Role of micronucleus-activated cGAS-STING signaling in antitumor immunity / 浙江大学学报·医学版

cGAS-STING signaling is a significant component of the innate immune system and functions as a vital sentinel mechanism to monitor cellular and tissue aberrations in microbial invasion and organ injury. cGAS, a cytosolic DNA sensor, is specialized in recognizing abnormally localized cytoplasmic double-stranded DNA (dsDNA) and catalytically synthesizes the second messenger cyclic-GMP-AMP (cGAMP), which initiates a cascade of type I interferon and inflammatory responses mediated by STING. Micronucleus, a byproduct of chromosomal missegregation during anaphase, are also significant contributors to cytoplasmic dsDNA. These unstable subcellular structures are susceptible to irreversible nuclear envelope rupture, exposing genomic dsDNA to the cytoplasm, which potently recruits cGAS and activates STING-mediated innate immune signaling and its downstream activities, including type I interferon and classical nuclear factor-κB (NF-κB) signaling pathways lead to senescence, apoptosis, autophagy activating anti-cancer immunity or directly killing tumor cells. However, sustained STING activation-induced endoplasmic reticulum stress, activated chronic type I interferon and nonclassical NF-κB signaling pathways remodel immunosuppressive tumor microenvironment, leading to immune evasion and facilitating tumor metastasis. Therefore, activated cGAS-STING signaling plays a dual role of suppressing or facilitating tumor growth in tumorigenesis and therapy. This review elaborates on research advances in mechanisms of micronucleus inducing activation of cGAS-STING signaling and its implications in tumorigenesis and therapeutic strategies of malignant tumors.

Cellular consequences of small supernumerary marker chromosome derived from chromosome 12: mosaicism in daughter and father

Constitutional genomic imbalances are known to cause malformations, disabilities, neurodevelopmental delay, and dysmorphia and can lead to dysfunctions in the cell cycle. In extremely rare genetic conditions such as small supernumerary marker chromosomes (sSMC), it is important to understand the cellular consequences of this extra marker, as well the factors that contribute to their maintenance or elimination through successive cell cycles and phenotypic impact. The study of chromosomal mosaicism provides a natural model to characterize the effect of aneuploidy on genome stability and compare cells with the same genetic background and environment exposure, but differing in the presence of sSMC. Here, we report the functional characterization of different cell lines from two familial patients with mosaic sSMC derived from chromosome 12. We performed studies of proliferation dynamics, stability, and variability of these cells using fluorescent in situ hybridization (FISH), sister chromatid exchanges (SCE), and conventional staining. We also quantified the telomere-related genomic instability of sSMC cells using 3D telomeric profile analysis by quantitative-FISH. sSMC cells exhibited differences in the cell cycle dynamics compared to normal cells. First, the sSMC cells exhibited lower proliferation index and higher frequency of SCE than normal cells, associated with a higher level of chromosomal instability. Second, sSMC cells exhibited more telomeric-related genomic instability. Lastly, the differences of sSMC cells distribution among tissues could explain different phenotypic repercussions observed in patients. These results will help in our understanding of the sSMC stability, maintenance during cell cycle, and the cell cycle variables involved in the different phenotypic manifestations.

Genome instability and lymphoma / 中南大学学报(医学版)

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.

Prognosis in colorectal cancer beyond TNM / Prognóstico no carcinoma colorretal para além do TNM

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.

Spontaneous chromatid break as clonal evolution in myelodysplastic syndrome patients / Quebra espontânea de cromátides como evolução clonal em pacientes com síndrome mielodisplásica

ABSTRACT Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by peripheral cytopenias due to ineffective erythropoiesis and an increased risk for evolving into acute myeloid leukemia (AML). Chromosomal abnormalities represent the most important marker of risk stratification for AML transformation. Chromatid break (chtb) is a discontinuity of a single chromatid. We report the case of a patient with MDS whose cytogenetic analysis showed spontaneous chromatid breakage (chrb): 46,XY,add(13)(q34),chtb(15)(q24) [3]/47,XY,chtb(2)(q22),del(5)(q35),del(7)(q32),+8,del(11q)(q23),del(q22)[cp17]. He was considered a high-risk patient due to the complex karyotype and the presence of chtb. We suggest that this chromosomal abnormality may be considered as a marker of genomic instability in MDS.

