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1.
Clin Epigenetics ; 12(1): 27, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32059745

RESUMO

BACKGROUND: Overcoming therapeutic resistance is one of the major hurdles in cancer care. One mechanism contributing to therapeutic resistance is a process in which epithelial cells switch to a mesenchymal state (epithelial-to-mesenchymal transition or EMT). The precise mechanisms driving EMT-mediated therapeutic resistance have, however, not been elucidated. RESULTS: Here, we study ten cell line pairs, for which parental cell lines were made resistant to either a targeted or chemotherapy-based treatment. First, we show by miRNA-200 overexpression that treatment resistance is driven by EMT. Next, we demonstrate that DNA methylation changes occur within each cell line pair and show that exposure to 5-azacytidine or knock down of DNA methyltransferases (DNMTs), both of which globally demethylate cells, result in EMT reversal and increased therapeutic sensitivity. This suggests DNA methylation to causally underlie EMT and treatment resistance. We also observe significant overlap in methylation profiles between resistant lines, suggesting a common epigenetic mechanism to cause resistance to therapy. In line with this hypothesis, cross-resistance to other targeted and chemotherapies is observed, while importantly, this is lost upon demethylation of the cells. Finally, we clinically validate that DNA methylation changes drive EMT-mediated resistance to sorafenib in patients with advanced hepatocellular carcinoma (HCC). Specifically, we develop a capture-based protocol to interrogate DNA methylation in low amounts of circulating tumor DNA (ctDNA). By interrogating the methylation status in liquid biopsies, longitudinally collected during sorafenib treatment, we assess whether DNA methylation changes also drive EMT and therapy resistance in a clinical setting. Particularly, by monitoring methylation changes in EMT genes, we are able to predict tumor response and acquired resistance to sorafenib. CONCLUSIONS: We propose methylation changes underlying EMT to constitute a common resistance mechanism to cancer therapies. This process can be reversed pharmacologically and monitored non-invasively in ctDNA to predict resistance to treatment.

2.
Environ Int ; 137: 105530, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32062310

RESUMO

INTRODUCTION: Inhalation of asbestos induces lung cancer via different cellular mechanisms. Together with the increased production of carbon nanotubes (CNTs) grows the concern about adverse effects on the lungs given the similarities with asbestos. While it has been established that CNT and asbestos induce epigenetic alterations, it is currently not known whether alterations at epigenetic level remain stable after withdrawal of the exposure. Identification of DNA methylation changes after a low dose of CNT and asbestos exposure and recovery can be useful to determine the fibre/particle toxicity and adverse outcome. METHODS: Human bronchial epithelial cells (16HBE) were treated with a low and non-cytotoxic dose (0.25 µg/ml) of multi-walled carbon nanotubes (MWCNTs-NM400) or single-walled carbon nanotubes (SWCNTs-SRM2483) and 0.05 µg/ml amosite (brown) asbestos for the course of four weeks (sub-chronic exposure). After this treatment, the cells were further incubated (without particle/fibre) for two weeks, allowing recovery from the exposure (recovery period). Nuclear depositions of the CNTs were assessed using femtosecond pulsed laser microscopy in a label-free manner. DNA methylation alterations were analysed using microarrays that assess more than 850 thousand CpG sites in the whole genome. RESULTS: At non-cytotoxic doses, CNTs were noted to be incorporated with in the nucleus after a four weeks period. Exposure to MWCNTs induced a single hypomethylation at a CpG site and gene promoter region. No change in DNA methylation was observed after the recovery period for MWCNTs. Exposure to SWCNTs or amosite induced hypermethylation at CpG sites after sub-chronic exposure which may involve in 'transcription factor activity' and 'sequence-specific DNA binding' gene ontologies. After the recovery period, hypermethylation and hypomethylation were noted for both SWCNTs and amosite. Hippocalcinlike 1 (HPCAL1), protease serine 3 (PRSS3), kallikrein-related peptidase 3 (KLK3), kruppel like factor 3 (KLF3) genes were hypermethylated at different time points in either SWCNT-exposed or amosite-exposed cells. CONCLUSION: These results suggest that the specific SWCNT (SRM2483) and amosite fibres studied induce hypo- or hypermethylation on CpG sites in DNA after very low-dose exposure and recovery period. This effect was not seen for the studied MWCNT (NM400).

