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1.
Biomédica (Bogotá) ; 42(supl.1): 154-171, mayo 2022. tab, graf
Article in Spanish | LILACS | ID: biblio-1394003

ABSTRACT

Introducción. El cáncer colorrectal tiene una alta incidencia en la población mundial. Diversas vías moleculares están involucradas en su desarrollo, entre ellas, la inestabilidad cromosómica, la inestabilidad microsatelital y la epigenética. Objetivo. Hacer la caracterización molecular de 44 individuos con cáncer colorrectal esporádico. Materiales y métodos. El análisis de mutaciones en los genes APC, KRAS, TP53 y BRAF se hizo mediante secuenciación de Sanger; la inestabilidad microsatelital se determinó mediante electroforesis capilar utilizando cinco marcadores de repetición corta en tándem (Short Tandem Repeat) y el estado de metilación del promotor del gen MLH1 se hizo con la técnica MS-PCR (Methylation-Specific PCR). Resultados. La frecuencia de mutación de los genes APC, KRAS y TP53 fue del 18,1, 25 y 4,5 %, respectivamente; las mutaciones detectadas se localizaron con mayor frecuencia en el colon derecho. La frecuencia de inestabilidad microsatelital fue del 27,2 % y el 73,1 % en los tumores con metilación en el gen MHL1, y el 91,6 % de los tumores con inestabilidad microsatelital presentaba metilación en el gen MLH1. En el grupo de tumores con estabilidad microsatelital, las mutaciones en los genes APC, KRAS y TP53 fueron más frecuentes que en el grupo de tumores con inestabilidad microsatelital. La metilación del gen MLH1 fue la alteración más predominante. Conclusiones. En los pacientes con cáncer colorrectal evaluados se demostró la presencia de alteraciones moleculares en las diferentes vías genéticas, las cuales son comunes en su carcinogénesis. Los pacientes presentaron un perfil de mutaciones diferente al de otras poblaciones. Los hallazgos obtenidos en este estudio confirman la heterogeneidad molecular descrita en el desarrollo del cáncer colorrectal.


Introduction: Colorectal cancer has a high incidence in the world population. Different molecular pathways, such as chromosomal instability, microsatellite instability, and epigenetics are involved in its development. Objective: To perform molecular characterization in 44 individuals with sporadic colorectal cancer. Materials and methods: We conducted mutation analyses of the APC, KRAS, TP53 y BRAF genes using Sanger sequencing techniques; microsatellite instability was determined by capillary electrophoresis with five STR genetic markers while the methylation status of the MHL1 promotor gene was analyzed using methylation-specific PCR. Results: APC, KRAS, and TP53 genes mutation frequency was 18.1%, 25%, and 4.5%, respectively; the somatic mutations detected were located more frequently in the right colon. The frequency of microsatellite instability was 27.2% and 73.1% of the tumors had the MHL1 gene methylated while 91.6% of microsatellite instability-positive tumors had the methylated MLH1 gene. The mutation profile of microsatellite stability tumors APC, KRAS, and TP53 genes was more frequent than in the microsatellite instability-positive tumors. The methylation of the MLH1 gene was the most predominant molecular alteration. Conclusions: We identified molecular alterations in different genetic pathways of the colorectal cancer patients evaluated, which are common in the carcinogenesis of this cancer. These patients showed a different mutational profile compared to other populations. Our findings confirm the molecular heterogeneity described in the development of colorectal cancer.


Subject(s)
Colorectal Neoplasms/genetics , Oncogenes , Genes, Tumor Suppressor , Genetic Heterogeneity , Microsatellite Instability , Epigenomics
2.
Article in Chinese | WPRIM | ID: wpr-936065

ABSTRACT

Microsatellite instability-high (MSI-H) colorectal cancer accounts for approximately 10%-15% of all colorectal cancer patients, while in metastatic diseases the MSI-H population accounts for only 5% of patients. Previous studies have shown that early-stage MSI-H colorectal cancer patients have a good prognosis, but those with advanced disease have a poor prognosis and are not sensitive to chemotherapy. The advent of PD-1 antibodies has significantly improved the prognosis and changed treatment landscape in this population, not only achieving good outcomes in late-line therapy, but also significantly outperforming traditional chemotherapy combined with targeted therapy in first-line therapy. How to overcome primary and secondary drug resistance is a key issue in improving the outcome of MSI-H metastatic colorectal cancer, and commonly used approaches include changing chemotherapy regimens, combining with other immunotherapies, combining with anti-angiogenesis, and local treatments (surgery, radiotherapy, or interventional therapy). It is worth noting that immunotherapy has certain lifelong or even lethal toxicity, and the indications for neoadjuvant immunotherapy must be evaluated with caution. Neoadjuvant immunotherapy in MSI-H advantaged population can achieve high rates of pathological complete remission (pCR) and clinical complete remission (cCR). Therefore, for MSI-H patients with a strong intention to preserve anal sphincter and a strict evaluation of cCR after neoadjuvant immunotherapy, the Watch-and-Wait strategy offers an opportunity to preserve sphincter function and improve long-term survival quality in a subset of mid-to-low rectal cancers. Research on adjuvant immunotherapy in the field of colorectal cancer is also in full swing, and the results are worth waiting for.


