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1.
Cell Physiol Biochem ; 53(5): 820-831, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31701729

RESUMO

BACKGROUND/AIMS: MLK4 (KIAA1804) is the second most frequently mutated kinase in microsatellite stable (MSS) colorectal carcinomas (CRC). This molecule is known to regulate different physiological cellular processes, including cell cycle, senescence and apoptosis, and mechanistic evidence has been provided that MLK4 plays a role in carcinogenesis. However, whether this kinase exerts a tumor suppressive role or an oncogenic function is still an object of debate. This study aims to elucidate the role of MLK4 in the pathogenesis of CRC by investigating human tumor specimens. METHODS: This study assessed MLK4 expression levels by immunohistochemistry in surgical tumor samples from 204 early-stage CRC patients and their correlation with various clinical-pathological features and patients' outcomes. In addition, MLK4 mRNA transcription was analysed in an independent cohort of 786 colon cancer samples. RESULTS: Loss of MLK4 staining was associated with poor overall (OS) and progression free survival (PFS) in CRC patients during a univariate analysis (OS:101 vs 164 months, p=0.0002; PFS:85 vs 125 months, p=0.0001), as well as in multivariate analysis (OS:HR=1.70; p=0.001; PFS:HR=1,61; p=0.001). This was confirmed by analysis of MLK4 mRNA in the second independent cohort. A subgroup analysis according to KRAS mutation status showed that MLK4 staining was associated with better OS and PFS in KRAS mutated cases (HR=2.77; p=0.0001 and HR=2.31; p=0.0003, respectively) and microsatellite stable tumors (HR=1.87; p=0.002 and HR=1.06; p=0.006) but not in KRAS wildtype and microsatellite unstable tumors. CONCLUSION: By providing the first report from clinical specimens on the prognostic significance of MLK4, we define an oncogenic loss-of-function of this kinase and suggest a possible role in the interaction with KRAS signaling in determining an aggressive phenotype of CRC. These findings warrant the further investigation of MLK4 in wider cohorts and various clinical settings.


Assuntos
Neoplasias Colorretais/patologia , MAP Quinase Quinase Quinases/metabolismo , Instabilidade de Microssatélites , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Idoso , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , MAP Quinase Quinase Quinases/genética , Masculino , Mutação , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas p21(ras)/genética
2.
J Surg Oncol ; 120(8): 1427-1435, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31729037

RESUMO

BACKGROUND AND OBJECTIVES: Mucinous adenocarcinoma is a distinct subtype of colorectal cancer (CRC) with a worse prognosis when compared with non-mucinous adenocarcinoma. The aim of this study was to compare somatic mutations and copy number alteration (CNA) between mucinous and non-mucinous CRC. METHODS: Data from The Cancer Genome Atlas-colon adenocarcinoma and rectum adenocarcinoma projects were utilized. Mucinous and non-mucinous CRC were compared with regard to microsatellite status, overall mutation rate, the most frequently mutated genes, mutations in genes coding for mismatch repair (MMR) proteins and genes coding for mucin glycoproteins. CNA analysis and pathway analysis was undertaken. RESULTS: Mucinous CRC was more likely to be microsatellite instability-high (MSI-H) and hypermutated. When corrected for microsatellite status the single-nucleotide variation and insertion-deletion rate was similar between the two cohorts. Mucinous adenocarcinoma was more likely to have mutations in genes coding for MMR proteins and mucin glycoproteins. Pathway analysis revealed further differences between the two histological subtypes in the cell cycle, RTK-RAS, transforming growth factor-ß, and TP53 pathways. CONCLUSIONS: Mucinous CRC has some distinct genomic aberrations when compared with non-mucinous adenocarcinoma, many of which are driven by the increased frequency of MSI-H tumors. These genomic aberrations may play an important part in the difference seen in response to treatment and prognosis in mucinous adenocarcinoma.


