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Browsing CNIO by Publisher "American Association for Cancer Research (AACR)"
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Publication A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human tumors.(American Association for Cancer Research (AACR), 2004-08-15) Fraga, Mario F; Herranz, Michel; Espada, Jesús; Ballestar, Esteban; Paz, Maria F; Ropero, Santiago; Erkek, Emel; Bozdogan, Onder; Peinado, Héctor; Niveleau, Alain; Mao, Jian-Hua; Balmain, Alan; Cano, Amparo; Esteller, ManelWhereas accepted models of tumorigenesis exist for genetic lesions, the timing of epigenetic alterations in cancer is not clearly understood. We have analyzed the profile of aberrations in DNA methylation occurring in cells lines and primary tumors of one of the best-characterized mouse carcinogenesis systems, the multistage skin cancer progression model. Initial analysis using high-performance capillary electrophoresis and immunolocalization revealed a loss of genomic 5-methylcytosine associated with the degree of tumor aggressiveness. Paradoxically, this occurs in the context of a growing number of hypermethylated CpG islands of tumor suppressor genes at the most malignant stages of carcinogenesis. We have observed this last phenomenon using two approaches, a candidate gene approach, studying genes with well-known methylation-associated silencing in human tumors, and a mouse cDNA microarray expression analysis after treatment with DNA demethylating drugs. The transition from epithelial to spindle cell morphology is particularly associated with major epigenetic alterations, such as E-cadherin methylation, demethylation of the Snail promoter, and a decrease of the global DNA methylation. Analysis of data obtained from the cDNA microarray strategy led to the identification of new genes that undergo methylation-associated silencing and have growth-inhibitory effects, such as the insulin-like growth factor binding protein-3. Most importantly, all of the above genes were also hypermethylated in human cancer cell lines and primary tumors, underlining the value of the mouse skin carcinogenesis model for the study of aberrant DNA methylation events in cancer cells.Publication Combined MEK and PI3K/p110β Inhibition as a Novel Targeted Therapy for Malignant Mesothelioma Displaying Sarcomatoid Features.(American Association for Cancer Research (AACR), 2020-02-15) Marqués, Miriam; Tranchant, Robin; Risa-Ebrí, Blanca; Suárez-Solís, María L; Fernández, Luis C; Carrillo-de-Santa-Pau, Enrique; Del Pozo, Natalia; Martínez de Villarreal, Jaime; Meiller, Clément; Allory, Yves; Blum, Yuna; Pirker, Christine; Hegedus, Balazs; Barry, Simon T; Carnero, Amancio; Berger, Walter; Jean, Didier; Real Arribas, Francisco; Ministerio de Ciencia, Innovación y Universidades (España); Institut National de la Santé et de la Recherche Médicale (Francia); Instituto de Salud Carlos III; American Association For Cancer ResearchAmong malignant mesotheliomas (MM), the sarcomatoid subtype is associated with higher chemoresistance and worst survival. Due to its low incidence, there has been little progress in the knowledge of the molecular mechanisms associated with sarcomatoid MM, which might help to define novel therapeutic targets. In this work, we show that loss of PTEN expression is frequent in human sarcomatoid MM and PTEN expression levels are lower in sarcomatoid MM than in the biphasic and epithelioid subtypes. Combined Pten and Trp53 deletion in mouse mesothelium led to nonepithelioid MM development. In Pten;Trp53-null mice developing MM, the Gαi2-coupled receptor subunit activated MEK/ERK and PI3K, resulting in aggressive, immune-suppressed tumors. Combined inhibition of MEK and p110β/PI3K reduced mouse tumor cell growth in vitro. Therapeutic inhibition of MEK and p110β/PI3K using selumetinib (AZD6244, ARRY-142886) and AZD8186, two drugs that are currently in clinical trials, increased the survival of Pten;Trp53-null mice without major toxicity. This drug combination effectively reduced the proliferation of primary cultures of human pleural (Pl) MM, implicating nonepithelioid histology and high vimentin, AKT1/2, and Gαi2 expression levels as predictive markers of response to combined MEK and p110β/PI3K inhibition. Our findings provide a rationale for the use of selumetinib and AZD8186 in patients with MM with sarcomatoid features. This constitutes a novel targeted therapy for a poor prognosis and frequently chemoresistant group of patients with MM, for whom therapeutic options are currently lacking. SIGNIFICANCE: Mesothelioma is highly aggressive; its sarcomatoid variants have worse prognosis. Building on a genetic mouse model, a novel combination therapy is uncovered that is relevant to human tumors.Publication Endoglin, a novel biomarker and therapeutical target to prevent malignant peripheral nerve sheath tumor growth and metastasis.