RESUMO A síndrome mielodisplásica (SMD) é uma desordem clonal das células-tronco hematopoiéticas caracterizada por citopenias periféricas devido à hematopoiese ineficaz e pelo aumento do risco de evolução para a leucemia mieloide aguda (LMA). As alterações cromossômicas representam o marcador mais importante da estratificação de risco para a transformação de LMA. Quebra das cromátides (chtb) é uma descontinuidade de uma única cromátide. Relatamos o caso de um paciente com SMD, cuja análise citogenética mostrou chtb espontâneo: 46,XY,add(13)(q34),chtb(15)(q24)[3]/47,XY,chtb(2)(q22),del(5) (q35),del(7)(q32),+8,del(11q)(q23),del(q22)[cp17]. O paciente foi considerado de alto risco devido ao cariótipo complexo e à presença de chtb. Sugerimos que essa anormalidade cromossômica possa ser considerada como marcador de instabilidade.

Caracterización de pacientes con cáncer colorrectal esporádico basado en la nueva subclasificación molecular de consenso / Characterization of patients with sporadic colorectal cancer following the new Consensus Molecular Subtypes (CMS)

Background: Colorectal cancer (CRC) is an heterogeneous disease. Three carcinogenic pathways determine its molecular profile: microsatellite instability (MSI), chromosomal instability (CIN) and CpG island methylator phenotype (CIMP). Based on the new molecular classification, four consensus CRC molecular subtypes (CMS) are established, which are related to clinical, pathological and biological characteristics of the tumor. Aim: To classify Chilean patients with sporadic CRC according to the new consensus molecular subtypes of carcinogenic pathways. Material and Methods: Prospective analytical study of 53 patients with a mean age of 70 years (55% males) with CRC, operated at a private clinic, without neoadjuvant treatment. From normal and tumor tissue DNA of each patient, CIN, MSI and CIMP were analyzed. Combining these variables, tumors were classified as CMS1/MSI-immune, CMS2/canonical, CMS3/metabolic and CMS4/mesenchymal. Results: CMS1 tumors (19%) were located in the right colon, were in early stages, had MMR complex deficiencies and 67% had an activating mutation of the BRAF oncogene. CMS2 tumors (31%) were located in the left colon, had moderate differentiation, absence of vascular invasion, lymphatic and mucin. CMS3 tumors (29%) were also left-sided, with absence of vascular and lymphatic invasion, and 29% had an activating mutation of the KRAS oncogene. CMS4 tumors (21%) showed advanced stages and presence of metastases. Conclusions: This new molecular classification contributes to understanding the heterogeneity of tumors. It is possible to differentiate molecular subgroups of a single pathological diagnosis of adenocarcinoma, opening the door to personalized medicine.

Research progress on molecular mechanism of sporadic colorectal cancer / 实用肿瘤学杂志

Colorectal cancer( CRC) is one of the most common tumor,which has complicated pathogene-sis.it is estimated that the vast majority of CRCs is non-hereditarysporadic cancerswith no apparent evidence of an inherited component.Sporadic CRC results from the cumulative effects of multiple genetic and epigenetic al-terations caused by somatic mutations, which may be the indirect result of several environmental factors them-selves.There are at least 3 major genetic alternations that lead to colorectal carcinogenesis:(1)The chromosomal instability(CIN)pathway;(2)The microsatellite instability(MSI)pathway;(3)The cytosine-phospho-guanine ( CpG) island methylator phenotype( CIMP) pathway,while DNA methylation,modifications in histone proteins and microRNAs( miRNAs) are analyzed in the field of epigenetic alterations.This review summarizes the newest bio-molecular progression involved in CRC pathogenesis,for the purpose of improving strategy for prevention,surveil-lance,early diagnosis and therapy.

