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  • American Association for Cancer Research (AACR)  (25)
  • 1
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 4 ( 2013-04-01), p. 530-541
    Abstract: Trabectedin is more active in nucleotide excision repair (NER)-efficient and homologous recombination repair (HRR)-deficient cells. As up to 25% of sporadic breast tumors present somatic inactivation of the HRR pathway (BRCAness phenotype), we sought to characterize trabectedin effect in BRCA1-proficient and BRCA1-null breast cancer cell lines. We evaluated whether HRR and NER gene expression correlates with trabectedin sensitivity and explored the response predictive value of the CUL4A ubiquitin ligase, which ubiquitinates NER pathway members. We characterized trabectedin cytotoxicity, cell-cycle effects, and BRCA1, BRCA2, XRCC3, XPG, ERCC1, and CUL4A expression in 10 breast cancer cell lines. Gene expression and trabectedin sensitivity association were determined in cell lines. Survival assays after trabectedin treatment were conducted in CUL4A-silenced BRCA1-proficient and -deficient cells. Because of limited phase II clinical trials evaluating trabectedin efficacy in patients with breast cancer, we assessed CUL4A immunohistochemical staining in a retrospective series of 118 sarcomas from trabectedin-treated patients to validate in vivo our in vitro observations. In cell lines, greater trabectedin sensitivity was associated with higher CUL4A expression and lower BRCA1/ERCC5, BRCA1/CUL4A, and XRCC3/CUL4A expression ratios. In agreement, BRCA1-deficient CUL4A-knockdown cells presented higher cell survival after trabectedin exposure than did scramble control cells. Lack of effect in BRCA1-proficient cells suggests that HRR impairment is key in CUL4A-mediated trabectedin sensitivity. High CUL4A expression in nontranslocation-related patients with sarcoma predicted improved progression-free survival [PFS; HR, 0.37; 95% confidence interval (CI), 0.20–0.68, P = 0.001] and overall survival (OS; HR, 0.44; 95% CI, 0.21–0.93, P = 0.026). Our observations support the notion of greater trabectedin activity in tumors exhibiting BRCAness and reveal CUL4A as a potential biomarker for definition of trabectedin target patients. Mol Cancer Ther; 12(4); 530–41. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 16 ( 2017-08-15), p. 4365-4377
    Abstract: ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B-cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here, we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ETV6-RUNX1 pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase (KDM) family. KDM5C loss of function resulted in increased levels of H3K4me3, which coprecipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an ETV6-RUNX1 preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches. Cancer Res; 77(16); 4365–77. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P4-10-28-P4-10-28
    Abstract: BACKGROUND The appearance of secondary hypertension (HTN) is one of the most common side effects of anti-angiogenic agents since it emerges in over 50% of the patients with these therapies. Independently of tumor type, in most clinical trials it was possible to observe a positive association between secondary HTN and better clinical outcome, including Progression Free Survival (PFS) and Overall Survival (OS). Preeclampsia is one of the biological models that better resembles the anti-VEGF/VEGFR action of these therapies. DNA methylation is one of the epigenetic mechanisms potentially related to variation in susceptibility to gestational HTN. The objective of our study is to define a specific epigenetic signature that could predict secondary HTN to anti-angiogenic treatment in patients that received bevacizumab in combination with chemotherapy (CT) from the BRECOL study. METHODS Patients (n=113) from BRECOL study (NCT01733628) received bevacizumab in combination with oxaliplatin or irinotecan + fluoropyrimidines for metastatic colorectal cancer (n=49), and with paclitaxel or capecitabine for metastatic breast cancer (n=64). Blood pressure (BP) was recorded with a Holter