(American Association for Cancer Research (AACR), 2023-07-11) González-Muñoz, Teresa; Di Giannatale, Angela; Garcia-Silva, Susana; Santos, Vanesa; Sanchez-Redondo, Sara; Savini, Claudia; Graña-Castro, Osvaldo; Blanco-Aparicio, Carmen; Fischer, Suzanne; De Wever, Olivier; Creus-Bachiller, Edgar; Ortega-Bertran, Sara; Pisapia, David J; Rodríguez-Peralto, José L; Fernández-Rodríguez, Juana; Romagosa, Cleofe; Alaggio, Rita; Benassi, Maria Serena; Pazzaglia, Laura; Scotlandi, Katia; Ratner, Nancy; Yohay, Kaleb; Theuer, Charles P; Peinado Selgas, Hector; United States Department of Defense; Asociación Española Contra el Cáncer; Ministerio de Ciencia e Innovación (España)PURPOSE Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGF-β coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs. EXPERIMENTAL DESIGN ENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell-specific ENG expression on gene expression, signaling pathway activation and in vivo MPNST growth and metastasis were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models. RESULTS ENG expression was found to be upregulated in both human MPNST tumor tissues and plasma circulating small extracellular vesicles. We demonstrated that ENG modulates Smad1/5 and MAPK/ERK pathway activation and pro-angiogenic and pro-metastatic gene expression in MPNST cells and plays an active role in tumor growth and metastasis in vivo. Targeting with ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST growth and metastasis in xenograft models by reducing tumor cell proliferation and angiogenesis. Moreover, combination of anti-ENG therapy with MEK inhibition effectively reduced tumor cell growth and angiogenesis. CONCLUSIONS Our data unveil a tumor-promoting function of ENG in MPNSTs and support the use of this protein as a novel biomarker and a promising therapeutic target for this disease.Publication Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation.(American Association for Cancer Research (AACR), 2014-07-01) Martínez-Bosch, Neus; Fernández-Barrena, Maite G; Moreno, Mireia; Ortiz-Zapater, Elena; Munné-Collado, Jessica; Iglesias, Mar; André, Sabine; Gabius, Hans-Joachim; Hwang, Rosa F; Poirier, Françoise; Navas, Carolina; Guerra, Carmen; Fernández-Zapico, Martin E; Navarro, Pilar; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Fundacio La Marato'TV3; AICR; Generalitat Catalunya; Instituto de Salud Carlos III; Ligue Nationale Contre le Cancer (Francia); EC GlycoHIT program; Fundacion Ramon Areces; Mayo Clinic Pancreatic SPORE; Mayo Clinic Center for Cell Signaling in GastroenterologyDespite some advances, pancreatic ductal adenocarcinoma (PDAC) remains generally refractory to current treatments. Desmoplastic stroma, a consistent hallmark of PDAC, has emerged as a major source of therapeutic resistance and thus potentially promising targets for improved treatment. The glycan-binding protein galectin-1 (Gal1) is highly expressed in PDAC stroma, but its roles there have not been studied. Here we report functions and molecular pathways of Gal1 that mediate its oncogenic properties in this setting. Genetic ablation of Gal1 in a mouse model of PDAC (EIa-myc mice) dampened tumor progression by inhibiting proliferation, angiogenesis, desmoplasic reaction and by stimulating a tumor-associated immune response, yielding a 20% increase in relative lifesplan. Cellular analyses in vitro and in vivo suggested these effects were mediated through the tumor microenvironment. Importantly, acinar-to-ductal metaplasia, a crucial step for initiation of PDAC, was found to be regulated by Gal1. Mechanistic investigations revealed that Gal1 promoted Hedgehog pathway signaling in PDAC cells and stromal fibroblasts as well as in Ela-myc tumors. Taken together, our findings establish a function for Gal1 in tumor-stroma crosstalk in PDAC and provide a preclinical rationale for Gal1 targeting as a microenvironment-based therapeutic strategy.Publication Genetic profiling of epithelial cells expressing E-cadherin repressors reveals a distinct role for Snail, Slug, and E47 factors in epithelial-mesenchymal transition.