3.
Cancer Cell ; 37(1): 21-36.e13, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31935371

RESUMO

Heterogeneity of lung tumor endothelial cell (TEC) phenotypes across patients, species (human/mouse), and models (in vivo/in vitro) remains poorly inventoried at the single-cell level. We single-cell RNA (scRNA)-sequenced 56,771 endothelial cells from human/mouse (peri)-tumoral lung and cultured human lung TECs, and detected 17 known and 16 previously unrecognized phenotypes, including TECs putatively regulating immune surveillance. We resolved the canonical tip TECs into a known migratory tip and a putative basement-membrane remodeling breach phenotype. Tip TEC signatures correlated with patient survival, and tip/breach TECs were most sensitive to vascular endothelial growth factor blockade. Only tip TECs were congruent across species/models and shared conserved markers. Integrated analysis of the scRNA-sequenced data with orthogonal multi-omics and meta-analysis data across different human tumors, validated by functional analysis, identified collagen modification as a candidate angiogenic pathway.

5.
Breast Cancer Res ; 21(1): 144, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847907

RESUMO

BACKGROUND: Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. METHODS: We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. RESULTS: In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52-0.74; at 10 years, 0.53-0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62-1.37), and the calibration slope was 0.90 (95% PI: 0.73-1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52-0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4-10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. CONCLUSIONS: We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.

6.
Int J Cancer ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31745979

RESUMO

Lung cancer is the number one cause of cancer-related death worldwide with cigarette smoking as its major risk factor. Although the incidence of lung cancer in never smokers is rising, this subgroup of patients is underrepresented in genomic studies of lung cancer. Here, we assembled a prospective cohort of 46 never-smoking, nonsmall cell lung cancer (NSCLC) patients and performed whole-exome and low-coverage whole-genome sequencing on tumors and matched germline DNA. We observed fewer somatic mutations, genomic breakpoints and a smaller fraction of the genome with chromosomal instability in lung tumors from never smokers compared to smokers. The lower number of mutations, enabled us to identify TSC22D1 as a potential driver gene in NSCLC. On the other hand, the frequency of mutations in actionable genes such as EGFR and ERBB2 and of amplifications in MET were higher, while the mutation rate of TP53, which is a negative prognostic factor, was lower in never smokers compared to smokers. Together, these observations suggest a more favorable prognosis for never smokers with NSCLC. Classification of somatic mutations into six-substitution type patterns or into 96-substitution type signatures revealed distinct clusters between smokers and never smokers. Particularly, we identified in never smokers signatures related to aging, homologous recombination damage and APOBEC/AID activity as the most important underlying processes of NSCLC. This further indicates that second-hand smoking is not driving NSCLC pathogenesis in never smokers.

7.
Kidney Int ; 96(5): 1195-1204, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31530476

RESUMO

During ageing, kidney function decreases due to renal tubular atrophy, interstitial fibrosis, glomerulosclerosis and arteriosclerosis. Recently, changes in DNA methylation were shown to contribute to various ageing processes. However, it is unknown whether such changes also contribute to age-related kidney dysfunction. To assess this, we profiled genome-wide changes in DNA methylation (over 800 000 CpG sites) in 95 renal biopsies obtained prior to kidney transplantation from donors aged 16 to 73 years. Donor age significantly associated with the methylation of 92 778 CpGs (false discovery rate under 0.05), corresponding to 10 285 differentially methylated regions. These regions were most frequently located in genes involved in the Wnt/beta-catenin signaling pathway. Using an independent cohort of 67 biopsies, we autonomously validated these findings. Interestingly, the methylation status of these 92 778 age-related CpGs was associated with glomerulosclerosis (34.4% of CpGs at a false discovery rate under 0.05) and interstitial fibrosis (0.9%) and graft function at one year after transplantation, but not with tubular atrophy and arteriosclerosis. No association was observed with any of these pathologies at the time of transplantation (0% at a false discovery rate under 0.05). Thus, age-associated changes in DNA methylation at the time of transplantation predict future injury of transplanted kidneys. Specifically, our epigenome-wide association study demonstrates that epigenetic renal ageing is implicated in progressive fibrosis in both the glomerulus and the interstitium.