Assuntos
Adenocarcinoma Mucinoso/genética , Adenocarcinoma/genética , Neoplasias do Colo/genética , Genômica , Neoplasias Retais/genética , Adenocarcinoma/patologia , Adenocarcinoma Mucinoso/patologia , Estudos de Coortes , Neoplasias do Colo/patologia , Variações do Número de Cópias de DNA , Proteínas de Ligação a DNA/genética , Conjuntos de Dados como Assunto , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação INDEL , Instabilidade de Microssatélites , Mucinas/genética , Mutação , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Retais/patologia , Proteína Smad4/genética , Fator de Crescimento Transformador beta/genética , Proteína Supressora de Tumor p53/genética
3.
Anticancer Res ; 39(11): 6379-6387, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704871

RESUMO

BACKGROUND/AIM: In the present retrospective study, we assessed the molecular profile and clinicopathological correlations of Greek colorectal carcinoma (CRC) patients. PATIENTS AND METHODS: Data from 157 CRC patients were collected. High Resolution Melting Analysis and Pyrosequencing/Sanger sequencing were applied to identify KRAS, BRAF, NRAS mutations and microsatellite instability (MSI) status. Immunohistochemistry was performed to characterize the associated Mismatch Repair Protein loss. Statistical calculations were performed using the statistical package SPSS v21.0. RESULTS: KRAS mutations were detected in 39.3% of cases, BRAF in 10.9% and NRAS in 4.9%. MSI status was recognized in 11.5% of CRC patients and was associated with right colon tumors. MSI phenotype was inversely correlated with stage, N status and KRAS mutations and positively correlated with BRAF mutations. CONCLUSION: MSI positive CRCs in the Greek population are more often right-sided, free of metastasis, KRAS wild type and BRAF mutated. Providing more detailed clinicopathological and molecular data for specific populations will enable better clinical management and individualized therapy in the future.


Assuntos
Neoplasias do Colo/genética , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Instabilidade de Microssatélites , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/patologia , Feminino , Grécia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Sexuais , Neoplasias do Colo Sigmoide/genética , Neoplasias do Colo Sigmoide/patologia
4.
Cancer Immunol Immunother ; 68(11): 1779-1790, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31620857

RESUMO

Human leukocyte antigen class I (HLA I) molecules composed of alpha (heavy) chain, including HLA-A, -B, or -C encoded by HLA genes, and beta-2-microglobulin (ß2M) are membrane proteins on all nucleated cells that display peptide antigens for recognition by CD8-positive cytotoxic T cells. Here, we examined the clinicopathologic signification of HLA I expression in patients with gastric cancer (GC). Immunohistochemistry was performed to detect HLA A/B/C, ß2M, CD8, p53, and programmed death-ligand 1 (PD-L1) in the center and invasive margin of the tumor in 395 stage II and III GCs using tissue array method. Additionally, Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status were investigated. Negative expression of HLA A/B/C and ß2M was observed in 258 (65.3%) and 235 (59.5%) of 395 stage II and III GCs, respectively. Negative HLA I expression was significantly associated with aggressive clinicopathologic features. Furthermore, negative expression of HLA A/B/C and ß2M was inversely correlated with CD8-positive cytotoxic T cell infiltration, EBV-positivity, and PD-L1 expression (all p < 0.001). Patients with HLA A/B/C-negative GC had worse overall survival (OS) (p = 0.019) and combined analysis with both HLA A/B/C and ß2M expression status significantly predicted OS in univariate (p = 0.004) and multivariate survival analysis (p = 0.016). Negative expression of HLA A/B/C and ß2M was frequently observed in stage II and III GCs, particularly with the aggressive clinicopathologic features, and correlated with an unfavorable prognosis and host immune response status. These findings contribute to further development of immunotherapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Antígenos HLA/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Gástricas/patologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/imunologia , Feminino , Seguimentos , Antígenos HLA/imunologia , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/cirurgia , Adulto Jovem , Microglobulina beta-2/imunologia , Microglobulina beta-2/metabolismo
5.
Medicine (Baltimore) ; 98(39): e17221, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574832