measurement (24 hours registration starting 2 hours after treatment administration). A methylation analysis was carried out on DNA obtained from pretreatment peripheral blood samples in 32 patients (28%) distributed in 4 experimental groups (8 patients / each) and classified according to their HTN history and to their BP variation upon bevacizumab plus CT: • Group A: patients with HTN history and with BP increase • Group B: patients with HTN history and with no BP increase • Group C: patients without HTN history and with BP increase • Group D: patients without HTN history and with no BP increase Analysis was realized with the “Infinium Human Methylation EPIC BeadChip” array (Illumina®) on bisulfite-converted DNA and differentially methylated sites were identified with the LIMMA (“Linear Models for Microarray Analysis”) bioinformatics tool (Bioconductor®). RESULTS Upon analysis of 850000 different methylation sites distributed all over the genome, we identified 27 (18 localized in the coding regions of the genes: FMNL2, METTL3, ACOT6, SCARNA20, PREX1, DNAI2, RAET1G, KCNJ8, GDF7, SYNPO2, CUGBP1, FRMD8, MKL2, HIF1A, TMEM177, UTP23, PXK and TNPO1; 9 localized in intergenic regions) that are differentially methylated in patients that showed secondary HTN to bevacizumab plus CT, independently of HTN history (Groups A + C vs. B + D). Based on Principal Components (PC) analysis, we defined a methylation score predictive of elevated BP. First PC (PC1) explains the 83.2% of the variability of the 27 identified methylation sites and allows to distinguish between patients that do and do not show secondary HTN. CONCLUSIONS High BP upon anti-angiogenic treatment is associated to specific DNA methylation profiles. We identified an epigenetic methylation signature putative predictive of secondary HTN to bevacizumab treatment in metastatic breast and colorectal cancer. Citation Format: Juan de la Haba, Teresa Morales-Ruiz, Pilar García-Alfonso, Jose Ponce Lorenzo, Lourdes Calvo, Antonio Antón, Raul Marquez, Pedro Sánchez-Rovira, Ana Santaballa, Eva Ciruelos, María Victoria García-Ortiz, Teresa Roldán-Arjona, Jesús Herranz, Massimo Chiesa, Rosalía Caballero, Javier Gallego, Álvaro Rodríguez-Lescure. Identification of a specific epigenetic signature in patients showing secondary hypertension upon anti-VEGF treatment from the GEICAM/2011-04 (BRECOL) study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-28.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 4
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), ( 2024-01-11), p. OF1-OF14
    Abstract: The gut microbiota plays important roles in health and disease. We questioned whether the gut microbiota and related metabolites are altered in monoclonal gammopathies and evaluated their potential role in multiple myeloma and its response to treatment. Patients and Methods: We used 16S rRNA sequencing to characterize and compare the gut microbiota of patients with monoclonal gammopathy of undetermined significance (n = 11), smoldering multiple myeloma (n = 9), newly diagnosed multiple myeloma (n = 11), relapsed/refractory multiple myeloma (n = 6), or with complete remission (n = 9). Short-chain fatty acids (SCFA) were quantified in serum and tested in cell lines. Relevant metabolites were validated in a second cohort of 62 patients. Results: Significant differences in alpha- and beta diversity were present across the groups and both were lower in patients with relapse/refractory disease and higher in patients with complete remission after treatment. Differences were found in the abundance of several microbiota taxa across disease progression and in response to treatment. Bacteria involved in SCFA production, including Prevotella, Blautia, Weissella, and Agathobacter, were more represented in the premalignant or complete remission samples, and patients with higher levels of Agathobacter showed better overall survival. Serum levels of butyrate and propionate decreased across disease progression and butyrate was positively associated with a better response. Both metabolites had antiproliferative effects in multiple myeloma cell lines. Conclusions: We demonstrate that SCFAs metabolites and the gut microbiota associated with their production might have beneficial effects in disease evolution and response to treatment, underscoring its therapeutic potential and value as a predictor.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2024
