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1.
Int J Mol Sci ; 25(20)2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39456850

RESUMO

The efficacy and cost-effectiveness of Multigene Panel Next-Generation Sequencing (NGS) in directing patients towards genomically matched therapies remain uncertain. This study investigated metastatic colorectal cancer (mCRC) patients who underwent NGS analysis on formalin-fixed paraffin-embedded tumor samples. Data from 179 patients were analyzed, revealing no mutations in 39 patients (21.8%), one mutation in 83 patients (46.4%), and two or more mutations in 57 patients (31.8%). KRAS mutations were found in 87 patients (48.6%), including KRAS G12C mutations in 5 patients (2.8%), PIK3CA mutations in 40 patients (22.4%), and BRAF mutations in 26 patients (14.5%). Less common mutations were identified: ERBB2 in five patients (2.8%) and SMO in four patients (2.2%). Additionally, MAP2K1, CTNNB1, and MYC were mutated in three patients (2.4%). Two mutations (1.1%) were observed in ERBB3, RAF1, MTOR, JAK1, and FGFR2. No significant survival differences were observed based on number of mutations. In total, 40% of patients had druggable molecular alterations, but only 1.1% received genomically guided treatment, suggesting limited application in standard practice. Despite this, expanded gene panel testing can identify actionable mutations, aiding personalized treatment strategies in metastatic CRC, although current eligibility for biomarker-guided trials remains limited.


Assuntos
Neoplasias Colorretais , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Medicina de Precisão , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Medicina de Precisão/métodos , Adulto , Idoso de 80 Anos ou mais , Metástase Neoplásica , Biomarcadores Tumorais/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
2.
Lancet Oncol ; 24(1): 91-106, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36436516

RESUMO

BACKGROUND: Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype-phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. METHODS: This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype-phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. FINDINGS: From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1-93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66-57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18-29·39], p=0·0017) and gastric cancer (7·81 [2·03-29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004). INTERPRETATION: CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria. FUNDING: European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme.


Assuntos
Neoplasias da Mama , Carcinoma Lobular , Neoplasias Gástricas , Feminino , Humanos , Antígenos CD/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/genética , Predisposição Genética para Doença , Genótipo , Células Germinativas/patologia , Mutação em Linhagem Germinativa , Linhagem , Fenótipo , Estudos Retrospectivos , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/genética , Mutação de Sentido Incorreto
3.
Int J Mol Sci ; 24(15)2023 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-37569793

RESUMO

Subjects with pathogenic (PV) and likely pathogenic (LPV) FLCN variants have an increased risk of manifesting benign and malignant disorders that are related to Birt-Hogg-Dubé syndrome (BHDS): an autosomal dominantly inherited disorder whose severity can vary significantly. Renal cell carcinoma (RCC) development in BHD (Birt-Hogg-Dubé) patients has a very high incidence; thus, identifying this rare syndrome at early stages and preventing metastatic spread is crucial. Over the last decade, the advancement of Next Generation Sequencing (NGS) and the implementation of multigene panels for hereditary cancer syndromes (HCS) have led to a subsequent focus on additional genes and variants, including those of uncertain significance (VUS). Here, we describe a novel FLCN variant observed in a subject manifesting disorders that were suspected to be related to BHDS and with a family history of multiple cancers.


Assuntos
Síndrome de Birt-Hogg-Dubé , Carcinoma de Células Renais , Neoplasias Renais , Síndromes Neoplásicas Hereditárias , Humanos , Síndrome de Birt-Hogg-Dubé/genética , Síndrome de Birt-Hogg-Dubé/patologia , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Neoplasias Renais/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética
4.
Int J Mol Sci ; 23(24)2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36555431