(American Association for Cancer Research (AACR), 2006-10-01) Moreno-Bueno, Gema; Cubillo, Eva; Sarrió, David; Peinado, Héctor; Rodríguez-Pinilla, Socorro María; Villa, Sonia; Bolós, Victoria; Jordá, Mireia; Fabra, Angels; Portillo, Francisco; Palacios, José; Cano, AmparoThe transcription factors Snail, Slug, and bHLH E47 have been recently described as direct repressors of E-cadherin and inducers of epithelial-mesenchymal transition (EMT) and invasion when overexpressed in epithelial cells. Although a role of those factors in tumor progression and invasion has been proposed, whether the different repressors play distinct or redundant roles in the tumorigenic process has not been established. To further investigate this important issue, we have analyzed the gene expression profiling of Madin-Darby canine kidney (MDCK) epithelial cells expressing the different repressors (MDCK-Snail, MDCK-Slug, and MDCK-E47 cells) versus control MDCK cells by cDNA microarrays. A total of 243 clones (228 genes and 15 expressed sequence tags) were found to be differentially expressed between either of the three MDCK-derived cell lines and control MDCK cells. Twenty two of the candidate genes were validated by Northern blot, Western blot, immunofluorescence, and promoter analyses in cell lines and by immunohistochemistry in xenografted tumors. Gene clustering analysis indicated that about a third of the 243 candidate genes were common to MDCK cells expressing Snail, Slug, or E47 factors, whereas the rest of the genes were regulated in only one or two cell types. Differentially regulated genes include those related to EMT (45 genes), transcriptional regulation (18 genes), cell proliferation and signaling (54 genes), apoptosis (12 genes), and angiogenesis (9 genes). These results indicate that Snail, Slug, and E47 transcription factors induce common and specific genetic programs, supporting a differential role of the factors in tumor progression and invasion.Publication Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk.(American Association for Cancer Research (AACR), 2020-09-15) Yuan, Fangcheng; Hung, Rayjean J; Walsh, Naomi; Zhang, Han; Platz, Elizabeth A; Wheeler, William; Song, Lei; Arslan, Alan A; Beane Freeman, Laura E; Bracci, Paige; Canzian, Federico; Du, Mengmeng; Gallinger, Steven; Giles, Graham G; Goodman, Phyllis J; Kooperberg, Charles; Le Marchand, Loic; Neale, Rachel E; Rosendahl, Jonas; Scelo, Ghislaine; Shu, Xiao-Ou; Visvanathan, Kala; White, Emily; Zheng, Wei; Albanes, Demetrius; Amiano, Pilar; Andreotti, Gabriella; Babic, Ana; Bamlet, William R; Berndt, Sonja I; Brennan, Paul; Bueno-de-Mesquita, Bas; Buring, Julie E; Campbell, Peter T; Chanock, Stephen J; Fuchs, Charles S; Gaziano, J Michael; Goggins, Michael G; Hackert, Thilo; Hartge, Patricia; Hassan, Manal M; Holly, Elizabeth A; Hoover, Robert N; Katzke, Verena; Kirsten, Holger; Kurtz, Robert C; Lee, I-Min; Malats, Nuria; Milne, Roger L; Murphy, Neil; Ng, Kimmie; Oberg, Ann L; Porta, Miquel; Rabe, Kari G; Real Arribas, Francisco; Rothman, Nathaniel; Sesso, Howard D; Silverman, Debra T; Thompson, Ian M; Wactawski-Wende, Jean; Wang, Xiaoliang; Wentzensen, Nicolas; Wilkens, Lynne R; Yu, Herbert; Zeleniuch-Jacquotte, Anne; Shi, Jianxin; Duell, Eric J; Amundadottir, Laufey T; Li, Donghui; Petersen, Gloria M; Wolpin, Brian M; Risch, Harvey A; Yu, Kai; Klein, Alison P; Stolzenberg-Solomon, Rachael; NIH - National Cancer Institute (NCI) (Estados Unidos)Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10-6, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P = 0.22) and primary sclerosing cholangitis (P = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. SIGNIFICANCE: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.Publication Glycolytic enzymes can modulate cellular life span.