RESUMO

To investigate the clinicopathological features and prognostic impact of Fusobacterium nucleatum (F nucleatum) status in patients with colorectal cancer (CRC) and its relationships with microsatellite instability (MSI) status.Retrospective analysis of consecutive 91 CRC tissues from surgically resected specimens of stage III or high-risk stage II CRC patients who had received curative surgery in Wuhan Union Hospital from January, 2017 to January, 2019 was conducted. F nucleatum DNA was quantitatively measured and classified into 1 of the 2 categories: F nucleatum-high, or F nucleatum-low/negative. The Cox risk ratio model analysis was performed to identify independent risk factors of F nucleatum. F nucleatum-high group was compared with the F nucleatum-low/negative group with respect to clinicopathological features and their relationships with MSI status. Kaplan-Meier method and log-rank test were used for univariate analysis of prognostic factors in patients with CRC.The number of total lymph node acquisition and positive lymph nodes, neurological invasion, vascular tumor thrombus were higher in F nucleatum-high group (27.44 ±â€Š25.213 vs 20.70 ±â€Š10.141; P = .018; 3.80 ±â€Š7.974 vs 1.74 ±â€Š3.531; P = .001; 68.0% vs 33.3%; P = .003; 60.0% vs 25.8%; P = .002). Moreover, microsatellite mutations were more frequent in patients with F nucleatum-high (84.0% vs 60.6%; P = .034). A higher abundance of F nucleatum in CRC is associated with a shorter survival time. The F nucleatum status, peripheral nerve invasion, vascular tumor thrombus, lymph node metastasis, and TNM staging were related factors affecting the prognosis of patients with CRC. The Cox risk ratio model analysis showed that the F nucleatum (odds ratio [OR] 2.094, 95% confidence interval [CI] 1.178-8.122, P = .032) and MSI status (OR 2.243, 95% CI 1.136-5.865, P = 0.039) were independent prognostic factors.Intratumoral F nucleatum load has a poor prognostic effect of CRC by increasing nerve invasion, vascular tumor thrombus, and microsatellite mutation.


Assuntos
Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/mortalidade , Fusobacterium nucleatum , Idoso , Carga Bacteriana , Neoplasias Colorretais/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfonodos/microbiologia , Linfonodos/patologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco
6.
J Cancer Res Clin Oncol ; 145(12): 2891-2899, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31617076

RESUMO

PURPOSE: Microsatellites are widely distributed repetitive DNA motifs, accounting for approximately 3% of the genome. Due to mismatch repair system deficiency, insertion or deletion of repetitive units often occurs, leading to microsatellite instability. In this review, we aimed to explore the relationship between MSI and biological behaviour of colorectal carcinoma, gastric carcinoma, lymphoma/leukaemia and endometrial carcinoma, as well as the application of frameshift peptide vaccines in cancer therapy. METHODS: The relevant literature from PubMed and Baidu Xueshu were reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic. RESULTS: Microsatellite instability is divided into three subtypes: high-level, low-level microsatellite instability, and stable microsatellites. The majority of tumour patients with high-level microsatellite instability often show a better efficacy and prognosis than those with low-level microsatellite instability or stable microsatellites. In coding regions, especially for genes involved in tumourigenesis, microsatellite instability often results in inactivation of proteins and contributes to tumourigenesis. Moreover, the occurrence of microsatellite instability in coding regions can also cause the generation of frameshift peptides that are thought to be unknown and novel to the individual immune system. Thus, these frameshift peptides have the potential to be biomarkers to raise tumour-specific immune responses. CONCLUSION: MSI has the potential to become a key predictor for evaluating the degree of malignancy, efficacy and prognosis of tumours. Clinically, MSI patterns will provide more valuable information for clinicians to create optimal individualized treatment strategies based on frameshift peptides vaccines.


Assuntos
Mutação da Fase de Leitura/genética , Repetições de Microssatélites/genética , Neoplasias/genética , Animais , Carcinogênese/genética , Ensaios Clínicos como Assunto , Reparo de Erro de Pareamento de DNA/genética , Humanos , Instabilidade de Microssatélites , Prognóstico
7.
BMC Genomics ; 20(1): 769, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646964

RESUMO

BACKGROUND: Microsatellite instability (MSI) accounts for about 15% of colorectal cancer and is associated with prognosis. Today, MSI is usually detected by polymerase chain reaction amplification of specific microsatellite markers. However, the instability is identified by comparing the length of microsatellite repeats in tumor and normal samples. In this work, we developed a qualitative transcriptional signature to individually predict MSI status for right-sided colon cancer (RCC) based on tumor samples. RESULTS: Using RCC samples, based on the relative expression orderings (REOs) of gene pairs, we extracted a signature consisting of 10 gene pairs (10-GPS) to predict MSI status for RCC through a feature selection process. A sample is predicted as MSI when the gene expression orderings of at least 7 gene pairs vote for MSI; otherwise the microsatellite stability (MSS). The classification performance reached the largest F-score in the training dataset. This signature was verified in four independent datasets of RCCs with the F-scores of 1, 0.9630, 0.9412 and 0.8798, respectively. Additionally, the hierarchical clustering analyses and molecular features also supported the correctness of the reclassifications of the MSI status by 10-GPS. CONCLUSIONS: The qualitative transcriptional signature can be used to classify MSI status of RCC samples at the individualized level.