RESUMO

BRCA1 and BRCA2 are the most frequently mutated genes in ovarian cancer (OC) crucial both for the identification of cancer predisposition and therapeutic choices. However, germline variants in other genes could be involved in OC susceptibility. We characterized OC patients to detect mutations in genes other than BRCA1/2 that could be associated with a high risk of developing OC and permit patients to enter the most appropriate treatment and surveillance program. Next-generation sequencing analysis with a 94-gene panel was performed on germline DNA of 219 OC patients. We identified 34 pathogenic/likely pathogenic variants in BRCA1/2 and 38 in other 21 genes. The patients with pathogenic/likely pathogenic variants in the non-BRCA1/2 genes mainly developed OC alone compared to the other groups that also developed breast cancer or other tumors (p = 0.001). Clinical correlation analysis showed that the low-risk patients were significantly associated with platinum sensitivity (p < 0.001). Regarding PARP inhibitors (PARPi) response, the patients with pathogenic mutations in the non-BRCA1/2 genes had worse PFS and OS. Moreover, a statistically significantly worse PFS was found for every increase of one thousand platelets before PARPi treatment. To conclude, knowledge about molecular alterations in genes beyond BRCA1/2 in OC could allow for more personalized diagnostic, predictive, prognostic, and therapeutic strategies for OC patients.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Humanos , Feminino , Predisposição Genética para Doença , Proteína BRCA1/genética , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Genes BRCA2 , Mutação em Linhagem Germinativa , Neoplasias da Mama/genética , Sequenciamento de Nucleotídeos em Larga Escala
5.
Br J Cancer ; 125(9): 1226-1232, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34333554

RESUMO

BACKGROUND: In a Phase 2 clinical trial, we aimed to determine the lutetium-177 [177Lu]-PSMA-617 activity and the clinical utility of levels of plasma androgen receptor (AR) gene in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). METHODS: We determined AR copy number in pretreatment plasma samples. We used logistic regression to estimate the odds ratio (OR) and 95% confidence intervals (95% CIs) in order to evaluate the independent relevance of AR status and to evaluate patients with early progressive disease (PD) defined as treatment interruption occurring within 4 months after the start of 177Lu-PSMA-617. RESULTS: Twelve of the 15 (80%) with AR gene gain and 5 of the 25 (20%) patients with no gain of AR had early PD (p = 0.0002). The OR for patients without PSA response having AR gain was 3.69 (95% CI 0.83-16.36, p = 0.085). The OR for patients with early PD having AR gain was 16.00, (95% CI 3.23-79.27, p = 0.0007). Overall, median PFS and OS were 7.5 and 12.4 months, respectively. AR-gained had a significant shorter OS compared to AR-normal patients (7.4 vs 19.1 months, p = 0.020). No treatment interruptions due to adverse effects were reported. DISCUSSION: Plasma AR status helped to indicate mCRPC with early resistance to 177Lu-PSMA-617. TRIAL REGISTRATION: NCT03454750.


Assuntos
Dipeptídeos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Amplificação de Genes , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Antígeno Prostático Específico/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Dipeptídeos/química , Compostos Heterocíclicos com 1 Anel/química , Humanos , Modelos Logísticos , Lutécio/química , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Antígeno Prostático Específico/química , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Radioisótopos/química , Receptores Androgênicos/sangue , Análise de Sobrevida
6.
BMC Cancer ; 21(1): 611, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34034685

RESUMO

BACKGROUND: Pancreatic cancer (PC) is a major cause of cancer death. In an effort to improve treatment strategies and outcomes, DNA damage repair (DDR) pathways have been introduced as a new target in PC and in other cancers, through the exploitation of synthetic lethality. Furthermore, genes involved in DDR are among the major determinants of cancer susceptibility. In addition to the well-known BRCA1 and BRCA2 genes, a plethora of other targets in the same pathways are now emerging. METHODS: We analyzed samples from 60 patients, affected by PC and already tested for BRCA, using a panel with 24 other cancer susceptibility genes. RESULTS: We detected 8 pathogenic or likely pathogenic mutations (13.3% of samples analyzed), 4 of which were found in non-BRCA genes (2 in ATM, 1 each in PALB2 and RAD50). Furthermore, 4 pathogenic or likely pathogenic mutations were found in patients without a personal or familial history of cancer. CONCLUSIONS: Our results suggest that genetic testing with a comprehensive gene panel should be perfomed in all patients with PC, in order to allow screening for PC and other gene-related cancers in all at risk family members and to assess patients' eligibility for emerging therapeutic options.