8.
Nat Cell Biol ; 21(8): 1041-1051, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31371824

RESUMO

Endometrial disorders represent a major gynaecological burden. Current research models fail to recapitulate the nature and heterogeneity of these diseases, thereby hampering scientific and clinical progress. Here we developed long-term expandable organoids from a broad spectrum of endometrial pathologies. Organoids from endometriosis show disease-associated traits and cancer-linked mutations. Endometrial cancer-derived organoids accurately capture cancer subtypes, replicate the mutational landscape of the tumours and display patient-specific drug responses. Organoids were also established from precancerous pathologies encompassing endometrial hyperplasia and Lynch syndrome, and inherited gene mutations were maintained. Endometrial disease organoids reproduced the original lesion when transplanted in vivo. In summary, we developed multiple organoid models that capture endometrial disease diversity and will provide powerful research models and drug screening and discovery tools.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Neoplasias do Endométrio/patologia , Organoides/patologia , Doenças Uterinas/patologia , Técnicas de Cultura de Células/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Endométrio/patologia , Feminino , Humanos , Organoides/efeitos dos fármacos , Organoides/metabolismo , Doenças Uterinas/tratamento farmacológico , Doenças Uterinas/metabolismo
9.
Acta Derm Venereol ; 99(12): 1154-1159, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31314121

RESUMO

The rising incidence of cutaneous melanoma and its stable high mortality rates despite innovative cancer care, require better prediction of the clinical outcome. In a large cutaneous melanoma population we explored whether the known clinical risk factors for melanoma susceptibility (nevus phenotype, phototype, family and personal history of melanoma and sun damage) affect melanoma outcomes. A total of 1,530 melanoma patients were included. Multivariable analysis adjusted for age, gender, melanoma stage, localization and subtype showed that familial melanoma, solar lentigines on head and neck, the back of hands, arms and shoulders were associated with a better relapse free survival. The presence of atypical naevi was associated with an increased risk of relapse. After Bonferroni correction, the correlation between presence of solar lentigines on the back of the hands and arms remained the most robust and significant prognostic factor for the relapse free survival in cutaneous melanoma patients.

10.
Oncogene ; 38(31): 5933-5941, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285551

RESUMO

Two out of 41 non-small cell lung cancer patients enrolled in a clinical study were found with a somatic CRAF mutation in their tumor, namely CRAFP261A and CRAFP207S. To our knowledge, both mutations are novel in lung cancer and CRAFP261A has not been previously reported in cancer. Expression of CRAFP261A in HEK293T cells and BEAS-2B lung epithelial cells led to increased ERK pathway activation in a dimer-dependent manner, accompanied with loss of CRAF phosphorylation at the negative regulatory S259 residue. Moreover, stable expression of CRAFP261A in mouse embryonic fibroblasts and BEAS-2B cells led to anchorage-independent growth. Consistent with a previous report, we could not observe a gain-of-function with CRAFP207S. Type II but not type I RAF inhibitors suppressed the CRAFP261A-induced ERK pathway activity in BEAS-2B cells, and combinatorial treatment with type II RAF inhibitors and a MEK inhibitor led to a stronger ERK pathway inhibition and growth arrest. Our findings suggest that the acquisition of a CRAFP261A mutation can provide oncogenic properties to cells, and that such cells are sensitive to combined MEK and type II RAF inhibitors. CRAF mutations should be diagnostically and therapeutically explored in lung and perhaps other cancers.

11.
Cancer Lett ; 459: 1-12, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31150822

RESUMO

High grade serous ovarian cancer (HGSOC) is the most frequent type of ovarian cancer. Most patients have primary response to platinum-based chemotherapy but frequently relapse, which leads to patient death. A lack of well documented and characterized patient-derived HGSOC cell lines is so far a major barrier to define tumor specific therapeutic targets and to study the molecular mechanisms underlying disease progression. We established 34 patient-derived HGSOC cell lines and characterized them at cellular and molecular level. Particularly, we demonstrated that a cancer-testis antigen PRAME and Estrogen Receptor could serve as therapeutic targets. Notably, data from the cell lines did not demonstrate acquired resistance due to tumor recurrence that matched with clinical observations. Finally, we presented that all HGSOC had no or very low CDKN1A (p21) expression due to loss of wild-type TP53, suggesting that loss of cell cycle control is the determinant for tumorigenesis and progression. In conclusion, patient-derived cell lines reveal that PRAME is a potential tumor specific therapeutic target in HGSOC and counteracting the down-regulation of p21 caused by loss of wild-type TP53 might be the key to impede disease progression.