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  • 5
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 21 ( 2022-11-01), p. 4771-4781
    Abstract: Early intervention in smoldering multiple myeloma (SMM) requires optimal risk stratification to avoid under- and overtreatment. We hypothesized that replacing bone marrow (BM) plasma cells (PC) for circulating tumor cells (CTC), and adding immune biomarkers in peripheral blood (PB) for the identification of patients at risk of progression due to lost immune surveillance, could improve the International Myeloma Working Group 20/2/20 model. Experimental Design: We report the outcomes of 150 patients with SMM enrolled in the iMMunocell study, in which serial assessment of tumor and immune cells in PB was performed every 6 months for a period of 3 years since enrollment. Results: Patients with & gt;0.015% versus ≤0.015% CTCs at baseline had a median time-to-progression of 17 months versus not reached (HR, 4.9; P  & lt; 0.001). Presence of & gt;20% BM PCs had no prognostic value in a multivariate analysis that included serum free light-chain ratio & gt;20, & gt;2 g/dL M-protein, and & gt;0.015% CTCs. The 20/2/20 and 20/2/0.015 models yielded similar risk stratification (C-index of 0.76 and 0.78). The combination of the 20/2/0.015 model with an immune risk score based on the percentages of SLAN+ and SLAN− nonclassical monocytes, CD69+HLADR+ cytotoxic NK cells, and CD4+CXCR3+ stem central memory T cells, allowed patient’ stratification into low, intermediate-low, intermediate-high, and high-risk disease with 0%, 20%, 39%, and 73% rates of progression at 2 years. Conclusions: This study showed that CTCs outperform BM PCs for assessing tumor burden. Additional analysis in larger series are needed to define a consensus cutoff of CTCs for minimally invasive stratification of SMM.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 84, No. 9_Supplement ( 2024-05-02), p. PO2-10-05-PO2-10-05
    Abstract: Background: Breast cancer (BC) is the most common malignancy and one of the leading causes of cancer death in women in Latin America (LATAM). Studies have highlighted the importance of understanding contextual characteristics of each patient population to inform health policy-making. However, few data are available on women from LATAM, a region with marked inequalities. Methods: LATINA (LACOG 0615/MO39485) is a multicenter prospective cohort study designed to describe sociodemographic characteristics, diagnosis, treatment, and outcomes of patients with BC in LATAM. Female and male patients aged ≥18 years newly diagnosed (i.e., & lt; 12 months from research site activation) histologically confirmed clinical stage I-IV BC were enrolled. Eligible patients provided informed consent and had data collected from medical records at diagnosis and every 6 months up to 5 years. Results: Between February 2020 and August 2022, 3276 patients with BC from 31 research sites in 10 LATAM countries were included. Median age was 54 years (range 23–95), 91.8% (N=3008) were Hispanic or Latinos, the majority (68%, N=2224) were diagnosed with stage II or III BC, and 73% (N=2362) were treated in the public health system. Age, stage and detection method stratified by education level, marital status and employment status are shown in Table 1. Overall, 38.8% (N=1149) of patients had not completed high school. These patients were more frequently diagnosed by symptoms and diagnosed at later stages than those who had completed high school or college. Half of the patients were married/in a civil partnership at BC diagnosis (50.5%, N=1497). Unmarried patients were more commonly diagnosed by symptoms (71.7%, N=835 vs. 64%, N=916, p & lt; 0.001) and with stage II/III BC (71.4%, N=868 vs. 67.6%, N=1038, p & lt; 0.001) than married patients. Most patients (54.1%, N=1603) were