Subject(s)
Colonic Neoplasms , Colorectal Neoplasms/therapy , Humans , Immunotherapy/methods , Microsatellite Instability , Microsatellite Repeats
3.
Article in Chinese | WPRIM | ID: wpr-936363

ABSTRACT

OBJECTIVE@#To assess the value of m7G-lncRNAs in predicting the prognosis and microenvironment of colorectal cancer (CRC).@*METHODS@#We screened m7G-lncRNAs from TCGA to construct an m7G-lncRNAs risk model using multivariate Cox analysis, which was validated using ROC and C-index curves. Calibration and nomogram were used to predict the prognosis of CRC patients. Point-bar charts and K-M survival curves were used to assess the correlation of risk scores with the patients' clinical staging and prognosis. CIBERSORT and ESTIMATE were used to explore the association between the tumor microenvironment and immune cell infiltration in patients in high and low risk groups and the correlation of risk scores with microsatellite instability, stem cell index and immune checkpoint expression. A protein-protein interaction network was constructed, and the key targets regulated by m7G-lncRNAs were identified and validated in paired samples of CRC and adjacent tissues by immunoblotting.@*RESULTS@#We identified a total of 1722 m7G-lncRNAs from TCGA database, from which 12 lncRNAs were screened to construct the risk model. The AUCs of the risk model for predicting survival outcomes at 1, 3 and 5 years were 0.727, 0.747 and 0.794, respectively. The AUC of the nomogram for predicting prognosis was 0.794, and the predicted results were consistent with actual survival outcomes of the patients. The patients in the high-risk group showed more advanced tumor stages and a greater likelihood of high microsatellite instability than those in the low-risk group (P < 0.05). The tumor stemness index was negatively correlated with the risk score (r=-0.19; P=7.3e-05). Patients in the high-risk group had higher stromal cell scores (P=0.0028) and higher total scores (P=0.007) with lowered expressions of activated mast cells (r=-0.11; P=0.045) and resting CD4+ T cells (r=-0.14; P=0.01) and increased expressions of most immune checkpoints (P < 0.05). ATXN2 (P= 0.006) and G3BP1 (P=0.007) were identified as the key targets regulated by m7G-lncRNAs, and their expressions were both higher in CRC than in adjacent tissues.@*CONCLUSION@#The risk model based on 12 m7G-lncRNAs has important prognostic value for CRC and can reflect the microenvironment and the efficacy of immunotherapy in the patients.


Subject(s)
Biomarkers, Tumor/metabolism , Colonic Neoplasms , DNA Helicases/metabolism , Gene Expression Regulation, Neoplastic , Humans , Microsatellite Instability , Poly-ADP-Ribose Binding Proteins/metabolism , Prognosis , RNA Helicases/metabolism , RNA Recognition Motif Proteins/metabolism , RNA, Long Noncoding/metabolism , Tumor Microenvironment
4.
Article in Chinese | WPRIM | ID: wpr-936339

ABSTRACT

OBJECTIVE@#To conduct a pan-cancer analysis of the expression of long non-coding RNA (lncRNA) MIR22HG and explore its association with clinical characteristics.@*METHODS@#We analyzed the expression of MIR22HG in different tumors and its association with clinical staging, lymph node metastasis, tumor mutation burden (TMB) and microsatellite instability (MSI) using R package based on the Cancer Genome Atlas (TCGA) datasets. The relationship between MIR22HG expression and infiltrating immune cells was analyzed using TIMER algorithm. The association of MIR22HG gene alteration frequency with the clinical outcomes was examined using cBioPortal online software. Data form Genomics of Drug Sensitivity in Cancer (GDSC) were used to analyze the relationship between MIR22HG and the sensitivity of chemotherapy drugs. We specifically analyzed MIR22HG expression in hepatocellular carcinoma (HCC) and its correlation with sorafenib treatment using GEO database and verified the results in 12 pairs of HCC specimens. Kaplan-Meier analysis was performed to analyze the correlation of MIR22HG with the outcomes of sorafenib treatment. We also tested the effects of MIR22HG overexpression and knockdown on IC50 of sorafenib in HCC cells.@*RESULTS@#MIR22HG was downregulated in most tumors (P < 0.05), where its deletion mutations were frequent, and associated with a poor prognosis (P < 0.05). In many tumors, MIR22HG expression level was correlated with clinical stage, lymph node metastasis, TMB, MSI, immune cell infiltration, immune checkpoint-related genes, and sensitivity to common chemotherapeutic drugs (P < 0.05). Among the 6 common infiltrating immune cells in cancers, neutrophil infiltration had the strongest correlation with MIR22HG expression level, especially in breast cancer, rectal cancer and kidney renal papillary cell carcinoma (P < 0.05). MIR22HG was downregulated in HCC in association with HCC progression (P < 0.05). In HCC patients, a low MIR22HG expression was associated with a favorable outcome after sorafenib treatment (HR=2.94, P=0.075) and was capable of predicting the response to sorafenib treatment (AUC=0.8095). Compared with the negative control, MIR22HG overexpression obviously reduced sorafenib sensitivity (with IC50 of 7.731 vs 15.61) while MIR22HG knockdown increased sorafenib sensitivity of HCC cells (with IC50 of 7.986 vs 5.085).@*CONCLUSION@#MIR22HG expression level is correlated with clinical stage, lymph node metastasis, TMB, MSI, immune cell infiltration, and chemosensitivity in most cancer, suggesting its potential as an immunotherapeutic target and also a prognostic biomarker for tumors.


Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/pathology , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/pathology , Lymphatic Metastasis , Microsatellite Instability , RNA, Long Noncoding/genetics , Sorafenib/pharmacology
5.
Rev. colomb. gastroenterol ; 36(3): 349-357, jul.-set. 2021. tab
Article in English, Spanish | LILACS | ID: biblio-1347351

ABSTRACT

Resumen Introducción y objetivos: la vía de inestabilidad de microsatélites (IMS) está implicada en la carcinogénesis de un 15 % de carcinomas colorrectales (CCR). La detección de esta alteración tiene relevancia en el pronóstico y en el tratamiento de los pacientes con CCR. El objetivo del presente estudio es determinar la prevalencia de IMS en CCR en una cohorte de pacientes de Bogotá, Colombia. Materiales y métodos: se evaluó por inmunohistoquímica la presencia de homólogo MutL 1 (MLH1), segregación posmeiótica aumentada 2 (PMS2), homólogo mutS 2 (MSH2) y homólogo mutS 6 (MSH6) en muestras de CCR prevenientes de colectomías. Adicionalmente, se analizaron las variables clinicopatológicas. A los casos con pérdida de MLH1 y PMS2 se les evaluó la mutación del gen BRAF. Resultados: en total se incluyeron 86 casos. La mediana de edad de los pacientes con CCR fue de 69 años, 52,3 % fueron hombres. De los pacientes con CCR, 12 (13,9 %) presentaron IMS, de los cuales 10 (83,3 %) tenían ausencia de expresión MLH1/PMS2 y 2 (16,7 %), de MSH2/MSH6. La mediana de edad de los pacientes con CCR e IMS fue de 52 años (45-76,5), 9 eran hombres y el 66,7 % de estos casos se localizaron en el colon derecho. El tipo histológico más frecuente fue adenocarcinoma moderadamente diferenciado (67 %). Los linfocitos infiltrantes al tumor fueron observados en el 83 %, la presencia de infiltrado de tipo Crohn estaba presente en el 42 %. La mutación de BRAF se observó en el 30 % de los pacientes con pérdida de MLH1 y PMS2. Conclusión: la prevalencia de la IMS en nuestra población fue de 14 %, datos similares a los observados en la población norteamericana y europea. Sin embargo, se observa que el 83 % presentó pérdida de expresión del complejo MLH1/PMS2, una prevalencia mayor comparada con otras poblaciones.


Abstract Introduction: The microsatellite instability (MSI) pathway is involved in the carcinogenesis of 15% of colorectal carcinomas (CRC). The detection of this alteration is relevant for the prognosis and treatment of CRC patients. Objective: The aim of this study is to determine the prevalence of MSI in CRC in a cohort of patients in Bogotá, Colombia. Materials and methods: The presence of MLH1, PMS2, MSH2, and MSH6 was evaluated by immunohistochemistry in CRC samples collected during colectomy. Clinicopathological variables were analyzed as well. Cases with loss of MLH1 and PMS2 were evaluated for BRAF gene mutation. Results: A total of 86 cases were included. The median age was 69 years, 52.3% were male. 12 (13.9%) patients had IMS, 10 (83.3%) had absence of MLH1/PMS2 expression and 2 (16.7%) absence of MSH2/MSH6 expression. The median age of patients with IMS was 52 years (45-76.5), of which 9 were male. 66.7% of carcinomas were located in the right colon and the most frequent histological type was moderately differentiated adenocarcinoma (67%). Tumor infiltrating lymphocytes were observed in 83% of the cases, while the presence of Crohn's-like infiltrate was present in 42%. BRAF mutation was observed in 30% of patients with loss of MLH1 and PMS2. Conclusion: The prevalence of IMS in our population was 14%, similar to the data observed in the North American and European populations. However, we observed that 83% had loss of expression of the MLH1/PMS2 complex, a higher prevalence compared to other populations.


Subject(s)
Humans , Male , Female , Immunohistochemistry , Colon , Microsatellite Instability , Patients , Colorectal Neoplasms , Prevalence , Colectomy
6.
Rev. colomb. cir ; 36(1): 120-131, 20210000. tab
Article in Spanish | LILACS | ID: biblio-1150526

ABSTRACT

La inestabilidad microsatelital es causada por una alteración de los sistemas de reparación de apareamiento incorrecto, que puede afectar los microsatélites dentro de todo el genoma humano, produciendo errores en su replicación. Los estudios publicados, principalmente en la literatura inglesa, han encontrado que algunos tumores, como los gástricos, pueden expresar inestabilidad microsatelital. En la siguiente revisión de tema, se presenta una descripción de los sistemas de reparación de apareamientos incorrectos y su relación con la presencia de inestabilidad microsatelital en los tumores gástricos, así como su posible utilidad clínica, como factor asociado en la respuesta al tratamiento con inmunoterapia en los pacientes con dicha patología


Microsatellite instability is caused by an alteration of the mismatch repair systems, which can affect microsatellites within the entire human genome, causing errors in their replication. Published studies, mainly in the English literature, have found that some tumors, such as gastric ones, can express microsatellite instability. In this review, a description of the mismatch repair systems and their relationship with the presence of microsatellite instability in gastric tumors is presented, as well as its possible clinical utility, as an associated factor in the response to immunotherapy treatment, in patients with gastric cancer


Subject(s)
Humans , Stomach Neoplasms , Microsatellite Instability , Immunotherapy , Neoplasms
7.
Rev. Assoc. Med. Bras. (1992) ; 67(1): 64-70, Jan. 2021. tab, graf
Article in English | LILACS | ID: biblio-1287776