Assuntos
Neoplasias do Colo/genética , Instabilidade de Microssatélites , Transcriptoma , Algoritmos , Análise por Conglomerados , Biologia Computacional , Humanos
8.
Zhonghua Zhong Liu Za Zhi ; 41(10): 734-741, 2019 Oct 23.
Artigo em Chinês | MEDLINE | ID: mdl-31648494

RESUMO

Microsatellite instability (MSI) which resulted from the deficiency of DNA mismatch repair (MMR), is an important clinical significance in the related solid tumors, such as colorectal cancer and endometrial cancer. There are several methods to detect MSI status, including immunohistochemistry for MMR protein, multiplex fluorescent polymerase chain reaction (PCR) for microsatellite site and MSI algorithm based on next generation sequencing (NGS). The consensus elaborates the definition and clinical significance of MSI as well as the advantages and disadvantages of the three detection methods. Through this expert consensus, we hope to promote the screening which based on MSI status in malignant tumors and improve the acknowledge of clinicians about various testing methods. Thereby, they could interpret the results more accurately and provide better clinical services to patients.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Colorretais/genética , Consenso , Assistência à Saúde/normas , Instabilidade de Microssatélites , Guias de Prática Clínica como Assunto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , China , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA , Sequência de DNA Instável , Neoplasias do Endométrio , Feminino , Humanos , Imuno-Histoquímica , Repetições de Microssatélites , Microscopia de Fluorescência , Reação em Cadeia da Polimerase
9.
J Cancer Res Clin Oncol ; 145(12): 3005-3019, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31650222

RESUMO

BACKGROUND: The role of tumour-associated macrophages (TAMs) in predicting the prognosis of colorectal cancer (CRC) remains controversial. This is especially so because the prognostic significance and clinicopathological relevance of different subtypes of TAMs in the immune microenvironment of CRC have not yet been established. OBJECTIVE: To assess the clinicopathological and prognostic value of pan-macrophages, M1-macrophages or M2-macrophages in patients with CRC. METHODS: Comprehensive searched on the Medline/PubMed, Web of Science (WoS) and Google Scholar databases was conducted to identify relevant studies published up to April 2019. The association between overall survival (OS), cancer-specific survival (CSS) or disease-free survival (DFS) and TAMs was analysed by meta-analysis. RESULTS: A total of 3749 patients from 17 studies were included. The pooled hazard ratios (HRs) indicated that high-density pan-macrophages improved OS (HR 0.67, P = 0.02). The pooled HR for M2-macrophages showed that high M2-macrophages infiltration was significantly associated with shorter OS (HR 2.93, P < 0.0001) and DFS (HR 2.04, P = 0.02). The pooled odds ratios (ORs) revealed that high-density TAMs was associated with high CD8+ T cell infiltration (OR 2.04, P = 0.007), no distant metastasis (NDM) (OR 0.38, P < 0.0001), microsatellite instability-high (MSI-H) (OR 0.38, P = 0.001), no lymph node metastasis (NLNM) (OR 0.54, P = 0.0002) and non-mucinous cancer (OR 0.39, P < 0.00001). CONCLUSIONS: Unlike other solid tumours, high-density CD68+ macrophage infiltration can be a good prognostic marker for CRC. However, when macrophages act as targets of combination therapy in CRC treatment, this might be more effective for CRC patients with high CD8+ T cell infiltrate, NDM, MSI-H, NLNM and non-mucinous cancer.


Assuntos
Neoplasias Colorretais/patologia , Macrófagos/patologia , Animais , Intervalo Livre de Doença , Humanos , Metástase Linfática/patologia , Instabilidade de Microssatélites , Razão de Chances , Fenótipo , Prognóstico , Modelos de Riscos Proporcionais , Microambiente Tumoral/fisiologia
10.
Cancer Sci ; 110(11): 3415-3423, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513320