not employed at BC diagnosis. Patients not employed were more frequently diagnosed by symptoms (68.8%, N=1044) than employees/self-employed (61.6%, N=675). After adjusting for age, country, health care provision (public or private), stage, and BC subtype, being diagnosed by symptoms was associated with not being married (adjusted odds ratio [aOR] 1.41, 95% CI 1.11–1.82, p=0.004), being not employed (aOR 1.41, 95% CI 1.08–1.84, p=0.011), and not having completed high school (aOR 1.46, 95% CI 1.00–2.13, p=0.031). Conclusions: Patients with a lower level of education, unmarried and not employed, are more likely not to perform BC screening and to be diagnosed by symptoms. Socioeconomic characteristics impact the method of detection of BC in LATAM and are associated with diagnosis at later stages. Further analyses of the LATINA study will provide invaluable data for informing regional health policy-making in LATAM. Citation Format: Gustavo Werutsky, Cynthia Villarreal-Garza, Henry Gómez, Juan Manuel Donaire, José Bines, Luis Henrique Fein, Maria Clara Horsburgh, Paula Cabrera-Galeana, Heloísa Resende, Rosa Vasallo Veras, Miriam Raimondo, Ricardo Elías Brugés Maya, Vidal Maria Del Rosario, Yeni Nerón, Ana Maria Donoso, Fernanda B. Damian, José D'Oliveira, Couto Filho, Maria Isabel Alonso, Victoria Costanzo, Tomás Reinert, Adriana Elizabeth Borello, Eduardo Cronenberger, Luis Fein, Marcela Urrego, Enrique Alanya, Jorge Luis Soriano García, Saúl Campos-Gomez, Eduardo A. Richardet, Hugo Castro-Salguero, Felipe Cruz, Diego Gómez, Angel Hernández, Carlos Alberto Farfan Tello, Ronald Rodríguez, Rafaela Jesus, Gustavo Gössling, Carlos Barrios. The Impact of Socioeconomic Factors on Breast Cancer Diagnosis in Latin America: The LATINA study (LACOG 0615/MO39485) [abstract] . In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-10-05.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2024
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 84, No. 9_Supplement ( 2024-05-02), p. PO2-10-04-PO2-10-04
    Abstract: Background: Breast cancer (BC) is the most common malignancy and one of the leading causes of cancer death in women in Latin America (LATAM). However, the region lacks a unified multinational initiative to investigate BC and to further understand regional disparities. Methods: LATINA (LACOG 0615/MO39485) is the first multinational prospective cohort study designed to describe clinicopathological characteristics, treatment patterns, and outcomes of patients with BC in LATAM. Patients aged ≥18 years diagnosed with primary or recurrent BC in the 12 months preceding site activation were included. Data were collected at enrollment and every 6 months for up to 5 years. We present here the results for clinicopathological and demographic characteristics at BC diagnosis. Multivariable logistic regression was performed to investigate characteristics associated with later diagnosis (stage II/III vs. stage I) and detection method (symptomatic vs. screening). Causal mediation analysis was performed to investigate the detection method as a mediator of the effect of health care provision (public or private) on stage at diagnosis. Results: Between February 2020 and August 2022, 3276 patients from 31 research sites in 10 LATAM countries were included. Most patients in this cohort (72.1%, N=2362) were treated in the public health system. Regarding ethnicity, most patients (91.8%, N=3008) self-identified as Latinos and were White (47.3%, N=1549), American Indian (21.0%, N=689), and Black or Brown (16.6%, N=544). The median age at diagnosis was 54 years (range 23–95), 41.8% (N=1368) were & lt; 50 years of age at BC diagnosis, and 54.1% (N=375) of the American Indian patients were ≤50 years of age. BC subtype distribution was: 43.2% (N=1336) luminal A, 14.3% (N=433) luminal B, 22.9% (N=709) human epidermal growth factor receptor 2-positive (HER2+), and 15.4% (N=477) triple negative. In patients older than 50 years old, most cases were detected with symptoms, particularly in the public health system (63.2%, N=836) vs. 50.5% (N=232) in the private health system, p & lt; 0.0001). This was also the