ABSTRACT

SUMMARY OBJECTIVE: Bladder cancer under the age of 40 is extremely rare. Bladder cancer development involves complex and multi-stage processes, one of which is the DNA damage repair mechanism. In this retrospective study, we aimed to evaluate the histopathological features of bladder urothelial carcinoma seen in patients under 40 years of age and tumor microsatellite instability status using immunohistochemistry. METHODS: A total of 50 patients under the age of 40 with urothelial bladder carcinoma from two different centers in the same country were included. Expression of the mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 was analyzed by immunohistochemistry. RESULTS: Age at the time of diagnosis ranged from 17 to 40 years old. Most tumors were non-invasive papillary urothelial carcinoma. Two cases had nuclear loss of MSH-6 and PMS-2. We observed that tumor grade, tumor stage, presence of tumor differentiation, and infiltrative growth pattern of the tumor have significant impact on prognosis, but microsatellite instability does not have an effective role in bladder carcinogenesis in young patients. CONCLUSIONS: Our results indicate that the presence of microsatellite instability is not related to the low tumor grade and stage in urothelial neoplasms in young patients, suggesting that urothelial carcinoma of the bladder in young patients may represent a genetically stable form of neoplasia.


Subject(s)
Humans , Adolescent , Adult , Young Adult , Carcinoma, Transitional Cell/genetics , Microsatellite Instability , Urinary Bladder/metabolism , Retrospective Studies , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , DNA Mismatch Repair
8.
Article in Chinese | WPRIM | ID: wpr-942983

ABSTRACT

Neuroendocrine neoplasms (NEN) is a rare and heterogeneous tumor. Different pathologic morphology, differentiation, grade and clinical stages of the tumors had various treatment and prognosis. Patients with recurrent or metastatic NEN have limited treatment options and poor prognosis. In recent years, PD-1 pathway blockade has become integral components of disease management for many cancers. Immunotherapy is being explored in NEN. Studies have shown that the efficacy of immune monotherapy in NEN is limited, and it can be considered for selected patients. Biomarkers for predicting efficacy of immunotherapy include PD-L1 expression, TMB-H, MSI-H/dMMR, etc. Combined regimens of anti-CTLA-4 and anti-PD-1/PD-L1 inhibitors, and immune checkpoint inhibitor combined with anti-angiogenic drugs or chemotherapy are promising in patients with NEN, and it is worthwhile to further explore of the responding populations.


Subject(s)
B7-H1 Antigen , Biomarkers, Tumor , Humans , Immunotherapy , Microsatellite Instability , Neoplasms , Neuroendocrine Tumors/therapy
9.
Article in English | WPRIM | ID: wpr-880694

ABSTRACT

Lymphoma is one of the most common malignant tumor of the hematologic system. The genome instability is not only an important molecular basis for the development of lymphoma, but also has important value in the diagnosis and prognosis of lymphoma. There are 2 types of genome instability: Microsatellite instability (MSI/MIN) at gene level and chromosomal instability at chromosome level. Through the study on genes associated with lymphoma, the unstable genes associated with lymphoma could be found, meanwhile the mechanism of its occurrence and development of lymphoma could be explored, and the important basis of molecular biology could also be provided in the field of current hot lymphoma precision medical research.


Subject(s)
Genomic Instability , Humans , Lymphoma/genetics , Microsatellite Instability , Microsatellite Repeats , Neoplasms
10.
Ciencia Tecnología y Salud ; 8(2): 232-244, 2021. il 27 c
Article in Spanish | LILACS, LIGCSA, DIGIUSAC | ID: biblio-1353229

ABSTRACT

El carcinoma colorrectal (CCR) es de las primeras causas de mortalidad del mundo, presentando Guatemala una incidencia anual de 7.4/millón de habitantes. El síndrome de Lynch se caracteriza clínicamente por un inicio temprano del CCR con lesiones causadas por alteraciones en genes que codifican proteínas reparadoras.Los microsatélites son regiones del ADN con una unidad repetitiva de uno o más nucleótidos y son susceptibles a errores durante la replicación de ADN de los enterocitos. Existe un sistema de reparación que corrige estos errores. Cuando las proteínas reparadoras de este sistema están mutadas o ausentes, dichos errores del ADN persisten. Estas proteínas reparadoras se expresan en el núcleo de las células colónicas normales y son detecta-bles utilizando estudios de inmunohistoquímica (IHQ). Los genes MLH1 y MSH2 pueden encontrarse mutados en el 90% de los casos de cáncer colorrectal y el resto corresponde a MSH6 y PMS2. Esta vía oncogénica se caracteriza por alteración del sistema de reparación de errores durante la replicación del ADN, controlado por los genes MMR (mismatch repair), principalmente MLH1, MSH2, MSH6 y PMS2. Se realizó una revisión extensa de la literatura en PubMed, Springer y JAMA, usando las palabras clave: fenotipo de CCR, Síndrome de Lynch e inestabilidad microsatelital, detectándose 55 artículos. El objetivo de esta revisión es describir la importancia de la identificación del fenotipo del CCR por medios de IHQ y de pruebas moleculares para el eficaz tratamiento con inmunoterapia anti-PD1/PD-L1.


Colorectal cancer (CRC) is one of the leading causes of mortality in the world. In Guatemala it's an important cause of morbidity (7.4 per million inhabitants). Lynch syndrome is clinically characterized by an early onset of nonpolyposis colorectal carcinoma, with multiple lesions and neoplasms. The syndrome is caused by mutations in genes encoding DNA mismatch repair proteins. The microsatellites are regions of the DNA that repeat between one or more nucleotides and are susceptible to errors during replication, these are corrected by a repair system, when genes are mutated, the errors persist. The genes encoding repair proteins are expressed in the nuclei of normal colonic cells which can be observed using immunohistochemical studies. The MLH1, MSH2 genes are found to be mutated in 90% of the cases and the rest corresponds to the MSH6 and PMS2 genes. This oncogenic pathway characteristically consists of an alteration in the DNA repair system that is controlled by mismatch repair genes (MMR). An extensive research was conducted on PubMed, Springer and JAMA, using the keyword: CRC phenotype, Lynch syndrome and microsatellite instability. 55 articles were found. This review«s objective is to understand the mechanisms of nonpolyposis colorectal cancer and the importance of identifying patients with a mutant phenotype as a predictive factor for the efficacy of the anti-PD1/PDL1 immunotherapy and for prognosis.