Assuntos
Biomarcadores Tumorais/genética , Reparo do DNA , Detecção Precoce de Câncer/métodos , Testes Genéticos/métodos , Neoplasias Pancreáticas/diagnóstico , Hidrolases Anidrido Ácido/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Dano ao DNA , Análise Mutacional de DNA/estatística & dados numéricos , Proteínas de Ligação a DNA/genética , Detecção Precoce de Câncer/estatística & dados numéricos , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Testes Genéticos/estatística & dados numéricos , Humanos , Masculino , Anamnese , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética
7.
BMC Cancer ; 20(1): 191, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143595

RESUMO

BACKGROUND: This case represents the first report of malignant primary cardiac tumour in a patient with Lynch Syndrome associated with MSH2 pathogenic variant. CASE PRESENTATION: A 57-year-old woman with previous ovarian cystadenocarcinoma was admitted to the emergency room for hematic pericardial effusion. Multimodal diagnostic imaging revealed two solid pericardial vascularized masses. After pericardiectomy, the final histological diagnosis was poorly differentiated pleomorphic sarcomatoid carcinoma. During follow-up she developed an ampulla of Vater adenocarcinoma. Genetic analysis identified an MSH2 pathogenic variant. CONCLUSION: This case contributes to expand the tumour spectrum of Lynch syndrome, suggesting that MSH2 pathogenic variants cause a more complex multi-tumour cancer syndrome than the classic Lynch Syndrome. In MSH2 variant carriers, symptoms such as dyspnoea and chest discomfort might alert for rare tumours and a focused cardiac evaluation should be considered.


Assuntos
Adenocarcinoma/complicações , Ampola Hepatopancreática/patologia , Carcinoma/complicações , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Cardíacas/complicações , Proteína 2 Homóloga a MutS/genética , Derrame Pericárdico/complicações , Pericárdio/patologia , Carcinoma/cirurgia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Seguimentos , Mutação em Linhagem Germinativa , Neoplasias Cardíacas/cirurgia , Humanos , Pessoa de Meia-Idade , Linhagem , Pericardiectomia , Pericárdio/cirurgia , Resultado do Tratamento
8.
Int J Mol Sci ; 21(10)2020 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-32429465

RESUMO

Very few data are reported in the literature on the association between elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) and prognosis in advanced colorectal cancer. Moreover, there is no information available in relation to the response to antiangiogenic treatment. We analyzed EMAST and vascular endothelial growth factor-B (VEGF-B) microsatellite status, together with standard microsatellite instability (MSI), in relation to prognosis in 141 patients with metastatic colorectal cancer (mCRC) treated with chemotherapy (CT) alone (n = 51) or chemotherapy with bevacizumab (B) (CT + B; n = 90). High MSI (MSI-H) was detected in 3% of patients and was associated with progression-free survival (PFS; p = 0.005) and overall survival (OS; p < 0.0001). A total of 8% of cases showed EMAST instability, which was associated with worse PFS (p = 0.0006) and OS (p < 0.0001) in patients treated with CT + B. A total of 24.2% of patients showed VEGF-B instability associated with poorer outcome in (p = 0.005) in the CT arm. In conclusion, our analysis indicated that EMAST instability is associated with worse prognosis, particularly evident in patients receiving CT + B.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/secundário , Instabilidade de Microssatélites , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Feminino , Humanos , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Resultado do Tratamento , Fator B de Crescimento do Endotélio Vascular/genética
9.
Int J Cancer ; 145(2): 390-400, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30613976