12.
Nature ; 569(7756): E4, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31043737

RESUMO

Further analysis has revealed that the signal reported in Extended Data Fig. 1c of this Letter is attributed to phosphorylethanolamine, not carbamoyl phosphate. A newly developed derivatization method revealed that the level of carbamoyl phosphate in these NSCLC extracts is below the detection threshold of approximately 10 nanomoles. These findings do not alter the overall conclusions of the Letter; see associated Amendment for full details. The Letter has not been corrected online.

13.
Neoplasia ; 21(6): 582-590, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31054497

RESUMO

BACKGROUND: Low-grade serous ovarian cancer (LGSOC) is a rare subtype of epithelial ovarian carcinoma. Limited data regarding the molecular-genetic background exist beyond mutations in the RAS signaling pathway. There is a growing need to better characterize these tumors due to chemoresistance and limited therapeutic options in advanced or recurrent disease. METHODS: We performed genome-wide copy number aberration (CNA) profiles and mutation hotspot screening (KRAS, BRAF, NRAS, ERBB2, PIK3CA, TP53) in 38 LGSOC tumor samples. RESULTS: We detected mutations in the RAS-signaling pathway in 36.8% of cases, including seven KRAS, four BRAF, and three NRAS mutations. We identified two mutations in PIK3CA and one mutation in MAP3K1, EGFR, and TP53. CNAs were detected in 86.5% of cases. None of the focal aberrations was correlated with specific clinical characteristics. The most frequently detected CNA was loss of 1p36.33 in 54.1% of cases, with a trend towards lower progression-free survival and overall survival in patients with 1p36.33 loss. CONCLUSIONS: Activating RAS mutations were dominant in our series, with supplementary detection of two PIK3CA mutations which may lead to therapeutic options. Furthermore, we detected 1p36.33 deletions in half of the cases, indicating a role in tumorigenesis, and these deletions may serve as a prognostic marker.


Assuntos
Cistadenocarcinoma Seroso/genética , Variações do Número de Cópias de DNA/genética , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Cromossomos Humanos Par 1/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Cistadenocarcinoma Seroso/patologia , Receptores ErbB/genética , Feminino , Genoma Humano/genética , Genótipo , Humanos , MAP Quinase Quinase Quinase 1/genética , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Neoplasias Ovarianas/patologia , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Proteínas ras/genética
14.
Mol Cancer Ther ; 18(6): 1168-1178, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30962320

RESUMO

Soft-tissue sarcomas (STS) represent a heterogeneous group of rare, malignant tumors of mesenchymal origin. Reliable in vivo sarcoma research models are scarce. We aimed to establish and characterize histologically and molecularly stable patient-derived xenograft (PDX) models from a broad variety of STS subtypes. A total of 188 fresh tumor samples from consenting patients with localized or advanced STS were transplanted subcutaneously in NMRI-nu/nu-immunodeficient mice. Once tumor growth was observed, the material was passaged to a next generation of mice. A patient-derived tumor sample was considered "successfully engrafted" whenever the sample was transplanted to passage 1. A PDX model was considered "established" when observing stable morphologic and molecular features for at least two passages. With every passage, histologic and molecular analyses were performed. Specific genomic alterations and copy-number profile were assessed by FISH and low coverage whole-genome sequencing. The tumor engraftment rate was 32% (61/188) and 188 patient samples generated a total of 32 PDX models, including seven models of myxofibrosarcoma, five dedifferentiated liposarcoma, five leiomyosarcoma, three undifferentiated pleomorphic sarcoma, two malignant peripheral nerve sheet tumor models, and single models of synovial sarcoma and some other (ultra)rare subtypes. Seventeen additional models are in early stages of engraftment (passage 1-2). Histopathologic and molecular features were compared with the original donor tumor and were stable throughout passaging. The platform is used for studies on sarcoma biology and suited for in vivo preclinical drug testing as illustrated by a number of completed and ongoing laboratory studies.