RESUMO

Anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy, which is one of the most promising cancer therapies, is licensed for treating various tumors. Programmed death-ligand 1, which is expressed on the surface of cancer cells, leads to the inhibition of T lymphocyte activation and immune evasion if it binds to the receptor PD-1 on CTLs. Anti-PD-1/PD-L1 Abs inhibit interactions between PD-1 and PD-L1 to restore antitumor immunity. Although certain patients achieve effective responses to anti-PD-1/PD-L1 therapy, the efficacy of treatment is highly variable. Clinical trials of anti-PD-1/PD-L1 therapy combined with radiotherapy/chemotherapy are underway with suggestive evidence of favorable outcome; however, the molecular mechanism is largely unknown. Among several molecular targets that can influence the efficacy of anti-PD-1/PD-L1 therapy, PD-L1 expression in tumors is considered to be a critical biomarker because there is a positive correlation between the efficacy of combined treatment protocols and PD-L1 expression levels. Therefore, understanding the mechanisms underlying the regulation of PD-L1 expression in cancer cells, particularly the mechanism of PD-L1 expression following DNA damage, is important. In this review, we consider recent findings on the regulation of PD-L1 expression in response to DNA damage signaling in cancer cells.


Assuntos
Antígeno B7-H1/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Neoplasias/metabolismo , Medicina de Precisão , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Comunicação Celular , Pontos de Checagem do Ciclo Celular , Morte Celular/fisiologia , Dano ao DNA , Fragmentação do DNA , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/efeitos da radiação , Humanos , Ativação Linfocitária , Proteínas de Membrana/metabolismo , Instabilidade de Microssatélites , Mutação , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapia , Nucleotidiltransferases/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA Mensageiro/metabolismo , Evasão Tumoral , Regulação para Cima
11.
Magy Onkol ; 63(3): 192-195, 2019 Sep 18.
Artigo em Húngaro | MEDLINE | ID: mdl-31533138

RESUMO

Colorectal carcinomas are heterogeneous in their morphologic, immunologic and molecular aspects. The smooth and sharply demarcated medullary carcinomas present with an expansive border and high tumor stroma ratio. The high load of cancer neoantigens as a consequence of microsatellite instability results in numerous reactive regional lymph nodes. In contrast, the low grade, MSS type carcinomas are spiculated, desmoplastic and hard, frequently with smaller and sometimes also desmoplastic lymph node metastases. This macroscopic and histological heterogeneity is mirrored on the immunohistochemical and molecular level and is decisive from prognostic and predictive point of view. As immunotherapy opened a new front in the therapy of colorectal cancer, the pathology report has to quantify and qualify the characteristics of the tumor microenvironment, the peritumoral and intratumoral lymphoid infiltration and tumor stroma ratio in order to improve patient selection.


Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/terapia , Imunoterapia , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Humanos , Metástase Linfática , Instabilidade de Microssatélites , Prognóstico , Microambiente Tumoral
12.
Semin Oncol ; 46(3): 261-270, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31537299

RESUMO

Deficient DNA mismatch repair causes a robust mutator phenotype known as microsatellite instability (MSI). MSI is a feature of Lynch syndrome-related cancers and is also found in approximately 15% of sporadic gastric, colorectal, and endometrial cancers. Epigenetic inactivation of the MLH1 gene is often associated with sporadic MSI cancers. Recent next-generation sequencing (NGS)-based analyses have comprehensively characterized MSI-positive (MSI+) cancers, and several approaches for detecting the MSI phenotype of tumors using NGS have been developed. The FDA has recently granted accelerated approval to an anti-PD-1 antibody, pembrolizumab, for use in pediatric and adult patients with MSI+ solid tumors. Genome-wide analyses using NGS have revealed that hypermutation defined as >10 somatic mutations per megabase appears to be more prevalent than previously estimated, affecting approximately 17% of adult cancers. These results potentially expand the use of immunotherapy, which is thought to be effective in cancers with an increased mutational burden. Therefore, evaluation of MSI and MSI-associated molecular changes in tumors has emerged as clinically important. MSI is a valuable diagnostic marker of Lynch syndrome and a potential predictive marker for chemotherapy and immunotherapy efficacy. Here, we provide an update on MSI-associated cancers, focusing on findings obtained by genome-wide analyses using NGS, and the predictive role of MSI in immune checkpoint immunotherapy.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL/genética , Neoplasias/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Medicina de Precisão , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
13.
Gynecol Oncol ; 155(2): 374-383, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31472940