Genetic evaluation of mesenchymal stem cells by G-banded karyotyping in a Cell Technology Center

OBJECTIVE: To present the initial results of first three years of implementation of a genetic evaluation test for bone marrow-derived mesenchymal stem cells in a Cell Technology Center. METHODS: A retrospective study was carried out of 21 candidates for cell therapy. After the isolation of bone marrow mononuclear cells by density gradient, mesenchymal stem cells were cultivated and expanded at least until the second passage. Cytogenetic analyses were performed before and after cell expansion (62 samples) using G-banded karyotyping. RESULTS: All the samples analyzed, before and after cell expansion, had normal karyotypes, showing no clonal chromosomal changes. Signs of chromosomal instability were observed in 11 out of 21 patients (52%). From a total of 910 analyzed metaphases, five chromatid gaps, six chromatid breaks and 14 tetraploid cells were detected giving as total of 25 metaphases with chromosome damage (2.75%). CONCLUSION: The absence of clonal chromosomal aberrations in our results for G-banded karyotyping shows the maintenance of chromosomal stability of bone marrow-derived mesenchymal stem cells until the second passage; however, signs of chromosomal instability such as chromatid gaps, chromosome breaks and tetraploidy indicate that the long-term cultivation of these cells can provide an intermediate step for tumorigenesis. .

Contributions of cytogenetics to cancer research / Contribuições da citogenética em pesquisas sobre o câncer

The two conflicting visions of tumorigenesis that are widely discussed are the gene-mutation hypothesis and the aneuploidy hypothesis. In this review we will summarize the contributions of cytogenetics in the study of cancer cells and propose a hypothetical model to explain the influence of cytogenetic events in carcinogenesis, emphasizing the role of aneuploidy. The gene mutation hypothesis states that gene-specific mutations occur and that they maintain the altered phenotype of the tumor cells, and the aneuploidy hypothesis states that aneuploidy is necessary and sufficient for the initiation and progression of malignant transformation. Aneuploidy is a hallmark of cancer and plays an important role in tumorigenesis and tumor progression. Aneuploid cells might be derived from polyploid cells, which can arise spontaneously or are induced by environmental agents or chemical compounds, and the genetic instability observed in polyploid cells leads to chromosomal losses or rearrangements, resulting in variable aberrant karyotypes. Because of the large amount of evidence indicating that the correct chromosomal balance is crucial to cancer development, cytogenetic techniques are important tools for both basic research, such as elucidating carcinogenesis, and applied research, such as diagnosis, prognosis and selection of treatment. The combination of classic cytogenetics, molecular cytogenetics and molecular genetics is essential and can generate a vast amount of data, enhancing our knowledge of cancer biology and improving treatment of this disease.

As duas visões conflitantes da tumorigênese que são amplamente discutidas são a hipótese da mutação gênica e a hipótese da aneuploidia. Nesta revisão vamos resumir as contribuições da citogenética no estudo das células tumorais e propor um modelo hipotético para explicar a influência dos eventos citogenéticos na carcinogênese, enfatizando o papel da aneuploidia. A teoria da mutação gênica estabelece que mutações específicas ocorrem e mantêm o fenótipo alterado das células de um tumor, enquanto a hipótese da aneuploidia estabelece que a aneuploidia é necessária e suficiente para a iniciação e progressão da transformação maligna. A aneuploidia é considerada um marcador do câncer e esta desempenha um importante papel tanto na tumorigênese, quanto na progressão tumoral. Células aneuplóides podem ser derivadas de células poliplóides, que surgem espontaneamente ou são induzidas por agentes ambientais ou compostos químicos. A instabilidade genética observada em células poliplóides leva a perdas ou rearranjos cromossômicos, resultando em cariótipos variavelmente aberrantes. Devido à grande quantidade de evidências indicando que um balanço cromossômico correto é crucial para o desenvolvimento do câncer, as técnicas citogenéticas são ferramentas importantes tanto para a pesquisa básica, tais como pesquisas para elucidar a carcinogênese, quanto pesquisas aplicadas, como no diagnóstico, prognóstico e escolha do tratamento. A combinação da citogenética clássica, citogenética molecular e genética molecular é essencial e pode gerar uma grande quantidade de dados, aumentando o nosso conhecimento da biologia do câncer, melhorando assim o tratamento desta doença.