case in Black/Brown (61.6%, N=178) and American Indian patients (89.5%, N=281) vs. White patients (45.6%, N=413) (p & lt; 0.0001). In the public system, 37.7% (N=890) and 31.7% (N=748) of cases were diagnosed at stage II and III vs. 37.6% (N=343) and 26.6% (N=243) of cases in the private system, respectively (p & lt; 0.0001). Users of the public health system had a significantly higher risk of being diagnosed with symptoms vs. screening (adjusted odds ratio [aOR] 3.54, 95% CI 2.17–5.76). Causal mediation analysis showed that the detection method (screening vs. symptomatic) mediated 21.8% (95% CI 1.7%–41.9%, p=0.034) of the effect of health care provision (public or private) on stage at diagnosis. Self-identifying as Black (aOR 2.11, 95% CI 1.29–3.45), age & lt; 40 years (aOR 1.97, 95% CI 1.20–3.23), public health care provision (aOR 2.18, 95% CI 1.32–3.59), and a diagnosis of HER2+ (aOR 1.74, 95% CI 1.20–2.52) or triple-negative BC (aOR 2.34, 95% CI 1.47–3.71) were associated with an increased risk of being diagnosed at a later stage. Conclusions: A significant proportion of new BC diagnoses in LATAM is observed in patients & lt; 50 years of age. Reflecting the low screening coverage throughout the region, most patients detect the disease with symptoms. Stage III BC accounted for 30.3% of new cases, being more common among users of the public health system. Differences in the stage at diagnosis related to health care provision (public or private), ethnicity, and country underscore significant disparities that need to be addressed. Further analyses of these data will help identify factors associated with late diagnosis and support the development of regional corrective health policies. Citation Format: Gustavo Werutsky, Cynthia Villarreal-Garza, Henry Gómez, Juan Manuel Donaire, José Bines, Luis Henrique Fein, Maria Clara Horsburgh, Paula Cabrera-Galeana, Heloísa Resende, Rosa Vasallo Veras, Miriam Raimondo, Ricardo Elías Brugés Maya, Vidal Maria Del Rosario, Yeni Nerón, Ana Maria Donoso, Fernanda B. Damian, José D'Oliveira, Couto Filho, Maria Isabel Alonso, Victoria Costanzo, Tomás Reinert, Adriana Elizabeth Borello, Eduardo Cronenberger, Luis Fein, Marcela Urrego, Enrique Alanya, Jorge Luis Soriano García, Saúl Campos-Gomez, Eduardo A. Richardet, Hugo Castro-Salguero, Felipe Cruz, Diego Gómez, Angel Hernández, Carlos Alberto Farfan Tello, Ronald Rodríguez, Rafaela Jesus, Gustavo Gössling, Carlos Barrios. Clinicopathological Characteristics and Factors Associated With Screening and Late-Stage Diagnosis in Patients With Breast Cancer in Latin America: The LATINA Study (LACOG 0615/MO39485) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-10-04.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2024
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  • 8
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 1 ( 2017-01-01), p. 225-238
    Abstract: Purpose: PIM kinases are a family of serine/threonine kinases recently proposed as therapeutic targets in oncology. In the present work, we have investigated the effects of the novel pan-PIM kinase inhibitor, PIM447, on myeloma cells and myeloma-associated bone disease using different preclinical models. Experimental Design: In vitro/ex vivo cytotoxicity of PIM447 was evaluated on myeloma cell lines and patient samples. Synergistic combinations with standard treatments were analyzed with Calcusyn Software. PIM447 effects on bone cells were assessed on osteogenic and osteoclastogenic cultures. The mechanisms of PIM447 were explored by immunoblotting, qPCR, and immunofluorescence. A murine model of disseminated multiple myeloma was employed for in vivo studies. Results: PIM447 is cytotoxic for myeloma cells due to cell-cycle disruption and induction of apoptosis mediated by a decrease in phospho-Bad (Ser112) and c-Myc levels and the inhibition of mTORC1 pathway. Importantly, PIM447 demonstrates a very strong synergy with different standard treatments such as bortezomib + dexamethasone (combination index, CI = 0.002), lenalidomide + dexamethasone (CI = 0.065), and pomalidomide + dexamethasone (CI = 0.077). PIM447 also inhibits