15.
Neurogastroenterol Motil ; 31(6): e13579, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30854791

RESUMO

BACKGROUND: Mucosal immune activation has been postulated to play an important role in the pathogenesis of irritable bowel syndrome (IBS). However, data are conflicting and often based on small patient cohorts. Here, we aimed to evaluate the gene expression of a large set of immune-related genes in mucosal biopsies from IBS patients and healthy volunteers (HV). METHODS: A total of 171 IBS patients and 127 HV were included in the study. Rectum biopsies were collected from a cohort of 70 HV and 77 IBS patients (Rome III) and colon descendens biopsies from another cohort of 57 HV and 94 IBS patients (Rome II). Gene expression was assessed using OpenArray technology, and validated questionnaires were used to evaluate clinical characteristics (GI symptoms, somatization, anxiety, and depression). KEY RESULTS: A subset of IBS patients (33%) with increased immune activation in the colon descendens was identified using multivariate analysis and displayed increased gene expression of IL1B (3-fold change), prostaglandin synthase PTGS2 (2.1-fold change), and the G-protein-coupled receptor MRGPRX2 (10.7-fold change). Clinical characteristics in this subgroup were however similar to the rest of the patient cohort. Analysis of rectal biopsies failed to identify such subgroup of "immuno-active" IBS patients in the other patient cohort. CONCLUSION: A subset of IBS patients reveals evidence of immune activation in the colon descendens, but not in the rectum; however, gene expression is unrelated to clinical symptoms. To what extent this subgroup might however respond to anti-inflammatory therapy remains to be investigated.

16.
Melanoma Res ; 29(6): 590-595, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30681428

RESUMO

The rising incidence of cutaneous melanoma (CM), an aggressive skin cancer, emphasizes the need for novel biomarkers to guide personalized care and better predict outcome. Genetic factors including germline risk variants are promising candidates for this aim. We explored the association between germline risk variants and melanoma outcome in a large genetically homogenous Belgian melanoma population, focusing on single nucleotide polymorphisms which generated the highest association with melanoma susceptibility. Between 2004 and 2014, blood samples of 1088 patients with histologically confirmed CM were collected and genotyped for nine variants. Cox proportional hazard models were used to assess the association between each single nucleotide polymorphism and relapse-free survival and overall survival, adjusted by age, sex, melanoma stage, site, and subtype. We identified significant associations for rs869330 (in the methylthioadenosine phosphorylase - MTAP gene) with overall survival (hazard ratio = 0.760, P = 0.048, 95% confidence interval: 0.580-0.998) and relapse-free survival (hazard ratio = 0.800, P = 0.020, 95% confidence interval: 0.650-0.970). This exploratory study is the first to show a significant association between the rs869330 variant (in the MTAP gene) and outcome in a large CM population.

18.
Breast Cancer Res Treat ; 174(1): 55-63, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30456437

RESUMO

PURPOSE: The human epidermal growth factor receptor 2 (ERBB2) may harbour somatic mutations that drive breast tumorigenesis. Here, we study prevalence, tumour characteristics and disease outcome of ERBB2 mutations in a large unselected cohort of metastatic breast cancer (mBC) patients. METHODS: We retrospectively included all mBC patients with sufficient primary breast tumour, diagnosed between 2000 and 2015 (n = 775). Genomic DNA was subjected to a targeted-resequencing assay to identify hotspot mutations in exon 8, 17, 19, 20, and 21 of ERBB2. We studied demographics, tumour characteristics, median distant disease-free survival (DDFS), using a time-to-event analysis and time to progression (TTP) and overall survival (OS) upon metastasis, using Kaplan-Meier and log-rank statistics to assess differences between ERBB2-mutation statuses. RESULTS: ERBB2 mutations were observed in 1.8% of the samples (13/721). Patient and tumour characteristics were independent of ERBB2 mutations. Luminal ERBB2-mutated (ERBB2mut+) cases (n = 5) had a shorter DDFS than ERBB2mut- cases (median DDFS 0.8 vs. > 4.0 years, p = 0.02). ER-positive ERBB2mut+ patients who received an aromatase inhibitor (AI) as first-line treatment (stage IV disease) had a worse TTP vs. ERBB2mut- patients (n = 3 vs. 156; median TTP 103 vs. 311 days, p = 0.04). OS for all subtypes was lower for ERBB2mut+ vs. ERBB2mut- cases (n = 11 vs. 669; median OS 1.1 vs. 2.3 years, p = 0.46). CONCLUSION: ERBB2mut+ are rare in patients in whom mBC developed and no evidence was found for an association with specific types of BC or patient characteristics, although outcomes of ERBB2mut+ carriers might be worse. The latter, however, needs to be validated in larger populations.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor ErbB-2/genética , Adulto , Idoso , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Resultado do Tratamento
19.
Acta Clin Belg ; 74(3): 180-188, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29792121