Clinical Application of Genetics in Management of Colorectal Cancer

The extensive study of genetic alterations in colorectal cancer (CRC) has led to molecular diagnostics playing an increasingly important role in CRC diagnosis and treatment. Currently, it is believed that CRC is a consequence of the accumulation of both genetic and epigenetic genomic alterations. It is known that there are at least 3 major pathways that lead to colorectal carcinogenesis: (1) the chromosomal instability pathway, (2) the microsatellite instability pathway, and (3) the cytosine-phospho-guanine island methylator phenotype pathway. With recent advances in CRC genetics, the identification of specific molecular alterations responsible for CRC pathogenesis has directly influences clinical care. Patients at high risk for developing CRC can be identified by genetic testing for specific molecular alterations, and the use of molecular biomarkers for predictive and prognostic purposes is also increasing. This is clearly supported by the recent advances in genetic testing for CRC whereby specific molecular alterations are identified for the purpose of guiding treatment with targeting therapies such as anti-endothelial growth factor receptor monoclonal antibodies.

Vías de carcinogénesis colorrectal y sus implicaciones clínicas / Pathways of colorectal carcinogenesis and their clinical implications

El cáncer colorrectal (CCR) es la cuarta causa de mortalidad por cáncer en Colombia y en el mundo, en ambos sexos; por esta razón, es considerado un problema de salud pública. El CCR es altamente heterogéneo en su fenotipo y genotipo, lo que está en relación con las diferentes vías de carcinogénesis descritas que implican diferentes mecanismos de progresión y agresividad de la enfermedad. Las vías clásicas, supresora y mutadora, se caracterizan por una serie de alteraciones genéticas relacionadas con los cambios fenotípicos de la progresión morfológica en la secuencia adenoma-carcinoma. Las vías alternas, originadas por mutaciones en los genes, BRAF y KRAS, se relacionan con la progresión de pólipo aserrado a carcinoma. Conocer estas vías es muy importante para comprender la enfermedad de manera integral y profundizar en el estudio de sus mecanismos de control, que incluyen: diagnóstico temprano, tratamiento y seguimiento.

Colorectal cancer (CRC) is ranked fourth among causes of cancer mortality in Colombia and in the world, for both genders; it is therefore regarded as a public health issue. CRC´s phenotype and genotype are highly heterogeneous, a fact related to the various carcinogenic pathways described, and which is also implicated in the different progression mechanisms and the aggressiveness of the disease. The classic pathways, suppressive and mutable, are characterized by a series of genetic alterations related to phenotype changes in the morphologic progression of the adenoma-carcinoma sequence. The alternate pathways, originated by BRAF and KRAS gene mutations, are linked to the serrated polyp progression to carcinoma. Knowledge of these pathwaysis very important in achieving a fuller understanding of the disease and for broadening the study of mechanisms for its control; these include: early diagnosis, treatment and follow-up.

Bases moleculares del cáncer colorrectal / Molecular bases of colorectal cancer

Se considera que el cáncer colorrectal (CCR) es un problema mundial de salud pública; es el tercer cáncer más común en hombres y el segundo en mujeres. Su distribución geográfica es variable: las tasas de incidencia son altas en países desarrollados de Europa, Norteamérica y Oceanía y bajas en países de regiones subdesarrolladas como África y Suramérica. Sin embargo, los datos de estudios recientes publicados por la Agencia Internacional de Investigaciones en Cáncer (IARC, International Agency for Research on Cancer) muestran un aumento rápido en la incidencia de CCR en los períodos 1983-1987 y 1998-2002 en países en vías de desarrollo (1), mientras que en países desarrollados la incidencia se ha estabilizado y en muchos casos ha disminuido (2). La carcinogénesis del CCR es un proceso de múltiples etapas, caracterizado por una gran inestabilidad genómica que permite la acumulación de mutaciones en protooncogenes y genes supresores de tumores, alteración en la expresión de genes y producción de proteínas no funcionales, que les confieren a las células ventajas de proliferación y aumento de la supervivencia. La inestabilidad genómica del CCR se produce por diferentes vías; entre las más importantes se encuentran: la de inestabilidad cromosómica (CIN), la de inestabilidad microsatelital (MSI) y la de metilación.

Worldwide, colorectal cancer (CRC) is a public health problem; it is the third most prevalent cancer in men and the second in women. There are some geographical variations in its incidence, with high rates in many developed countries of Europe, North America and Oceania, and low rates in countries of less developed regions such as Africa and South America. Recent studies on cancer, published by the International Agency for Research on Cancer (IARC), show a rapid increase in the incidence of CRC in developing countries between 1983-1987 and 1998-2002 (1), while in the developed world incidence has stabilized and in many cases decreased (2). Carcinogenesis of CRC is a multiple step process, characterized by high genomic instability that may lead to the accumulation of mutations in proto-oncogenes, tumor suppressor genes, repair machinery failures, epigenetic changes in DNA and production of non-functional proteins; these changes lead to cell proliferation advantages and to an increase in cell survival. Genomic instability of CRC occurs through different pathways, the most important of which are: chromosomal instability (CIN), microsatellite instability (MSI) and methylation.