RESUMO

BACKGROUND: After The Cancer Genome Atlas (TCGA) findings, four novel prognostic groups may direct the management of endometrial cancer (EC): POLE-mutated/ultramutated (POLEmt), microsatellite-instable/hypermutated (MSI), copy-number-low/p53-wild-type (p53wt), and copy-number-high/p53-mutated (p53mt). However, data about prognosis in each group are different across the studies, and definitive pooled estimates are lacking after validation series. Such data may be crucial in directing clinical study design and establishing the optimal tailored management of patients. AIM: To provide pooled estimates of hazard ratio (HR) for overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS) in each prognostic group. MATERIALS AND METHODS: A systematic review and meta-analysis was performed by searching 7 electronic databases, from their inception to April 2019, for studies assessing prognosis in each TCGA EC group. Both univariable and multivariable HR analysis was performed for OS, DSS and PFS in each group, using p53wt as reference group. RESULTS: Six studies with 2818 patients were included. Regarding OS, pooled HRs were 3.179 and 1.986 for p53mt group, 1.522 and 1.192 for MSI group, and 0.589 and 0.795 for POLEmt group at univariable and multivariable analyses, respectively. Regarding DSS, pooled HR were 5.052 and 2.133 for p53mt group, 1.965 and 1.068 for MSI group, and 0.552 and 0.325 for POLEmt group at univariable and multivariable analyses, respectively. Regarding PFS, pooled HR were 3.512 and 1.833 for p53mt group, 1.354 and 0.817 for MSI group, and 0.287 and 0.217 for POLEmt group at univariable and multivariable analyses, respectively. CONCLUSIONS: Prognosis of p53mt group is consistently the worst one and is further worsened by unfavorable clinicopathological factors. Prognosis of MSI group overlaps with p53wt group but is worsened by unfavorable clinicopathological factors. Prognosis of POLEmt group is the best one and does not seem to be significantly affected by clinicopathological factors.


Assuntos
Neoplasias do Endométrio/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Endométrio/genética , Métodos Epidemiológicos , Feminino , Genoma Humano , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , Proteína Supressora de Tumor p53/metabolismo
15.
Cancer Sci ; 110(9): 2894-2904, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31348579

RESUMO

Nivolumab is a human monoclonal antibody against the immune checkpoint receptor programmed death-1, inhibiting binding to programmed death-ligand 1 or 2 (PD-L1 or PD-L2). This phase 2 study evaluated the efficacy and safety of nivolumab in patients with advanced/recurrent uterine cervical cancer, uterine corpus cancer, or soft tissue sarcoma (STS). Patients received nivolumab 240 mg at 2-week intervals. Primary endpoint was objective response rate; secondary endpoints included overall survival, progression-free survival, and safety. PD-L1 expression and microsatellite-instability (MSI) status were analyzed as potential efficacy biomarkers. Objective response rate was 25%, 23%, and 0% in patients with cervical cancer (n = 20), corpus cancer (n = 22), and STS (n = 21), respectively. The lower 80% confidence intervals of objective response rates in patients with cervical or corpus cancer exceeded the threshold rate (5%); the primary endpoint was met in cervical and corpus cancer, but not in STS. Median progression-free survival was 5.6, 3.4, and 1.4 months, and 6-month overall survival was 84%, 73%, and 86% in cervical cancer, corpus cancer, and STS, respectively. The objective response rate was higher in patients with cervical cancer with PD-L1-positive (n = 5/15; 33%) versus PD-L1-negative (n = 0/5; 0%) tumors. The two patients with corpus cancer classified as MSI-high responded; the six patients classified as microsatellite stable did not respond. Overall, nivolumab showed acceptable toxicity in all cohorts, with evidence of clinical activity in uterine cervical or corpus cancer, but not in STS. PD-L1 expression in cervical cancer and MSI-high in corpus cancer may predict clinical activity of nivolumab in these cancers.


Assuntos
Antineoplásicos/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Nivolumabe/administração & dosagem , Sarcoma/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antígeno B7-H1/metabolismo , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Japão/epidemiologia , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Intervalo Livre de Progressão , Estudos Prospectivos , Sarcoma/genética , Sarcoma/mortalidade , Sarcoma/patologia , Análise de Sobrevida , Neoplasias Uterinas/genética , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/patologia , Útero/patologia
16.
Gynecol Oncol ; 154(3): 516-523, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31340883