RESUMO

Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well-characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non-BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer-associated genes. The main clinical-pathologic characteristics of MBC in pathogenic variant carriers and non-carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 non-BRCA1/2 MBC patients were examined in our study. Twenty-seven of the non-BRCA1/2 MBC patients were carriers of germline pathogenic variants in other genes, including two APC p.Ile1307Lys variant carriers and one MUTYH biallelic variant carrier. PALB2 was the most frequently altered gene (1.2%) and PALB2 pathogenic variants were significantly associated with high risk of MBC. Non-BRCA1/2 pathogenic variant carriers were more likely to have personal (p = 0.0005) and family (p = 0.007) history of cancer. Results of our study support a central role of PALB2 in MBC susceptibility and show a low impact of CHEK2 on MBC predisposition in the Italian population. Overall, our data indicate that a multigene testing approach may benefit from appropriately selected patients with implications for clinical management and counseling of MBC patients and their family members.


Assuntos
Neoplasias da Mama Masculina/genética , Quinase do Ponto de Checagem 2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Mutação , Análise de Sequência de DNA/métodos , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , DNA Glicosilases/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Int J Colorectal Dis ; 34(11): 1999-2002, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31655866

RESUMO

BACKGROUND: Lynch syndrome (LS) is associated with germline mutations in one of the mismatch repair genes or EPCAM. The majority of the causative alterations are point mutations. Large genomic rearrangements represent only 5-20%. Hypothetically, the allelic imbalance, like the loss of heterozygosity, may be another high penetrance risk factor. CASE PRESENTATION: We describe the case of a patient who developed 5 tumors during her lifetime and with a family history characterized by a high frequency of tumors associated with LS. The proband was tested for mutations and copy number alterations with a panel of hereditary cancer genes and by SNP array. She showed a 187 Kb duplication including EPCAM and the first 7 exons of MSH2, plus two loss of heterozygosity (LOHs) in chromosome 20 and one in chromosome X which include many tumor suppressor genes. CONCLUSION: We found a novel large EPCAM-MSH2 duplication associated with LS and the presence of LOHs in regions containing numerous tumor suppressors, raising the hypothesis that these alterations could contribute to cancer susceptibility. Our results underline the importance to deepen the knowledge of molecular mechanisms in order to determine the role in cancer predisposition of novel genetic alterations.


Assuntos
Cromossomos Humanos Par 20/genética , Cromossomos Humanos X/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Molécula de Adesão da Célula Epitelial/genética , Duplicação Gênica , Perda de Heterozigosidade/genética , Proteína 2 Homóloga a MutS/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem
11.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509966

RESUMO

CDH1 gene, encoding E-cadherin, is a tumor suppressor gene frequently altered in gastric cancers (GCs) of both diffuse (DGC) and intestinal (IGC) histotypes, albeit through different mechanisms. The study aimed to characterize CDH1 expression in sporadic IGC and to investigate whether microRNAs (miRs) are involved in its transcriptional control. We evaluated CDH1 expression by quantitative real-time PCR (RT-qPCR) in 33 IGC patients and found a significant downregulation in tumor tissues compared to normal counterparts (p-value = 0.025). Moreover, 14 miRs, predicted to be involved in CDH1 regulation in both a direct and indirect manner, were selected and analyzed by RT-qPCR in an independent case series of 17 IGCs and matched normal tissues. miR-101, miR-26b, and miR-200c emerged as significantly downregulated and were confirmed in the case series of 33 patients (p-value < 0.001). Finally, we evaluated EZH2 expression, a target of both miR-101 and miR-26b, which showed significant upregulation in IGCs (p-value = 0.005). A significant inverse correlation was observed between EZH2 overexpression and CDH1, miR-101, and miR-26b levels (p-value < 0.001). Our results reinforce the link between CDH1 and IGC, highlighting the role of miRs in its transcriptional control and improving our understanding of GC subtypes and biomarkers.