Subject(s)
Humans , Carcinoma/mortality , Colorectal Neoplasms/mortality , Microsatellite Instability , Immunohistochemistry , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Microsatellite Repeats , Enterocytes , Molecular Diagnostic Techniques , Mismatch Repair Endonuclease PMS2/genetics , MutL Protein Homolog 1/genetics , Mutation
11.
Clinics ; 76: e3318, 2021. tab, graf
Article in English | LILACS | ID: biblio-1350611

ABSTRACT

OBJECTIVE: To determine the role of RNA-binding protein with serine-rich domain 1 (RNPS1) in uterine corpus endometrial carcinoma (UCEC), the role of RNPS1 knockdown in UCEC development in vitro and in vivo, and the relationship between RNPS1 and mismatch repair (MMR) in UCEC. METHODS: We predicted the potential function of RNPS1 using bioinformatics systems. The expression of RNPS1 in tissues and cell lines was analyzed by western blotting and immunohistochemistry. The expression of RNPS1 in MMR was assessed using bioinformatics and western blotting. The proliferation and apoptosis of UCEC cells were assessed under RNPS1 knockdown conditions, and RNPS1 regulation in MMR was detected by suppressing Notch signaling. Associations between RNPS1 and gene mutations in UCEC and prognosis were analyzed. RESULTS: The RNPS1 level was higher in UCEC tumors than in normal tissues and tumors or RL952 cells. Prognostic outcomes were worse when UCEC showed abundant RNPS1 expression. Lentiviral RNPS1 knockdown weakened tumor cell proliferation and suppressed biomarker expression, reduced the tumor volume, promoted apoptosis in vitro and in vivo, and inhibited UCEC development. Increased MutS homolog 2 (MSH2) and MutS homolog 6 (MSH6) levels in MMR after RNPS1 knockdown were reversed by inhibiting Notch signaling. Furthermore, RNPS1 was associated with mutations in NAA11, C2orf57, NUPR1, and other genes involved in UCEC prognosis. CONCLUSION: RNPS1 may regulate the expression levels of MSH2 and MSH6 in MMR, enhancing the proliferation, development, and prognosis of UCEC through a Notch signaling pathway in UCEC. Our study offers a new method and strategy for delaying UCEC development through modulating MMR.


Subject(s)
Humans , Female , Ribonucleoproteins/genetics , Endometrial Neoplasms/genetics , Carcinoma, Endometrioid/congenital , Serine , RNA-Binding Proteins , Cell Line, Tumor , Microsatellite Instability
12.
J. coloproctol. (Rio J., Impr.) ; 40(4): 412-420, Oct.-Dec. 2020. tab, graf
Article in English | LILACS | ID: biblio-1143169

ABSTRACT

ABSTRACT Introduction: Colorectal cancer is the third most common cancer worldwide, with about 15% of these tumours related with microsatellite instability, which confers distinct characteristics to these tumours, both clinicopathological and in the response to treatments. In fact, the poor response to chemotherapy in these tumours has led to the investigation for new treatments, with immunotherapy being the most successful one to date. The focus of this review is to assess the response of microsatellite unstable colorectal cancer to PD-1 blockade, and the mechanisms behind that response. Methods: A PubMed research was conducted, resulting in the inclusion of 47 articles in this review. Results: Microsatellite instability results in a high neoantigen load, leading to a highly active immune microenvironment of the tumour, mainly due to T-cells. To counteract this, there is an upregulation of PD-1, acting as a "brake" for immune cells, facilitating tumour growth and metastasis. This upregulation makes these tumours great candidates for treatment with PD-1 blockade, as seen in many clinical trials, where the overall responses and progression free survival rates were higher than those observed in microsatellite stable tumours. Conclusion: With the importance of colorectal cancer with microsatellite instability new treatments are necessary. Therefore, PD-1 blockade is a promising treatment for colorectal cancer with microsatellite instability, with improvement in survival rates and a better prognosis for these patients.


RESUMO Introdução: O câncer colorretal é o terceiro mais comum em todo o mundo, com cerca de 15% desses tumores relacionados com instabilidade dos microssatélites, o que confere características distintas a esses tumores, tanto clínico patológicas quanto na resposta aos tratamentos. De fato, a fraca resposta à quimioterapia nesses tumores levou à investigação de novos tratamentos, sendo a imunoterapia a mais bem sucedida até o momento. O foco desta revisão é avaliar a resposta do câncer colorretal com microssatélites instáveis ao bloqueio do PD-1 e os mecanismos por trás dessa resposta. Métodos: Foi realizada uma pesquisa na base de dados PubMed, resultando na inclusão de 47 artigos nesta revisão. Resultados: A instabilidade de microssatélites resulta em uma alta carga de neoantígenos, levando a um microambiente imunológico altamente ativo do tumor, principalmente devido às células T. Para neutralizar isso, há uma maior expressão do PD-1, atuando como um "freio" para as células imunes, facilitando o crescimento do tumor e suas metástases. Essa expressão faz desses tumores grandes candidatos ao tratamento com bloqueio PD-1, como demonstrado em vários ensaios clínicos, onde as respostas globais e as taxas de sobrevivência livres de progressão foram maiores do que as observadas em tumores com microssatélites estáveis. Conclusão: Com a importância do câncer colorretal com instabilidade de microssatélites, novos tratamentos são necessários. Portanto, o bloqueio do PD-1 é um tratamento promissor para o câncer colorretal com instabilidade de microssatélites, com melhora nas taxas de sobrevivência e melhor prognóstico para esses pacientes.