(American Association for Cancer Research (AACR), 2005-01-01) Kondoh, Hiroshi; Lleonart, Matilde E; Gil, Jesús; Wang, Jing; Degan, Paolo; Peters, Gordon; Martinez Garcia, Maria Dolores; Carnero, Amancio; Beach, David; Wellcome TrustAn unbiased screen for genes that can immortalize mouse embryonic fibroblasts identified the glycolytic enzyme phosphoglycerate mutase (PGM). A 2-fold increase in PGM activity enhances glycolytic flux, allows indefinite proliferation, and renders cells resistant to ras-induced arrest. Glucosephosphate isomerase, another glycolytic enzyme, displays similar activity and, conversely, depletion of PGM or glucosephosphate isomerase with short interfering RNA triggers premature senescence. Immortalized mouse embryonic fibroblasts and mouse embryonic stem cells display higher glycolytic flux and more resistance to oxidative damage than senescent cells. Because wild-type p53 down-regulates PGM, mutation of p53 can facilitate immortalization via effects on PGM levels and glycolysis.Publication Hematologic β-tubulin VI isoform exhibits genetic variability that influences paclitaxel toxicity.(American Association for Cancer Research (AACR), 2012-09-15) Leandro-García, Luis J; Leskelä, Susanna; Inglada-Pérez, Lucía; Landa, Iñigo; de Cubas, Aguirre A; Maliszewska, Agnieszka; Comino-Méndez, Iñaki; Letón, Rocío; Gómez-Graña, Álvaro; Torres, Raúl; Ramírez, Juan Carlos; Álvarez, Sara; Rivera, José; Martínez, Constantino; Lozano, María Luisa; Cascón, Alberto; Robledo Batanero, Mercedes; Rodriguez Antona, Cristina; Ministerio de Ciencia e Innovación (España)Cellular microtubules composed of α-β-tubulin heterodimers that are essential for cell shape, division, and intracellular transport are valid targets for anticancer therapy. However, not all the conserved but differentially expressed members of the β-tubulin gene superfamily have been investigated for their role in these settings. In this study, we examined roles for the hematologic isoform β-tubulin VI and functional genetic variants in the gene. β-tubulin VI was highly expressed in blood cells with a substantial interindividual variability (seven-fold variation in mRNA). We characterized DNA missense variations leading to Q43P, T274M, and R307H, and a rare nonsense variant, Y55X. Because variations in the hematologic target of microtubule-binding drugs might alter their myelosuppressive action, we tested their effect in cell lines stably expressing the different β-tubulin VI full-length variants, finding that the T274M change significantly decreased sensitivity to paclitaxel-induced tubulin polymerization. Furthermore, patients treated with paclitaxel and carrying β-tubulin VI T274M exhibited a significantly lower thrombocytopenia than wild-type homozygous patients (P = 0.031). Together, our findings define β-tubulin VI as a hematologic isotype with significant genetic variation in humans that may affect the myelosuppresive action of microtubule-binding drugs. A polymorphism found in a tubulin isoform expressed only in hemapoietic cells may contribute to the patient variation in myelosuppression that occurs after treatment with microtubule-binding drugs.Publication Long Noncoding RNA NIHCOLE Promotes Ligation Efficiency of DNA Double-Strand Breaks in Hepatocellular Carcinoma.(American Association for Cancer Research (AACR), 2021-10-01) Unfried, Juan P; Marín-Baquero, Mikel; Rivera-Calzada, Ángel; Razquin, Nerea; Martín-Cuevas, Eva M; de Bragança, Sara; Aicart-Ramos, Clara; McCoy, Christopher; Prats-Mari, Laura; Arribas-Bosacoma, Raquel; Lee, Linda; Caruso, Stefano; Zucman-Rossi, Jessica; Sangro, Bruno; Williams, Gareth; Moreno-Herrero, Fernando; Llorca Blanco, Oscar Antonio; Lees-Miller, Susan P; Fortes, Puri; Llorca, Oscar; Unfried, Juan P.; Martín-Cuevas, Eva M.; Lees-Miller, Susan P; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Economía y Competitividad (España); Ligue Nationale Contre le Cancer (Francia); Natural Sciences and Engineering Research Council of Canada (NSERC); Canada Foundation for Innovation; Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Unión Europea. Comisión Europea. European Research Council (ERC); United States Department of Health and Human ServicesLong noncoding RNAs (lncRNA) are emerging as key players in cancer as parts of poorly understood molecular mechanisms. Here, we investigated lncRNAs that play a role in hepatocellular carcinoma (HCC) and identified NIHCOLE, a novel lncRNA induced in HCC with oncogenic potential and a role in the ligation efficiency of DNA double-stranded breaks (DSB). NIHCOLE expression was associated with poor prognosis and survival of HCC patients. Depletion of NIHCOLE from HCC cells led to impaired proliferation and increased apoptosis. NIHCOLE deficiency led to accumulation of DNA damage due to a specific decrease in the activity of the nonhomologous end-joining (NHEJ) pathway of DSB repair. DNA damage induction in NIHCOLE-depleted cells further decreased HCC cell