in vitro osteoclast formation and resorption, downregulates key molecules involved in these processes, and partially disrupts the F-actin ring, while increasing osteoblast activity and mineralization. Finally, PIM447 significantly reduced the tumor burden and prevented tumor-associated bone loss in a disseminated murine model of human myeloma. Conclusions: Our results demonstrate dual antitumoral and bone-protective effects of PIM447. This fact, together with the very strong synergy exhibited with standard-of-care treatments, supports the future clinical development of this drug in multiple myeloma. Clin Cancer Res; 23(1); 225–38. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3488-3488
    Abstract: Aims: LOXL2 is a protein with a key role in epithelial-to-mesenchymal transition (EMT). EMT was established as an early event in GEP-NET. LOXL2 emerged as a new prognostic marker in the analysis of a 115 GEP-NET cases (training cohort (TC); Barriuso et al, ASCO 2014). Our main objective was to validate LOXL2 expression by immunohistochemistry (IHC) in an independent cohort. Methods: Formalin-fixed paraffin-embedded samples (FFPEs) of consecutive GEP-NET patients from 1999 to 2010 who underwent surgery and their clinical data were collected from a different Spanish institution (validation cohort (VC)). Tissue microarrays were constructed from two non-necrotic areas of tumour foci. LOXL2 expression was studied by IHC and classified as presence (P) vs absence (A). Log rank test and cox regression were used to study Disease Free Survival (DFS) and Overall Survival (OS) in the VC and the combined series (TC+VC; n = 206). Univariate (UVA) and multivariable analysis (MVA) were performed. Results: A total of 91 FFPE samples were included in the VC. Median follow up was 77 months. Tumor grade was differently distributed between the TC and the VC (p & lt;0.001) while stage was not (p = 0.195). LOXL2 P was associated with better OS (p = 0.023) and showed a trend for better DFS (p = 0.066) in the VC. DFS at 3 years was 85% in LOXL2-P group vs 45% in LOXL2-A group. OS at 5 years was 82% vs 51% respectively. LOXL2 P was associated with better DFS and OS (p & lt;0.001) when the combined series was analysed. LOXL2 remained as an independent prognostic factor for OS adjusted for grade and stage in the MVA in both settings. Conclusion: Our results validated LOXL2 as a novel prognostic biomarker candidate for GEP-NETs in an independent cohort. Further testing in prospective studies to depict its potential value in the clinic is warranted. LOXL2 could also represent an actionable target in this scenario. UVA for DFSMVA for DFSUVA for OSMVA for OSTraining cohort (TC) (n = 115)0.3 (0.1-0.7) P = 0.012*0.5 (0.1-1.8) P = 0.280.2 (0.1-0.5) P = 0.001*0.2 (0.04-0.8) P = 0.024*Validation cohort (VC) (n = 91)0.5 (0.2-1.1) P = 0.0790.3 (0.1-0.7) P = 0.011*0.4 (0.1-0.9) P = 0.029*0.2 (0.1-0.6) P = 0.01*Combined series (n = 206)0.3 (0.2-0.6) P & lt;0.001*0.3 (0.1-0.6) P = 0.002*0.2 (0.1-0.4) P & lt;0.001*0.2 (0.1-0.5) P & lt;0.001*Cox regression for LOXL2. MVA adjusted for grade and stage. Hazard ratios, 95% confidence intervals and p values. *statistically significant differences. Citation Format: Jorge Barriuso, Marta Benavent, Angela Lamarca, Elsa Bernal, Laura Guerra Pastrian, Victoria Heredia, Maria Miguel, Clara Beatriz Garcia-Calderon, Cristina Alvarez-Escola, Jose Castell, Ana Custodio, Emilio Burgos, Jaime Feliu, Rocio Garcia-Carbonero, Marta Mendiola. External validation of lysyl oxidase-like 2 (LOXL2) as a novel prognostic marker for gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3488.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 20 ( 2014-10-15), p. 5808-5818
    Abstract: A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2 ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09–1.27, P = 4.67 × 10−5] versus OR = 1.01 (95% CI, 0.93–1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (Ptrend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. Cancer Res; 74(20); 5808–18. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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