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1.
Cancer ; 129(16): 2581-2592, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37096763

RESUMO

BACKGROUND: Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes. METHODS: Forty-six paraffin tumor samples from ASCC patients were analyzed by whole-exome sequencing. Copy number variants (CNVs) were identified and their relation to disease-free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors. RESULTS: On the discovery cohort, the median age was 61 years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33 months, and overall survival was 45 months. Twenty-nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5 years than those with two CYP2D6 copies (21% vs. 84%; p < .0002, hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.7-24.9). In the GEMCAD validation cohort, patients with CYP2D6 CNV also had worse DFS at 5 years (56% vs. 87%; p = .02, HR = 3.6; 95% CI, 1.1-5.7). Mitochondria and mitochondrial cell-cycle proteins were overexpressed in patients with CYP2D6 CNV. CONCLUSIONS: Tumor CYP2D6 CNV identified patients with a significantly worse DFS at 5 years among localized ASCC patients treated with 5-fluorouracil, mitomycin C, and radiotherapy. Proteomics pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets for these high-risk patients. PLAIN LANGUAGE SUMMARY: Anal squamous cell carcinoma is an infrequent tumor whose treatment has not been changed since the 1970s. However, disease-free survival in late staged tumors is between 40% and 70%. The presence of an alteration in the number of copies of CYP2D6 gene is a biomarker of worse disease-free survival. The analysis of the proteins in these high-risk patients pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets. Therefore, the determination of the number of copies of CYP2D6 allows the identification of anal squamous carcinoma patients with a high-risk of relapse that could be redirected to a clinical trial. Additionally, this study may be useful to suggest new treatment strategies to increase current therapy efficacy.


Assuntos
Neoplasias do Ânus , Carcinoma de Células Escamosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias do Ânus/genética , Neoplasias do Ânus/terapia , Neoplasias do Ânus/patologia , Biomarcadores , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/tratamento farmacológico , Citocromo P-450 CYP2D6/genética , Variações do Número de Cópias de DNA , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos
2.
J Pathol ; 257(1): 68-81, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35066875

RESUMO

Optimal selection of high-risk patients with stage II colon cancer is crucial to ensure clinical benefit of adjuvant chemotherapy. Here, we investigated the prognostic value of genomic intratumor heterogeneity and aneuploidy for disease recurrence. We combined targeted sequencing, SNP arrays, fluorescence in situ hybridization, and immunohistochemistry on a retrospective cohort of 84 untreated stage II colon cancer patients. We assessed the clonality of copy-number alterations (CNAs) and mutations, CD8+ lymphocyte infiltration, and their association with time to recurrence. Prognostic factors were included in machine learning analysis to evaluate their ability to predict individual relapse risk. Tumors from recurrent patients displayed a greater proportion of CNAs compared with non-recurrent (mean 31.3% versus 23%, respectively; p = 0.014). Furthermore, patients with elevated tumor CNA load exhibited a higher risk of recurrence compared with those with low levels [p = 0.038; hazard ratio (HR) 2.46], which was confirmed in an independent cohort (p = 0.004; HR 3.82). Candidate chromosome-specific aberrations frequently observed in recurrent cases included gain of the chromosome arm 13q (p = 0.02; HR 2.67) and loss of heterozygosity at 17q22-q24.3 (p = 0.05; HR 2.69). CNA load positively correlated with intratumor heterogeneity (R = 0.52; p < 0.0001). Consistently, incremental subclonal CNAs were associated with an elevated risk of relapse (p = 0.028; HR 2.20), which we did not observe for subclonal single-nucleotide variants and small insertions and deletions. The clinico-genomic model rated an area under the curve of 0.83, achieving a 10% incremental gain compared with clinicopathological markers (p = 0.047). In conclusion, tumor aneuploidy and copy-number intratumor heterogeneity were predictive of poor outcome and improved discriminative performance in early-stage colon cancer. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Neoplasias do Colo , Recidiva Local de Neoplasia , Aneuploidia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Variações do Número de Cópias de DNA , Humanos , Hibridização in Situ Fluorescente , Recidiva Local de Neoplasia/genética , Prognóstico , Estudos Retrospectivos
3.
Cancer Invest ; 40(6): 475-482, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35468046

RESUMO

This study examines the mediating role of social support between anxious preoccupation and resilience in patients with cancer during COVID-19. NEOetic_SEOM is a prospective, multicenter study involving individuals with advanced, unresectable cancer who completed the following scales: Resilience (BCRS), Social Support (Duke-UNC-11), and anxious preoccupation subscale of the Mini-Mental Adjustment to Cancer (M-MAC) before starting antineoplastic treatment. Between March 2020 and July 2021, 507 patients (55% male; mean age, 65) were recruited. No differences in resilience were observed based on sociodemographic or clinical characteristics. Social support in people with advanced, unresectable cancer promotes both decreased anxious preoccupation and greater resilience.