Subject(s)
Humans , Male , Female , Colorectal Neoplasms/pathology , Programmed Cell Death 1 Receptor/therapeutic use , Immunotherapy/methods , Microsatellite Instability
13.
J. coloproctol. (Rio J., Impr.) ; 40(4): 404-411, Oct.-Dec. 2020.
Article in English | LILACS | ID: biblio-1143186

ABSTRACT

ABSTRACT Introduction: Colorectal cancer is one of the neoplasms with the greatest social impact. Given the great molecular heterogeneity and diversity of pathophysiological mechanisms, it is difficult to define prognostic factors that could guide therapy. Objectives: To identify the molecular prognostic factors that may be of interest in clinical practice and to synthesize the existing evidence. Material and methods: The search for the articles was carried out using the PubMed platform and the keywords "sporadic colorectal cancer and prognosis", for articles published between 2014 and 2019. We selected all articles published on studies in humans and written in English or Portuguese. Of the 215 articles found, 35 articles were selected to perform this review. Results: Current evidence supports the use of four molecular markers in clinical practice − KRAS, NRAS and BRAF (EGFR signalling pathway) and the mismatch repair status. Conclusion: The use of molecular biomarkers in clinical practice to define prognosis is still little supported by the existent evidence. The studies are slightly contradictory, so new projects and international collaborations must be carried out in this area to obtain more robust evidence.


RESUMO Introdução: O carcinoma colorretal é uma das neoplasias com maior impacto social. Dada a grande heterogeneidade molecular e diversidade de mecanismos fisiopatológicos, torna-se difícil definir fatores de prognóstico que orientem a terapêutica. Objetivos: Identificar os fatores de prognóstico moleculares que poderão vir a ter interesse na prática clínica e fazer uma síntese da evidência existente. Material e métodos: A pesquisa dos artigos foi realizada recorrendo à plataforma PubMed e utilizou-se as palavras-chave "sporadic colorectal cancer and prognosis", para artigos publicados entre 2014 e 2019. Foram selecionados todos os artigos publicados sobre estudos em humanos e escritos em inglês ou em português. Dos 215 artigos encontrados, foram selecionados 35 artigos para realizar esta revisão. Resultados: A evidência atual apoia a utilização de quatro marcadores moleculares na prática clínica - KRAS, NRAS e BRAF (via de sinalização do EGFR) e o estado mismatch repair. Conclusão: A utilização na prática clínica de biomarcadores moleculares para definir o prognóstico é ainda pouco apoiada pela evidência disponível. Os estudos são algo contraditórios, pelo que novos projetos e colaborações internacionais devem ser realizados neste âmbito para se obter evidência mais robusta.


Subject(s)
Humans , Carcinoma , Biomarkers , Colorectal Neoplasms/diagnosis , Chromosomal Instability , Microsatellite Instability , Prognosis
14.
Article in Chinese | WPRIM | ID: wpr-880786

ABSTRACT

OBJECTIVE@#To explore the clinicopathological features and types of genic mutations in DNA mismatch repair (MMR) in colorectal cancer (CRC).@*METHODS@#Immunohistochemistry was used to determine the expression of MMR proteins in 1394 patients with CRC, and PCR-capillary electrophoresis (PCR-CE) was used to detect microsatellite instability (MSI) in 106 cases of defective MMR (dMMR), 46 cases of proficient MMR (pMMR) with heterogeneous expression and 147 randomly selected cases of pMMR. The relationship between the expressions of MMR proteins and the clinicopathological features of the patients was evaluated. The consistency between the results of immunohistochemistry and PCR-CE was assessed.@*RESULTS@#Immunohistochemical staining showed an incidence of dMMR of 7.6% in the patients. The main type of dMMR was co-deletion of MLH1 and PMS2, accounting for 55.7% of the total dMMR cases. The deletion of MMR proteins was significantly correlated with the patients' age, tumor location, tumor size, gross type, histological type, degree of differentiation, lymph node status and TNM stage (@*CONCLUSIONS@#The main type of dMMR is co-deletion of MLH1 and PMS2 in patients with colorectal cancer. dMMR colorectal cancer has typical clinicopathological features and a lower incidence in China than in Western countries. The results of immunohistochemistry and PCR-CE are highly consistent for detecting dMMR in colorectal cancer patients.