Síndrome de Nijmegen: una enfermedad genética a considerar en un paciente con microcefalia, retardo mental y lesiones de la piel / Nijmegen breakage syndrome

Se presenta el caso de un paciente masculino que a los 6 años de edad es derivado a Neurología Infantil para su estudio por presentar microcefalia y retardo mental. Tras ser evaluado por Inmunología y Genética se realiza en el Laboratorio de citogenética humana, programa de genética ICBM, Facultad de Medicina Universidad de Chile, PCR para deleción 657 del5 que confirma el diagnóstico de Nijmegen dando como resultado deleción nucleótido 5, mutación 657 del5, característico del Síndrome de Nijmegen. Actualmente el niño tiene 13 años y es tratado en el Servicio de Oncología infantil por el desarrollo de linfoma difuso de células grandes B, patología frecuente en este sindrome.

A case of a male patient at 6 years old was referred to child neurology for study due to microcephaly and mental retardation. After being evaluated for Immunology and Genetics Laboratory is performed in human cytogenetics, genetic program ICBM, Faculty of Medicine University of Chile, PCR for deletion 657 of the 5 that confirms the diagnosis of Nijmegen nucleotide deletion resulting in 5, 657 mutation del 5 Characteristic of the syndrome of Nijmegen. Currently the child is 13 and is treated at the Children’s Oncology Service in the development of lymphoma diffuse large B cell, common pathology in this syndrome.

Effects of Chromosomal Polyploidy on Survival of Colon Cancer Cells / 대한소화기학회지

BACKGROUND/AIMS: Tetraploid cells are frequently observed in the inflamed mucosal epithelial cells of the patients with Barrett's esophagus or chronic ulcerative colitis. Polyploidy often occurs during cell fusion, abortive cell cycle, and endoreplication. Most tetraploid cells are engaged to apoptotic pathway, but some remaining stable tetraploid cells consequently cause aneuploidization and chromosomal instability. We investigated whether tetraploid cells could acquire survival advantage and hold a dominant position for natural selection. METHODS: We established tetraploid cell line (HCT116GH) from parental diploid colorectal cancer cell line (HCT116) via PEG-mediated cell fusion and compared its cell viability, cell cycle response and apoptotic fractions responded to H2O2 with diploid HCT116 and p53 suppressed HCT116/H6 cell lines. RESULTS: Using MTT assay, plating efficiency and clonogenicity, we evaluated the survival of each cell line. Tetraploid cell line HCT116GH demonstrated an 83 fold greater resistance to 100 microM H2O2 than the parental diploid HCT116, and 6 fold greater than even the p53 negative diploid HCT116/E6. Cellular sensitivity, G2/M arrests, and apoptotic proportion were observed less in response to H2O2 in HCT116GH compared with HCT116 and HCT116/E6. HCT116GH expressed lower level of p53 and p21 than diploid HCT116. CONCLUSIONS: Stable tetraploid cell lines showed enhanced viability in comparison to parental diploid cell lines. The enhanced viability observed in tetraploidization surpassed that from downregulation of p53. Frequent appearance of tetraploid cells in stressful condition can be caused by natural selection owing to their enhanced viability and may consequently contribute to cancer cell transformation.

Cytogenetic aberrations in primary cell cultures of the ovarian surface epithelium / Aberraciones citogenéticas en cultivos primarios del epitelio superficial del ovario