Assuntos
COVID-19 , Neoplasias , Adaptação Psicológica , Idoso , Feminino , Humanos , Masculino , Pandemias , Estudos Prospectivos , Apoio Social
4.
Br J Cancer ; 117(12): 1777-1786, 2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-29123263

RESUMO

BACKGROUND: Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. METHODS: We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation. RESULTS: Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R. CONCLUSIONS: Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Núcleo Celular/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Transporte Proteico/efeitos dos fármacos , Receptor IGF Tipo 1/metabolismo , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Sobrevivência Celular/efeitos dos fármacos , Cetuximab/administração & dosagem , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Curcumina/farmacologia , Dasatinibe/farmacologia , Ácidos Graxos Insaturados/farmacologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Inativação Gênica , Células HCT116 , Células HT29 , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Terapia de Alvo Molecular , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Panitumumabe , Compostos de Fenilureia/farmacologia , Proteínas Inibidoras de STAT Ativados/genética , Proteínas Inibidoras de STAT Ativados/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirimidinas/farmacologia , Pirróis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sorafenibe
5.
Sci Rep ; 13(1): 18997, 2023 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-37923774

RESUMO

Somatic single-nucleotide variants (SNVs) occur every time a cell divides, appearing even in healthy tissues at low frequencies. These mutations may accumulate as neutral variants during aging, or eventually, promote the development of neoplasia. Here, we present the SP-ddPCR, a droplet digital PCR (ddPCR) based approach that utilizes customized SuperSelective primers aiming at quantifying the proportion of rare SNVs. For that purpose, we selected five potentially pathogenic variants identified by whole-exome sequencing (WES) occurring at low variant allele frequency (VAF) in at-risk colon healthy mucosa of patients diagnosed with colorectal cancer or advanced adenoma. Additionally, two APC SNVs detected in two cancer lesions were added to the study for WES-VAF validation. SuperSelective primers were designed to quantify SNVs at low VAFs both in silico and in clinical samples. In addition to the two APC SNVs in colonic lesions, SP-ddPCR confirmed the presence of three out of five selected SNVs in the normal colonic mucosa with allelic frequencies ≤ 5%. Moreover, SP-ddPCR showed the presence of two potentially pathogenic variants in the distal normal mucosa of patients with colorectal carcinoma. In summary, SP-ddPCR offers a rapid and feasible methodology to validate next-generation sequencing data and accurately quantify rare SNVs, thus providing a potential tool for diagnosis and stratification of at-risk patients based on their mutational profiling.


Assuntos
Neoplasias , Humanos , Mutação , Primers do DNA , Colo , Reação em Cadeia da Polimerase , Sequenciamento de Nucleotídeos em Larga Escala/métodos
6.
Eur J Surg Oncol ; 48(5): 1123-1132, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34872775

RESUMO

INTRODUCTION: Retrospective studies and meta-analyses suggest that upfront primary tumour resection (UPTR) confers a survival benefit in patients with asymptomatic unresectable metastatic colorectal cancer (mCRC) undergoing chemotherapy, however a consensus of its role in routine clinical practice in the current era of targeted therapies is lacking. This retrospective study aimed to analyse the survival benefit of UPTR in terms of tumour location and mutational status, in patients with synchronous mCRC receiving chemotherapy and targeted therapy. PATIENTS AND METHODS: Survival was analysed in a pooled cohort of synchronous mCRC patients treated with a first-line anti-VEGF or anti-EGFR inhibitor in seven trials of the Spanish TTD group, according to UPTR, tumour-sidedness and mutational profiling. RESULTS: Of 1334 eligible patients, 642 (48%) had undergone UPTR. UPTR was associated with significantly longer overall survival (OS; 25.0 vs 20.3 months; HR 1.30, 95%CI 1.15-1.48; p < 0.0001). UPTR was associated with significant OS benefit in both left-sided (HR 1.38, 95%CI 1.13-1.69; p = 0.002) and right-sided (HR 1.39, 95%CI 1.00-1.94; p = 0.049) tumours, RASwt (HR 1.29, 95%CI 1.05-1.60; p = 0.016) and BRAFwt (HR 1.49, 95%CI 1.21-1.84; p = 0.0002) tumours, and treatment with anti-EGFRs (HR 1.47, 95%CI 1.13-1.92; p = 0.004) and anti-VEGFs (HR 1.25, 95%CI 1.08-1.44; p = 0.003). Multivariate analysis identified number of metastatic sites, RAS status, primary tumour location and UPTR as independent prognostic factors for OS. CONCLUSION: Considering the selection bias inherent to this study, our results support UPTR before first-line anti-EGFR or anti-VEGF targeted therapy in right and left-sided asymptomatic unresectable synchronous mCRC patients. RAS/BRAF mutational status may also influence UPTR function.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/patologia , Humanos , Neoplasias Retais/tratamento farmacológico , Estudos Retrospectivos
7.
Sci Rep ; 10(1): 9152, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32499568