RESUMO

OBJECTIVE: Endometrioid ovarian carcinomas (EOCs) comprise 5-10% of all ovarian cancers and commonly co-occur with synchronous endometrioid endometrial cancer (EEC). We sought to examine the molecular characteristics of pure EOCs in patients without concomitant EEC. METHODS: EOCs and matched normal samples were subjected to massively parallel sequencing targeting 341-468 cancer-related genes (n = 8) or whole-genome sequencing (n = 28). Mutational frequencies of EOCs were compared to those of high-grade serous ovarian cancers (HGSOCs; n = 224) and EECs (n = 186) from The Cancer Genome Atlas, and synchronous EOCs (n = 23). RESULTS: EOCs were heterogeneous, frequently harboring KRAS, PIK3CA, PTEN, CTNNB1, ARID1A and TP53 mutations. EOCs were distinct from HGSOCs at the mutational level, less frequently harboring TP53 but more frequently displaying KRAS, PIK3CA, PIK3R1, PTEN and CTNNB1 mutations. Compared to synchronous EOCs and pure EECs, pure EOCs less frequently harbored PTEN, PIK3R1 and ARID1A mutations. Akin to EECs, EOCs could be stratified into the four molecular subtypes: 3% POLE (ultramutated), 19% MSI (hypermutated), 17% copy-number high (serous-like) and 61% copy-number low (endometrioid). In addition to microsatellite instability, a subset of EOCs harbored potentially targetable mutations, including AKT1 and ERBB2 hotspot mutations. EOCs of MSI (hypermutated) subtype uniformly displayed a good outcome. CONCLUSIONS: EOCs are heterogeneous at the genomic level and harbor targetable genetic alterations. Despite the similarities in the repertoire of somatic mutations between pure EOCs, synchronous EOCs and EECs, the frequencies of mutations affecting known driver genes differ. Further studies are required to define the impact of the molecular subtypes on the outcome and treatment of EOC patients.


Assuntos
Carcinoma Endometrioide/classificação , Carcinoma Epitelial do Ovário/classificação , Neoplasias Ovarianas/classificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso/classificação , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Análise Mutacional de DNA , Feminino , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Intervalo Livre de Progressão , Estudos Retrospectivos
17.
J Clin Pathol ; 72(11): 762-770, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31256008

RESUMO

AIMS: Knowledge regarding the genetic features of ampullary carcinoma (AC) in European patients is limited. The utility of tumour markers for the establishment of a malignant diagnosis in biopsies from the ampullary region has not been fully elucidated. We aimed to describe the clinical, pathological, immunohistochemical (IHC) and genetic features of a Danish series of surgically resected ACs. METHODS: Surgically resected ACs (n=59) were examined regarding (1) clinicopathological features, (2) histological subtypes, (3) expression of IMP3, maspin, MUC5AC and S100P and (4) next-generation sequencing using a hybrid capture-based platform (Illumina HiSeq2500), including 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer. Tumour mutational burden (TMB) and microsatellite instability (MSI) were also evaluated. RESULTS: Pancreatobiliary adenocarcinomas (PB-AC), intestinal adenocarcinomas (INT-AC), other ampullary tumours and mixed adenocarcinomas represented 45.8%, 23.7%, 16.9% and 13.6%. The proportion of IHC-positive ACs (score ≥2) was: Maspin (94.9%), IMP3 (67.8%), S100P (39.0%) and MUC5AC (18.6%). Most frequently altered genes were TP53 (59.3%), KRAS (40.7%), APC (27.8%), SMAD4 (20.4%), CDKN2A (16.7%) and ARID2/PIK3CA (each 11.1%). MUC5AC and S100P were frequently expressed in PB-AC, APC alterations frequent in INT-AC, SOX9 alterations were exclusive in INT-AC and MDM2 and FRS2 alterations in PB-AC. Four of 49 ACs (8.2%) were TMB-high/MSI-high and showed loss of MLH1 and PMS2. CONCLUSIONS: PB-AC was the most frequent histological subtype of AC. Maspin and IMP3 were the IHC tumour markers with the highest sensitivity. Adenocarcinoma subtypes differed regarding several genetic alterations, whose predictive value remains to be evaluated.