Assuntos
Caderinas/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Gástricas/genética , Idoso , Caderinas/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
12.
J Transl Med ; 16(1): 172, 2018 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-29925389

RESUMO

BACKGROUND: In chronic lymphocytic leukemia (CLL) disease onset and progression are influenced by the behavior of specific CD4+ T cell subsets, such as T regulatory cells (Tregs). Here, we focused on the phenotypic and functional characterization of Tregs in CLL patients to improve our understanding of the putative mechanism by which these cells combine immunosuppressive and effector-like properties. METHODS: Peripheral blood mononuclear cells were isolated from newly diagnosed CLL patients (n = 25) and healthy volunteers (n = 25). The phenotypic and functional characterization of Tregs and their subsets was assessed by flow cytometry. In vitro analysis of TH1, TH2, TH17 and Tregs cytokines was evaluated by IFN-γ, IL-4, IL-17A and IL-10 secretion assays. The transcriptional profiling of 84 genes panel was evaluated by RT2 Profiler PCR Array. Statistical analysis was carried out using exact non parametric Mann-Whitney U test. RESULTS: In all CLL samples, we found a significant increase in the frequency of IL-10-secreting Tregs and Tregs subsets, a significant rise of TH2 IL-4+ and TH17 IL-17A+ cells, and a higher percentage of IFN-γ/IL-10 and IL-4/IL-10 double-releasing CD4+ T cells. In addition, we also observed the up-regulation of innate immunity genes and the down-regulation of adaptive immunity ones. CONCLUSIONS: Our data show that Tregs switch towards an effector-like phenotype in CLL patients. This multifaceted behavior is accompanied by an altered cytokine profiling and transcriptional program of immune genes, leading to a dysfunction in immune response in the peripheral blood environment of CLL patients.


Assuntos
Imunossupressores/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Linfócitos T Reguladores/imunologia , Imunidade Adaptativa , Idoso , Idoso de 80 Anos ou mais , Candida albicans/fisiologia , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Imunidade Inata , Interferon gama/metabolismo , Interleucina-23/sangue , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/genética , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Fenótipo
13.
Int J Mol Sci ; 19(1)2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29361687

RESUMO

Targeting angiogenesis in the treatment of colorectal cancer (CRC) is a common strategy, for which potential predictive biomarkers have been studied. miRNAs are small non-coding RNAs involved in several processes including the angiogenic pathway. They are very stable in biological fluids, which turns them into potential circulating biomarkers. In this study, we considered a case series of patients with metastatic (m) CRC treated with a bevacizumab (B)-based treatment, enrolled in the prospective multicentric Italian Trial in Advanced Colorectal Cancer (ITACa). We then analyzed a panel of circulating miRNAs in relation to the patient outcome. In multivariate analysis, circulating basal levels of hsa-miR-20b-5p, hsa-miR-29b-3p and hsa-miR-155-5p resulted in being significantly associated with progression-free survival (PFS) (p = 0.027, p = 0.034 and p = 0.039, respectively) and overall survival (OS) (p = 0.044, p = 0.024 and p = 0.032, respectively). We also observed that an increase in hsa-miR-155-5p at the first clinical evaluation was significantly associated with shorter PFS (HR 3.03 (95% CI 1.06-9.09), p = 0.040) and OS (HR 3.45 (95% CI 1.18-10.00), p = 0.024), with PFS and OS of 9.5 (95% CI 6.8-18.7) and 15.9 (95% CI 8.4-not reached), respectively, in patients with an increase ≥30% of hsa-miR-155-5p and 22.3 (95% CI 10.2-25.5) and 42.9 (24.8-not reached) months, respectively, in patients without such increase. In conclusion, our results highlight the potential usefulness of circulating basal levels of hsa-miR-20b-5p, hsa-miR-29b-3p and hsa-miR-155-5p in predicting the outcome of patients with mCRC treated with B. In addition, the variation of circulating hsa-miR-155-5p could also be indicative of the patient survival.