Our objective was to determine the presence of chromosomal abnormalities in primary cultures of ovarian surface epithelial cells in women of different ages with no history of cancer. Throughout conventional cytogenetic techniques, we analyzed chromosome spreads of cultured ovarian epithelial cells from 10 donors who were 50 or more years old (B) and 16 controls between 20 and 49 years old (A), belonging to the mestizo population in Bogota DC, Colombia. Of the 26 cultures that were analyzed in passage 1, 61.5% had an abnormal chromosome complement (62.5% in A, and 60% in B). Abnormalities included polyploidies, endoduplications and monosomies. Deletions in chromosomes 3 and 11 were found in just one metaphase. None of the samples showed weaknesses or breakpoints. After transforming and applying the exact student’s t-test for variance heterogeneity, we found significant differences in the frequency of metaphases, that were higher in A than in B (p=0.05), and in the frequency of polyploidies, which were higher in B than in A (p=0.044). Through the application of the Mann-Whitney test, we determined that the frequency of endoduplications was higher in A than in B (p=0.126), without reaching significant differences. There were no significant differences in the frequency of monosomies. The level of significance was set at p £ 0.05. Taking into account that polyploidization is a marker of chromosomal instability and that the risk of cancer arising from the ovarian surface epithelium augments substantially after menopause, the increase in the frequency of age-associated polyploidies could be used as a predictor of ovarian cancer in women from an ethnically homogeneous population as the mestizo one in Bogota DC.

El objetivo del presente trabajo fue determinar la presencia de anormalidades cromosómicas en cultivos primarios de células del epitelio superficial ovárico en mujeres de diferentes edades, sin antecedentes de cáncer. Mediante técnicas de citogenética convencional fueron analizados extendidos de células epiteliales ováricas histológicamente normales, provenientes de cultivos primarios de 10 donantes de 50 o más años (B) y de 16 donantes entre 20 y 49 años que se utilizaron como grupo control (A), pertenecientes a la población mestiza de Bogotá DC, Colombia. De 26 cultivos examinados en pase 1, 61,5% presentó complemento cromosómico anormal, 62,5% en A y 60% en B. Las anomalías numéricas halladas, todas en mosaico, incluyeron poliploidías, endoduplicaciones y monosomías. En una única célula en metafase de un cultivo, se presentaron deleciones en los cromosomas 3 y 11. Ninguna muestra presentó fragilidades o roturas. Previa aplicación de transformaciones, con la prueba exacta t-student para varianzas heterogéneas, se encontraron diferencias significativas en la frecuencia de células con metafase normal, mayor en A que en B (p=0,05) y en la de poliploidías, mayor en B que en A (p=0,044). Con la prueba exacta de Mann-Whitney se determinó que la frecuencia de endoduplicaciones en A fue mayor que en B (p=0,126), sin alcanzar diferencias significativas y que no hubo diferencias significativas en la frecuencia de monosomías. El nivel de significación fue p £ 0,05. Si se tiene en cuenta que la poliploidización es un marcador de inestabilidad cromosómica y, que además, el riesgo de aparición de cáncer derivado del epitelio superficial del ovario aumenta sustancialmente después de la menopausia, el incremento en la frecuencia de poliploidías asociado con la edad podría ser utilizado como predictor de cáncer ovárico en mujeres de una población étnicamente homogénea como la población mestiza de Bogotá DC.

The Relationship between the Presence of Chromosomal Instability and Prognosis of Squamous Cell Carcinoma of the Lung: Fluorescence in situ Hybridization Analysis of Paraffin-embedded Tissue from 47 Korean Patients

To evaluate the prognostic importance of chromosomal instability (CIN) in squamous cell carcinoma (SCC) of the lung, the relationship between CIN detected by fluorescence in situ hybridization (FISH) and survival in SCC patients was examined. Forty-seven surgical specimens of lung SCC were analyzed. To identify tumors with CIN, p16 and multi-target DNA FISH assays for c-myc, chromosome 6, EGFR, and chromosome 5 (LAVysion, Vysis) were performed on nuclei extracted from paraffin-embedded tumor tissues. Survival rates were compared in terms of age, T factor, N factor, CIN, and smoking status. A sample was defined as CIN-positive if at least four of the five chromosomes were positive. Among the 47 specimens, 9 (19%) were CIN-positive. The overall survival rate was 66%. Overall survival rates were estimated as 33.3% for CIN-positive patients and 76.7% for CIN-negative patients (Hazard ratio 3.47; 95% Confidence interval, 1.25-9.67; P=0.017). In multivariate analysis, the presence of CIN was a predictive factor for survival. CIN-positive based on FISH can be prognostic factor of lung SCC.