Assuntos
Adenocarcinoma/química , Adenocarcinoma/genética , Ampola Hepatopancreática/química , Biomarcadores Tumorais , Neoplasias do Sistema Digestório/química , Neoplasias do Sistema Digestório/genética , Perfilação da Expressão Gênica , Imuno-Histoquímica , Mutação , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Ampola Hepatopancreática/patologia , Ampola Hepatopancreática/cirurgia , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Proteínas de Ligação ao Cálcio/análise , Proteínas de Ligação ao Cálcio/genética , Dinamarca , Neoplasias do Sistema Digestório/patologia , Neoplasias do Sistema Digestório/cirurgia , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mucina-5AC/análise , Mucina-5AC/genética , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/genética , Fenótipo , Valor Preditivo dos Testes , Sistema de Registros , Ribonucleoproteínas Nucleolares Pequenas/análise , Ribonucleoproteínas Nucleolares Pequenas/genética , Serpinas/análise , Serpinas/genética
18.
Gynecol Oncol ; 154(3): 461-466, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31257009

RESUMO

OBJECTIVES: To assess whether comprehensive genomic profiling (CGP) in the setting of routine clinical care allows molecular classification of recurrent endometrial cancer (EC) into the four Cancer Genome Atlas (TCGA) categories: POLE ultramutated, microsatellite instable, copy-number low, and copy-number high and whether this approach can identify genomic alterations (GAs) which inform treatment decisions. METHODS: Archival tissues from 74 patients diagnosed with recurrent EC were prospectively analyzed using hybrid-capture-based genomic profiling. Tumor mutational burden and microsatellite instability were measured. Clinically relevant GAs (CRGAs) were defined as GAs associated with targeted therapies available on-label or in mechanism-driven clinical trials. RESULTS: Using POLE mutational analysis, mismatch repair status, and p53 mutational analysis as surrogate for 'copy-number' status CGP segregated all cases into four TCGA molecular subgroups. While recurrent serous ECs were predominantly copy-number high, we found no clear prevalence of a specific molecular subtype in endometrioid, clear cell or undifferentiated tumors. Every tumor sample had at least one GA and 91% (67/74) had at least one CRGA. In this series 32% (24/74) of patients received a matched therapy based on the results of CGP. Objective responses to the matched therapy were seen in 25% (6/24) of patients with an additional 37.5% (9/24) achieving stable disease leading to a clinical benefit rate of 62.5% with a median treatment duration of 14.6 months (range 4.3-69 months). CONCLUSIONS: CGP allows molecular classification of EC into four TCGA categories and allows identification of potential biomarkers for matched therapy in the setting of routine clinical care.


Assuntos
Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Neoplasias do Endométrio/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos
19.
Nat Commun ; 10(1): 2977, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278255

RESUMO

Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. To define the biological features driving this phenotype, we performed an integrated analysis of whole-exome and RNA sequencing of UTUC. Here we report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-papillary; 2) UTUC has a T-cell depleted immune contexture; 3) High FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immune microenvironment; 4) Sporadic UTUC is characterized by a lower total mutational burden than urothelial carcinoma of the bladder. Our findings lay the foundation for a deeper understanding of UTUC biology and provide a rationale for the development of UTUC-specific treatment strategies.


Assuntos
Carcinoma de Células de Transição/patologia , Neoplasias Renais/patologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Linfócitos T/imunologia , Neoplasias Ureterais/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/imunologia , Análise Mutacional de DNA , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Análise de Sequência de RNA , Transdução de Sinais/genética , Microambiente Tumoral/imunologia , Neoplasias Ureterais/genética , Neoplasias Ureterais/imunologia , Urotélio/patologia , Sequenciamento Completo do Exoma
20.
Expert Opin Pharmacother ; 20(14): 1767-1775, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31314604

RESUMO

Introduction: The liver is the most common metastatic site in colorectal cancer with more than half the patients developing a liver metastasis either at the time of their diagnosis (synchronous) or later (metachronous). Surgical resection remains the principal curative approach that offers significant survival improvements. However, upfront surgery is only possible in about 10-20% of patients at the time of diagnosis, making the consideration of other treatment modalities essential. Areas covered: In this review, the authors provide an overview of the standard approaches for the initial management of patients with colorectal cancer with liver metastases. They then provide an up-to-date discussion of first-line systemic chemotherapy/targeted therapy options in the contexts of initially resectable and unresectable disease and review toxicities and complications following these options. Expert opinion: Advances in chemotherapeutic agents and biological targeted therapies have improved the prognosis of colorectal cancer with liver metastases. However, there is still no 'single best approach', making further trials necessary to provide more evidence.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/patologia , Antineoplásicos/efeitos adversos , Bevacizumab/efeitos adversos , Bevacizumab/uso terapêutico , Neoplasias Colorretais/patologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Instabilidade de Microssatélites , Terapia Neoadjuvante , Prognóstico
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