Assuntos
Biomarcadores Tumorais , MicroRNA Circulante , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , MicroRNAs/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Terapia Combinada , Feminino , Regulação Neoplásica da Expressão Gênica , Genes ras , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
14.
Int J Mol Sci ; 18(6)2017 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-28598398

RESUMO

There is evidence of a different response to treatment with regard to the primary tumor localization (right-sided or left-sided) in patients with metastatic colorectal cancer (mCRC). We analyzed the different outcomes and biomolecular characteristics in relation to tumor localization in 122 of the 370 patients with metastatic colorectal cancer enrolled onto the phase III prospective multicenter "Italian Trial in Advanced Colorectal Cancer (ITACa)", randomized to receive first-line chemotherapy (CT) or CT plus bevacizumab (CT + B). RAS and BRAF mutations; baseline expression levels of circulating vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), cyclooxygenase-2 (COX2), ephrin type-B receptor 4 (EPHB4), hypoxia-inducible factor 1-alpha (HIF-1α), lactate dehydrogenase (LDH), and high-sensitivity C reactive protein (hs-CRP); and inflammatory indexes such as the neutrophil-to-lymphocyte ratio, platelet-lymphocyte rate and systemic immune-inflammation index were evaluated. Patients with right-sided tumors showed a longer median progression-free survival in the CT + B arm than in the CT group (12.6 vs. 9.0 months, respectively, p = 0.017). Baseline inflammatory indexes were significantly higher in left-sided tumors, whereas eNOS and EPHB4 expression was significantly higher and BRAF mutation more frequent in right-sided tumors. Our data suggest a greater efficacy of the CT + B combination in right-sided mCRC, which might be attributable to the lower inflammatory status and higher expression of pro-angiogenic factors that appear to characterize these tumors.


Assuntos
Colo/patologia , Neoplasias Colorretais/patologia , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Biomarcadores , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Terapia Combinada , Feminino , Genes ras , Humanos , Mediadores da Inflamação , Masculino , Mutação , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Óxido Nítrico Sintase Tipo III/genética , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/genética
16.
J Transl Med ; 14(1): 249, 2016 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-27576364

RESUMO

BACKGROUND: Epigenetic silencing mediated by CpG island methylation is a common feature of many cancers. Characterizing aberrant DNA methylation changes associated with prostate carcinogenesis could potentially identify a tumour-specific methylation pattern, facilitating the early diagnosis of prostate cancer. The objective of the study was to assess the methylation status of 40 tumour suppressor genes in prostate cancer and healthy prostatic tissues. METHODS: We used methylation specific-multiplex ligation probe amplification (MS-MLPA) assay in two independent case series (training and validation set). The training set comprised samples of prostate cancer tissue (n = 40), healthy prostatic tissue adjacent to the tumor (n = 26), and healthy non prostatic tissue (n = 23), for a total of 89 DNA samples; the validation set was composed of 40 prostate cancer tissue samples and their adjacent healthy prostatic tissue, for a total of 80 DNA samples. Methylation specific-polymerase chain reaction (MSP) was used to confirm the results obtained in the validation set. RESULTS: We identified five highly methylated genes in prostate cancer: GSTP1, RARB, RASSF1, SCGB3A1, CCND2 (P < 0.0001), with an area under the ROC curve varying between 0.89 (95 % CI 0.82-0.97) and 0.95 (95 % CI 0.90-1.00). Diagnostic accuracy ranged from 80 % (95 % CI 70-88) to 90 % (95 % CI 81-96). Moreover, a concordance rate ranging from 83 % (95 % CI 72-90) to 89 % (95 % CI 80-95) was observed between MS-MLPA and MSP. CONCLUSIONS: Our preliminary results highlighted that hypermethylation of GSTP1, RARB, RASSF1, SCGB3A1 and CCND2 was highly tumour-specific in prostate cancer tissue.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA/genética , Reação em Cadeia da Polimerase/métodos , Neoplasias da Próstata/genética , Idoso , Estudos de Casos e Controles , Análise por Conglomerados , Genes Supressores de Tumor , Humanos , Masculino , Neoplasias da Próstata/diagnóstico , Curva ROC , Reprodutibilidade dos Testes
17.
J Neurooncol ; 128(2): 333-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27029617