Subject(s)
China , Colorectal Neoplasms/genetics , DNA Mismatch Repair/genetics , Humans , Microsatellite Instability
15.
Repert. med. cir ; 29(1): 32-40, 2020. ilus., tab.
Article in English, Spanish | LILACS, COLNAL | ID: biblio-1116551

ABSTRACT

El carcinoma colorrectal es una de las neoplasias con mayor incidencia a nivel mundial. Algunos de los tipos tienen componente hereditario y asociación con defectos en la reparación génica a nivel replicacional, por mutaciones en los genes encargados (MLH1, MSH2, MSH6 y PMS2), llamándose esto la inestabilidad microsatelital. Esta situación se acompaña de mayor predisposición a desarrollar carcinoma colorrectal y algunos extracolónicos que incluyen cáncer de estómago, endometrio, ovarios y tracto urinario, entre otros. Es importante, entonces, evaluar la presencia de la inestabilidad microsatelital a nivel histopatológico conociendo que hay ciertos hallazgos que hacen sospechar la presencia de estas alteraciones genéticas, tales como la presencia de linfocitos intraepiteliales, infiltrado inflamatorio Crohn-like , el subtipo histológico y la localización. El objetivo de este artículo es revisar en detalle algunas características de las variables mencionadas, así como resaltar la importancia de otras variables histopatológicas con impacto pronóstico.


Colorectal cancer (CRC) is one of the most common cancers in the world. Some have a heritable component and are associated with a genetic defect in replication error repair due to MLH1, MSH2, MSH6 and PMS2 genes mutations known as microsatellite instability. This entails a greater predisposition to CRC and other extracolonic cancers including stomach, endometrium, ovary and urinary tract cancers, among other. Thus, it is important to detect histologic microsatellite instability through certain findings such as intraepithelial infiltrating lymphocytes, Crohn-like inflammatory reaction, histologic subtype and anatomical location leading to suspect the presence of genetic alterations. The objective of this article was to examine some features of said variables in detail and highlight the importance of other histopathologic variables with prognostic significance.


Subject(s)
Colorectal Neoplasms , Microsatellite Repeats , Microsatellite Instability , Intraepithelial Lymphocytes
16.
Yonsei Medical Journal ; : 132-139, 2019.
Article in English | WPRIM | ID: wpr-742526

ABSTRACT

PURPOSE: Clinical implications of single patient classifier (SPC) and microsatellite instability (MSI) in stage II/III gastric cancer have been reported. We investigated SPC and the status of MSI and Epstein-Barr virus (EBV) as combinatory biomarkers to predict the prognosis and responsiveness of adjuvant chemotherapy for stage II/III gastric cancer. MATERIALS AND METHODS: Tumor specimens and clinical information were collected from patients enrolled in CLASSIC trial, a randomized controlled study of capecitabine plus oxaliplatin-based adjuvant chemotherapy. The results of nine-gene based SPC assay were classified as prognostication (SPC-prognosis) and prediction of chemotherapy benefit (SPC-prediction). Five quasimonomorphic mononucleotide markers were used to assess tumor MSI status. EBV-encoded small RNA in situ hybridization was performed to define EBV status. RESULTS: There were positive associations among SPC, MSI, and EBV statuses among 586 patients. In multivariate analysis of disease-free survival, SPC-prognosis [hazard ratio (HR): 1.879 (1.101–3.205), 2.399 (1.415–4.067), p=0.003] and MSI status (HR: 0.363, 95% confidence interval: 0.161–0.820, p=0.015) were independent prognostic factors along with age, Lauren classification, TNM stage, and chemotherapy. Patient survival of SPC-prognosis was well stratified regardless of EBV status and in microsatellite stable (MSS) group, but not in MSI-high group. Significant survival benefit from adjuvant chemotherapy was observed by SPC-Prediction in MSS and EBV-negative gastric cancer. CONCLUSION: SPC, MSI, and EBV statuses could be used in combination to predict the prognosis and responsiveness of adjuvant chemotherapy for stage II/III gastric cancer.


Subject(s)
Biomarkers , Capecitabine , Chemotherapy, Adjuvant , Classification , Disease-Free Survival , Drug Therapy , Herpesvirus 4, Human , Humans , In Situ Hybridization , Microsatellite Instability , Microsatellite Repeats , Multivariate Analysis , Prognosis , RNA , Stomach Neoplasms
17.
Article in English | WPRIM | ID: wpr-742147

ABSTRACT

BACKGROUND/AIMS: Colorectal cancer (CRC) with microsatellite instability (MSI) has a better prognosis than CRC with microsatellite stable (MSS). Recent studies have reported biological differences according to tumor location in CRC. In this study, we investigated the clinical significance of MSI in patients with right-sided CRC. METHODS: The medical records of 1,009 CRC patients diagnosed at our institute between October 2004 and December 2016 with MSI test results were retrospectively reviewed. The long-term outcomes of CRC patients with MSI were assessed with respect to tumor location using Kaplan-Meier curves and Cox regression models. RESULTS: The median follow-up duration for all 1,009 study subjects was 25 months (interquartile range, 15–38). One hundred twenty-four of the study subjects had MSI (12.3%) and 250 had right-sided CRC (24.8%). The patients with MSI and right-sided CRC had better disease-free survival (DFS) than those with MSS as determined by the log-rank test (p=0.013), and this result was significant in females (p=0.035) but not in males with right-sided CRC. Multivariate Cox regression analysis showed MSS significantly predicted poor DFS in patients with right-sided CRC (hazard ratio 3.97, 95% CI 1.30–12.15, p=0.016) and in female patients (hazard ratio 4.69, 95% CI 1.03–21.36, p=0.045). CONCLUSIONS: The study shows MSI is a useful predictor of DFS in patients with right-sided CRC, especially in female patients.