Genomic Instability in Colorectal Cancer; from Bench to Bed

Colorectal cancer is a disease developed by the accumulation of genomic alteration. Two genomic instability pathways, chromosomal instability pathway and microsatellite instability pathway, are known as the main pathways of the development of colorectal cancer. These are almost always mutually exclusive and tumors developed through each pathways show distinct clinicopathologic features. For the reason, molecular markers which represent each genomic instability pathways have been a candidate for translational research to find out prognostic or predictive factors. Loss of heterozygosity and aneuploidy are the hallmark of chromosomal instability and regarded as poor prognostic markers, whereas tumors with high frequency of microsatellite instability show better prognosis than microsatellite stable tumor. As a predictive factor of response from chemotherapy, loss of heterozygosity seems to be associated with a survival benefit from 5-FU adjuvant therapy. MSI-H has been reported as a predictive factor for poor response to 5-FU adjuvant chemotherapy. However, these molecular markers are not accepted to use in the clinic yet, since some of this kind of studies reported contradictory results. Further study will be needed to make more concrete evidences for these markers and to identify new molecular markers for routine use in the clinic.

Promoter Methylation in the Genesis of Gastrointestinal Cancer

Colorectal cancers (CRC)-and probably all cancers-are caused by alterations in genes. This includes activation of oncogenes and inactivation of tumor suppressor genes (TSGs). There are many ways to achieve these alterations. Oncogenes are frequently activated by point mutation, gene amplification, or changes in the promoter (typically caused by chromosomal rearrangements). TSGs are typically inactivated by mutation, deletion, or promoter methylation, which silences gene expression. About 15% of CRC is associated with loss of the DNA mismatch repair system, and the resulting CRCs have a unique phenotype that is called microsatellite instability, or MSI. This paper reviews the types of genetic alterations that can be found in CRCs and hepatocellular carcinoma (HCC), and focuses upon the epigenetic alterations that result in promoter methylation and the CpG island methylator phenotype (CIMP). The challenge facing CRC research and clinical care at this time is to deal with the heterogeneity and complexity of these genetic and epigenetic alterations, and to use this information to direct rational prevention and treatment strategies.

Bloom's syndrome in a 12-year-old Iranian girl.

BACKGROUND: Bloom's syndrome, an autosomal recessive inherited disorder, belongs to the group of chromosomal breakage syndromes. The clinical diagnosis of BS is confirmed cytogenetically. Its frequency in the general population is unknown but it is common in eastern European Ashkenazi Jews. CASE REPORT: A 12-year-old girl was referred to us because of short stature. She was the second child of the first cousin marriage. She had a slender body frame, short stature, and microcephaly. Her face was long and narrow with prominent nose, and malar and mandibular hypoplasia. The spots of hyper and hypo pigmentation were observed in the trunk and limbs. Telangectasia spots were observed in some areas of the trunk. Additionally, generalized hirsutism was present in the whole body. Cytogenetic findings revealed an abnormality in the structural chromosome. CONCLUSION: This is the first BS case that has been reported in Iranian female population.

Correlation between over expression of BUBR1 and chromosomal instability in colorectal carcinoma / 现代生物医学进展

Objective:Over expression of BUBR1 protein was reported in several human malignancies,however whether BUBR1 plays a role in chromosomal instability phenotype remains in controversy.This study was to explore the roll of BUBR1 protein in CIN phenotype in CRC.Methods:BUBR1 expression was studied immunohistochemieally in a panel of 93 advanced sporadic eolorectal cancers.Microsatellite status was evaluated by high resolution microsatellite analysis assay,TP53 gene mutation by direct sequencing and DNA ploidy by laser scanning cytometery.The relationship between BUBR1 overexpression and TP53 gene mutation,mierosatellite status,and DNA ploidy were studied.Results:BUBR1 overexpression was confirmed in 69% of cases.The overexpression was more frequent in tumor without high frequency microsatellite instability (P＜0.01) and TP53 mutation (P＜0.05).There was no statistic correlation between DNA aneuploidy and BUBR1 overexpression; however,a tendency that aneuploidy tumors had higher percentage of BUBR1 overexpression was shown.BUBR1 overexpression was not statistically related with clinieopathological factors.Conclusion:The linkage between BUBR1 overexpression and molecular factors indicating a CIN background implied that BUBR1 overexpression was indeed related with chromosomal instability in colorectal cancer.