was observed in the current study. CONCLUSIONS: Despite being a safe therapeutic method, the absence of histopathological or immunohistochemical response suggests that clinical improvement may not be accompanied by histopathological cure for AC treated with IM.

Biomarkers and Redox Balance in Aging Rats after Dynamic and Isometric Resistance Training.

Aging muscle is prone to sarcopenia and its associated telomere shortening and increased oxidative stress. Telomeres are protected by a shelterin protein complex, proteins expressed in response to DNA damage. Aerobic exercise training has shown to positively modulate these proteins while aging, but the effects of resistance training are less clear. This investigation was to examine the role of dynamic and isometric RT on markers of senescence and muscle apoptosis: checkpoint kinase 2, 53 kDa protein, shelterin telomere repeat binding 1 and 2, DNA repair, telomere length and redox state in the quadriceps muscle. Fifteen 49-week-old male rats were divided into three groups: control, dynamic resistance training, and isometric resistance training. Dynamic and isometric groups completed five sessions per week during 16 weeks at low to moderate intensity (20-70% maximal load). Only dynamic group decreased expression of 53 kDa protein, proteins from shelterin complex, oxidative stress, and improved antioxidant defense. There was no difference among groups regarding telomere length. In conclusion, dynamic resistance training was more effective than isometric in reducing markers of aging and muscle apoptosis in elderly rats. This modality should be considered as valuable tool do counteract the deleterious effects of aging.