RESUMO

BACKGROUND AND AIM: Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) cause significant adverse events including thyroid dysfunction, mainly hypothyroidism, in a considerable proportion of patients. In a series of metastatic renal cell carcinoma (mRCC) patients treated with sunitinib, we aimed to study the correlation between hypothyroidism and single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics and pharmacodynamics. PATIENTS AND METHODS: We included 79 mRCC patients who started sunitinib between November 2005 and March 2016. Serum thyroid function markers were collected at start and during sunitinib therapy. Germ-line DNA genotyping for 16 SNPs in 8 candidate genes was performed. Endpoints were time to increase in thyroid stimulating hormone (TSH) and time to decrease in T4 or free T4 (FT4) on day 1 and day 28 of each sunitinib cycle. RESULTS: Patients with the ABCG2 rs2231142 CC-genotype had a significantly longer time-to-TSH-increase on day 1 (11 vs. 5 cycles; p = 0.0011), and time-to-T4/FT4-decrease on day 1 (not reached vs. 10 cycles; p = 0.013) and day 28 (28 vs. 7 cycles; p = 0.03) compared to CA-carriers. Patients with the CYP3A5 rs776746 GG-genotype had a significantly longer time-to-TSH-increase at day 1 compared to GA-patients: 11 vs. 5 cycles (p = 0.0071). Significant associations were also found between PDGFRA rs35597368 and rs1800812 and time-to-TSH-increase at day 28. CONCLUSION: Polymorphism rs2231142 in the efflux pump ABCG2 is associated with hypothyroidism in mRCC patients treated with sunitinib.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Hipotireoidismo/induzido quimicamente , Neoplasias Renais/tratamento farmacológico , Proteínas de Neoplasias/genética , Sunitinibe/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/secundário , Feminino , Humanos , Hipotireoidismo/genética , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico
20.
Clin Genitourin Cancer ; 17(2): e235-e246, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30527746

RESUMO

BACKGROUND: There are no validated markers that predict response or resistance in patients with metastatic clear-cell renal cell carcinoma (mccRCC) treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors such as sunitinib and pazopanib. Recently, single nucleotide polymorphism (SNP) rs2981582 in Fibroblast Growth Factor Receptor 2 (FGFR2) was found to be associated with clinical outcome in patients with mccRCC treated with pazopanib and sunitinib. We aimed to validate these findings in patients treated with sunitinib. MATERIALS AND METHODS: Germline DNA was collected in patients with mccRCC starting first-line systemic therapy with sunitinib. SNP rs2981582 in FGFR2 C>T was genotyped. Association of the genotype with response rate, tumor shrinkage, median progression-free survival (mPFS), and median overall survival (mOS) was studied. RESULTS: We collected clinical data from 154 patients with available germline DNA. Baseline prognostic markers were well-balanced between both subgroups. Patients with the TT genotype had a poorer outcome compared with patients with the CT/CC genotype. The median shrinkage of selected tumor target lesions during treatment with sunitinib was -16% versus -31% (P = .002), mPFS was 8 versus 15 months (P = .0007), and mOS was 22 versus 33 months (P = .04), respectively. On multivariate analysis, rs2981582 remained an independent predictor of PFS (hazard ratio, 2.858; 95% confidence interval, 1.659-4.923; P < .0001) and OS (hazard ratio, 1.795; 95% confidence interval, 1.003-3.212; P = .049). CONCLUSION: Polymorphism rs2981582 in FGFR2 is correlated to PFS and OS in patients with mccRCC treated with sunitinib. Prospective validation of the impact of this SNP is warranted.

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