Subject(s)
Colorectal Neoplasms , Disease-Free Survival , Female , Follow-Up Studies , Gender Identity , Humans , Male , Medical Records , Microsatellite Instability , Microsatellite Repeats , Prognosis , Retrospective Studies
18.
Article in English | WPRIM | ID: wpr-741210

ABSTRACT

BACKGROUND: This study aimed to investigate the prognostic impact of intratumoral Fusobacterium nucleatum in colorectal cancer (CRC) treated with adjuvant chemotherapy. METHODS: F. nucleatum DNA was quantitatively measured in a total of 593 CRC tissues retrospectively collected from surgically resected specimens of stage III or high-risk stage II CRC patients who had received curative surgery and subsequent oxaliplatin-based adjuvant chemotherapy (either FOLFOXor CAPOX). Each case was classified into one of the three categories: F. nucleatum–high, –low, or –negative. RESULTS: No significant differences in survival were observed between the F.nucleatum–high and –low/negative groups in the 593 CRCs (p = .671). Subgroup analyses according to tumor location demonstrated that disease-free survival was significantly better in F.nucleatum–high than in –low/negative patients with non-sigmoid colon cancer (including cecal, ascending, transverse, and descending colon cancers; n = 219; log-rank p = .026). In multivariate analysis, F. nucleatum was determined to be an independent prognostic factor in non-sigmoid colon cancers (hazard ratio, 0.42; 95% confidence interval, 0.18 to 0.97; p = .043). Furthermore, the favorable prognostic effect of F. nucleatum–high was observed only in a non-microsatellite instability-high (non-MSI-high) subset of non-sigmoid colon cancers (log-rank p = 0.014), but not in a MSI-high subset (log-rank p = 0.844), suggesting that the combined status of tumor location and MSI may be a critical factor for different prognostic impacts of F. nucleatum in CRCs treated with adjuvant chemotherapy. CONCLUSIONS: Intratumoral F. nucleatum load is a potential prognostic factor in a non-MSI-high/non-sigmoid/non-rectal cancer subset of stage II/III CRCs treated with oxaliplatin-based adjuvant chemotherapy.


Subject(s)
Chemotherapy, Adjuvant , Colon, Descending , Colonic Neoplasms , Colorectal Neoplasms , Disease-Free Survival , DNA , Fusobacterium nucleatum , Fusobacterium , Gastrointestinal Microbiome , Humans , Microsatellite Instability , Microsatellite Repeats , Multivariate Analysis , Prognosis , Retrospective Studies
19.
Article in English | WPRIM | ID: wpr-740193

ABSTRACT

This extensive review summarizes clinical evidence on immunotherapy and targeted therapy currently available for endometrial cancer (EC) and reports the results of the clinical trials and ongoing studies. The research was carried out collecting preclinical and clinical findings using keywords such as immune environment, tumor infiltrating lymphocytes, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) expression, immune checkpoint inhibitors, anti-PD-1/PD-L1 antibodies and others' on PubMed. Finally, we looked for the ongoing immunotherapy trials on ClinicalTrials.gov. EC is the fourth most common malignancy in women in developed countries. Despite medical and surgical treatments, survival has not improved in the last decade and death rates have increased for uterine cancer in women. Therefore, identification of clinically significant prognostic risk factors and formulation of new rational therapeutic regimens have great significance for enhancing the survival rate and improving the outcome in patients with advanced or metastatic disease. The identification of genetic alterations, including somatic mutations and microsatellite instability, and the definition of intracellular signaling pathways alterations that have a major role in in tumorigenesis is leading to the development of new therapeutic options for immunotherapy and targeted therapy.


Subject(s)
Antibodies , Biological Therapy , Carcinogenesis , Developed Countries , Endometrial Neoplasms , Female , Humans , Immunotherapy , Lymphocytes, Tumor-Infiltrating , Microsatellite Instability , Molecular Targeted Therapy , Mortality , Risk Factors , Survival Rate , Uterine Neoplasms
20.
Article in English | WPRIM | ID: wpr-762294

ABSTRACT

PURPOSE: We evaluate the prognostic value of primary tumor location for oncologic outcomes in patients with colon cancer (CC). METHODS: CC patients treated with curative surgery between 2009 and 2012 were classified into 2 groups: right-sided colon cancer (RCC) and left-sided colon cancer (LCC). Recurrence-free survival (RFS) and overall survival (OS) were examined based on tumor stage. Propensity scores were created using eight variables (age, sex, T stage, N stage, histologic grade, presence of lymphovascular invasion/perineural invasion, and microsatellite instability status). RESULTS: Overall, 2,329 patients were identified. The 5-year RFSs for RCC and LCC patients were 89.7% and 88.4% (P = 0.328), respectively, and their 5-year OSs were 90.9% and 93.4% (P = 0.062). Multivariate survival analyses were carried out by using the Cox regression proportional hazard model. In the unadjusted analysis, a marginal increase in overall mortality was seen in RCC patients (hazard ratio [HR], 1.297; 95% confidence interval [CI], 0.987–1.704, P = 0.062); however, after multivariable adjustment, similar OSs were observed in those patients (HR, 1.219; 95% CI, 0.91–1.633; P = 0.183). After propensity-score matching with a total of 1,560 patients, no significant difference was identified (P = 0.183). A slightly worse OS was seen for stage III RCC patients (HR, 1.561; 95% CI, 0.967–2.522; P = 0.068) than for stage III LCC patients. The 5-year OSs for patients with stage III RCC and stage III LCC were 85.5% and 90.5%, respectively (P = 0.133). CONCLUSION: Although the results are inconclusive, tumor location tended to be associated with OS in CC patients with lymph node metastasis, but it was not related to oncologic outcome.


Subject(s)
Colon , Colonic Neoplasms , Humans , Lymph Nodes , Microsatellite Instability , Mortality , Neoplasm Metastasis , Propensity Score , Proportional Hazards Models , Treatment Outcome
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