RESUMO

Tetraploidy, a common feature in cancer, results in the presence of extra centrosomes, which has been associated with chromosome instability (CIN) and aneuploidy. Deregulation in the number of centrosomes triggers tumorigenesis. However, how supernumerary centrosomes evolve during the emergence of tetraploid cells remains yet to be elucidated. Here, generating tetraploid isogenic clones in colorectal cancer and in non-transformed cells, we show that near-tetraploid clones exhibit a significant increase in the number of centrosomes. Moreover, we find that centrosome area in near-tetraploids is twice as large as in near-diploids. To evaluate whether centrosome clustering was occurring, we next analysed the number of centrioles revealing centriole amplification. Notwithstanding, more than half of the near-tetraploids maintained in culture do not present centrosome aberrations. To test whether cells progressively lost centrioles after becoming near-tetraploid, we transiently transfected diploid cells with siRNA against ESPL1/Separase, a protease responsible for triggering anaphase, to generate newly near-tetraploid cells. Finally, using this model, we assessed the number of centrioles at different time-points after tetraploidization finding that near-tetraploids rapidly lose centrosomes over time. Taken together, these data demonstrate that although most cells reduce supernumerary centrosomes after tetraploidization, a small fraction retains extra centrioles, potentially resulting in CIN.


Assuntos
Centrossomo/fisiologia , Separase/genética , Linhagem Celular Tumoral , Instabilidade Cromossômica , Humanos , Hibridização in Situ Fluorescente , Metáfase , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Separase/antagonistas & inibidores , Separase/metabolismo , Tetraploidia
8.
Cancers (Basel) ; 12(5)2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32365785

RESUMO

Tetraploidy, or whole-genome duplication, is a common phenomenon in cancer and preludes chromosome instability, which strongly correlates with disease progression, metastasis, and treatment failure. Therefore, it is reasonable to hypothesize that tetraploidization confers multidrug resistance. Nevertheless, the contribution of whole-genome duplication to chemo-radiotherapy resistance remains unclear. Here, using isogenic diploid and near-tetraploid clones from three colorectal cancer cell lines and one non-transformed human epithelial cell line, we show a consistent growth impairment but a divergent tumorigenic potential of near-tetraploid cells. Next, we assessed the effects of first-line chemotherapeutic drugs, other commonly used agents and ionizing radiation, and found that whole-genome duplication promoted increased chemotherapy resistance and also conferred protection against irradiation. When testing the activation of apoptosis, we observed that tetraploid cells were less prone to caspase 3 activation after treatment with first-line chemotherapeutic agents. Furthermore, we found that pre-treatment with ataxia telangiectasia and Rad3 related (ATR) inhibitors, which targets response to replication stress, significantly enhanced the sensitivity of tetraploid cells to first-line chemotherapeutic agents as well as to ionizing radiation. Our findings provide further insight into how tetraploidy results in greater levels of tolerance to chemo-radiotherapeutic agents and, moreover, we show that ATR inhibitors can sensitize near-tetraploid cells to commonly used chemo-radiotherapy regimens.

9.
Exp Neurol ; 211(1): 180-93, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18316076

RESUMO

We have studied whether electrical stimulation immediately after nerve injury may enhance axonal regeneration and modulate plastic changes at the spinal cord level underlying the appearance of hyperreflexia. Two groups of adult rats were subjected to sciatic nerve section followed by suture repair. One group (ES) received electrical stimulation (3 V, 0.1 ms at 20 Hz) for 1 h after injury. A second group served as control (C). Nerve conduction, H reflex, motor evoked potentials, and algesimetry tests were performed at 1, 3, 5, 7 and 9 weeks after surgery, to assess muscle reinnervation and changes in excitability of spinal cord circuitry. The electrophysiological results showed higher levels of reinnervation, and histological results a significantly higher number of regenerated myelinated fibers in the distal tibial nerve in group ES in comparison with group C. The monosynaptic H reflex was facilitated in the injured limb, to a higher degree in group C than in group ES. The amplitudes of motor evoked potentials were similar in both groups, although the MEP/M ratio was increased in group C compared to group ES, indicating mild central motor hyperexcitability. Immunohistochemical labeling of sensory afferents in the spinal cord dorsal horn showed prevention of the reduction in expression of substance P at one month postlesion in group ES. In conclusion, brief electrical stimulation applied after sciatic nerve injury promotes axonal regeneration over a long distance and reduces facilitation of spinal motor responses.


Assuntos
Estimulação Elétrica/métodos , Regeneração Nervosa/efeitos da radiação , Plasticidade Neuronal/efeitos da radiação , Neuropatia Ciática , Medula Espinal/fisiopatologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Modelos Animais de Doenças , Eletromiografia , Potencial Evocado Motor/efeitos da radiação , Feminino , Hiperalgesia/fisiopatologia , Lectinas/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos da radiação , Recuperação de Função Fisiológica/efeitos da radiação , Reflexo/efeitos da radiação , Neuropatia Ciática/patologia , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/terapia , Medula Espinal/efeitos da radiação , Substância P/metabolismo , Fatores de Tempo
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