RESUMO

Despite advances in the treatment of glioblastoma (GBM), median survival is 12-15 months. O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation status is acknowledged as a predictive marker for temozolomide (TMZ) treatment. When MGMT promoter values fall into a "methylated" range, a better response to chemotherapy is expected. However, a cutoff that discriminates between "methylated" and "unmethylated" status has yet to be defined. We aimed to identify the best cutoff value and to find out whether variability in methylation profiles influences the predictive capacity of MGMT promoter methylation. Data from 105 GBM patients treated between 2008 and 2013 were analyzed. MGMT promoter methylation status was determined by analyzing 10 CpG islands by pyrosequencing. Patients were treated with radiotherapy followed by TMZ. MGMT promoter methylation status was classified into unmethylated 0-9 %, methylated 10-29 % and methylated 30-100 %. Statistical analysis showed that an assumed methylation cutoff of 9 % led to an overestimation of responders. All patients in the 10-29 % methylation group relapsed before the 18-month evaluation. Patients with a methylation status ≥30 % showed a median overall survival of 25.2 months compared to 15.2 months in all other patients, confirming this value as the best methylation cutoff. Despite wide variability among individual profiles, single CpG island analysis did not reveal any correlation between single CpG island methylation values and relapse or death. Specific CpG island methylation status did not influence the predictive value of MGMT. The predictive role of MGMT promoter methylation was maintained only with a cutoff value ≥30 %.


Assuntos
Neoplasias Encefálicas/genética , Metilação de DNA , Glioblastoma/genética , Regiões Promotoras Genéticas , Adulto , Fatores Etários , Idoso , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Ilhas de CpG , Feminino , Seguimentos , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Glioblastoma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Adulto Jovem
18.
J Transl Med ; 13: 258, 2015 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-26259598

RESUMO

BACKGROUND: Bevacizumab plus chemotherapy is a widely used therapeutic option for first-line treatment of metastatic colorectal cancer (mCRC). However, molecular predictors of bevacizumab efficacy have not yet been identified. We analyzed vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) polymorphisms in relation to response to bevacizumab. METHODS: Two hundred and thirty-seven patients with mCRC enrolled onto the phase III prospective multicentre randomized "Italian Trial in Advanced Colorectal Cancer (ITACa)" trial were evaluated. One hundred fourteen patients received chemotherapy plus bevacizumab (CT + B) and 123 received chemotherapy (CT) alone. Five single nucleotide polymorphisms (SNPs) (-2578, -1498, -1154, -634 and +936) for VEGF and 2 SNPs (-786, +894) and one variable number tandem repeat in intron 4 for eNOS were analyzed for each patient. The polymorphisms were assessed in relation to progression-free survival (PFS), objective response rate (ORR) and overall survival (OS). RESULTS: VEGF 936C/T, eNOS +894 G/T and VNTR were significantly correlated with outcome in CT + B patients, but not in CT-only patients. In particular, patients with a specific haplotype combination of the 2 eNOS polymorphisms (defined eNOS Haplo1/Haplo1 and eNOS Haplo 2/Haplo2) showed significantly longer PFS (15.0 vs 9.1 months, P = 0.001) and OS (34.5 vs 20.5 months P = 0.002), and a higher ORR (71 vs 45.9%, P = 0.013) than those with the other genotypes, respectively. CONCLUSIONS: Specific eNOS polymorphisms may be capable of identifying a subset of mCRC patients who are more responsive to bevacizumab-based chemotherapy. If confirmed, these results would permit individually tailored treatment with bevacizumab.


Assuntos
Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/enzimologia , Intervalo Livre de Doença , Feminino , Estudos de Associação Genética , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/genética
19.
Oncologist ; 19(12): 1276-83, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25342315

RESUMO

OBJECTIVE: The study objective was to evaluate whether there are clinical or genetic differences between patients with cancer-induced bone pain (CIBP) and patients with non-CIBP, and, in the CIBP group, in those with good versus poor opioid response. MATERIALS AND METHODS: A total of 2,294 adult patients with cancer who were receiving opioids for moderate or severe pain were included in the European Pharmacogenetic Opioid Study. Pain intensity and pain relief were measured using the Brief Pain Inventory. Linkage disequilibrium of 112 single nucleotide polymorphisms was evaluated in 25 candidate genes, and 43 haplotypes were assessed. Correlations among demographical factors, disease-related factors, genetic factors, CIBP, and pain relief were analyzed by logistic regression models corrected for multiple testing. Patients with bone metastases and bone/soft tissue pain were defined as having prevalent bone pain (CIBP population). This population was compared with patients who had other types of cancer pain (non-CIBP). RESULTS: A total of 577 patients (26.2%) had CIBP, and 1,624 patients (73.8%) had non-CIBP. Patients with CIBP had more breakthrough cancer pain episodes (64.2% vs. 56.4%, p = .001), had significantly higher pain interference in "walking ability in the past 24 hours" (p < .0001), used more adjuvant drugs (84.1% vs. 78.3%, p = .003), and had a higher, albeit nonsignificant, median overall survival (3.8 vs. 2.9 months, p = .716) than patients with non-CIBP. None of the examined haplotypes exceeded p values corrected for multiple testing for the investigated outcomes. CONCLUSION: Patients with CIBP who were taking opioids had a clinical profile slightly different from that of the non-CIBP group. However, no specific genetic pattern emerged for CIBP versus non-CIBP or for responsive versus nonresponsive patients with CIBP.


Assuntos
Analgésicos Opioides/uso terapêutico , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Dor Intratável/tratamento farmacológico , Dor Intratável/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Limitação da Mobilidade , Manejo da Dor , Medição da Dor , Polimorfismo de Nucleotídeo Único , Qualidade de Vida , Fatores de Risco
20.
BMC Cancer ; 14: 478, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24986639

RESUMO

BACKGROUND: CHEK2 is a multi-cancer susceptibility gene whose common germline mutations are known to contribute to the risk of developing breast and prostate cancer. CASE PRESENTATION: Here, we describe an Italian family with a high number of cases of breast cancer and other types of tumour subjected to the MLPA test to verify the presence of BRCA1, BRCA2 and CHEK2 deletions and duplications. We identified a new 23-kb duplication in the CHEK2 gene extending from intron 5 to 13 that was associated with breast cancer in the family. The presence and localisation of the alteration was confirmed by a second analysis by Next-Generation Sequencing. CONCLUSIONS: This finding suggests that CHEK2 mutations are heterogeneous and that techniques other than sequencing, such as MLPA, are needed to identify CHEK2 mutations. It also indicates that CHEK2 rare variants, such as duplications, can confer a high susceptibility to cancer development and should thus be studied in depth as most of our knowledge of CHEK2 concerns common mutations.


Assuntos
Quinase do Ponto de Checagem 2/genética , Duplicação Gênica , Predisposição Genética para Doença , Adulto , Idoso , Neoplasias da Mama/genética , Feminino , Estudos de Associação Genética , Variação Genética , Mutação em Linhagem Germinativa , Humanos , Itália , Pessoa de Meia-Idade , Linhagem , Análise de Sequência de DNA
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