growth. NIHCOLE was associated with DSB markers and recruited several molecules of the Ku70/Ku80 heterodimer. Further, NIHCOLE putative structural domains supported stable multimeric complexes formed by several NHEJ factors including Ku70/80, APLF, XRCC4, and DNA ligase IV. NHEJ reconstitution assays showed that NIHCOLE promoted the ligation efficiency of blunt-ended DSBs. Collectively, these data show that NIHCOLE serves as a scaffold and facilitator of NHEJ machinery and confers an advantage to HCC cells, which could be exploited as a targetable vulnerability. SIGNIFICANCE: This study characterizes the role of lncRNA NIHCOLE in DNA repair and cellular fitness in HCC, thus implicating it as a therapeutic target.See related commentary by Barcena-Varela and Lujambio, p. 4899.Publication Regulatory polymorphisms in β-tubulin IIa are associated with paclitaxel-induced peripheral neuropathy.(American Association for Cancer Research (AACR), 2012-08-15) Leandro-García, Luis J; Leskelä, Susanna; Jara, Carlos; Gréen, Henrik; Avall-Lundqvist, Elisabeth; Wheeler, Heather E; Dolan, M Eileen; Inglada-Perez, Lucia; Maliszewska, Agnieszka; de Cubas, Aguirre A; Comino-Méndez, Iñaki; Mancikova, Veronika; Cascón, Alberto; Rodríguez-Antona, Cristina; Robledo Batanero, Mercedes; Ministerio de Ciencia (España); NIH - National Cancer Institute (NCI) (Estados Unidos); Swedish Cancer Society (Cancerfonden); Ministerio de Economía y Competitividad (España); NIH - National Institute of General Medical Sciences (NIGMS) (Estados Unidos); Instituto de Salud Carlos IIIPURPOSE Peripheral neuropathy is the dose-limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat several solid tumors such as breast, lung, and ovary. The cytotoxic effect of paclitaxel is mediated through β-tubulin binding in the cellular microtubules. In this study, we investigated the association between paclitaxel neurotoxicity risk and regulatory genetic variants in β-tubulin genes. EXPERIMENTAL DESIGN We measured variation in gene expression of three β-tubulin isotypes (I, IVb, and IIa) in lymphocytes from 100 healthy volunteers, sequenced the promoter region to identify polymorphisms putatively influencing gene expression and assessed the transcription rate of the identified variants using luciferase assays. To determine whether the identified regulatory polymorphisms were associated with paclitaxel neurotoxicity, we genotyped them in 214 patients treated with paclitaxel. In addition, paclitaxel-induced cytotoxicity in lymphoblastoid cell lines was compared with β-tubulin expression as measured by Affymetrix exon array. RESULTS We found a 63-fold variation in β-tubulin IIa gene (TUBB2A) mRNA content and three polymorphisms located at -101, -112, and -157 in TUBB2A promoter correlated with increased mRNA levels. The -101 and -112 variants, in total linkage disequilibrium, conferred TUBB2A increased transcription rate. Furthermore, these variants protected from paclitaxel-induced peripheral neuropathy [HR, 0.62; 95% confidence interval (CI), 0.42-0.93; P = 0.021, multivariable analysis]. In addition, an inverse correlation between TUBB2A and paclitaxel-induced apoptosis (P = 0.001) in lymphoblastoid cell lines further supported that higher TUBB2A gene expression conferred lower paclitaxel sensitivity. CONCLUSIONS This is the first study showing that paclitaxel neuropathy risk is influenced by polymorphisms regulating the expression of a β-tubulin gene.Publication Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy.(American Association for Cancer Research (AACR), 2017-03-01) Apellániz-Ruiz, María; Tejero, Héctor; Inglada-Pérez, Lucía; Sánchez-Barroso, Lara; Gutiérrez-Gutiérrez, Gerardo; Calvo, Isabel; Castelo, Beatriz; Redondo, Andrés; García-Donás, Jesús; Romero-Laorden, Nuria; Sereno, María; Merino, María; Currás-Freixes, María; Montero-Conde, Cristina; Mancikova, Veronika; Åvall-Lundqvist, Elisabeth; Green, Henrik; Al-Shahrour, Fátima; Cascón, Alberto; Robledo Batanero, Mercedes; Rodríguez-Antona, Cristina; Ministerio de Ciencia (España); Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España); Asociación Española Contra el Cáncer; Swedish Cancer Society; LiU CancerPurpose: Neuropathy is the dose-limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for interindividual differences remain unexplained. In this study, we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes.Experimental Design: We sequenced the coding region of 4 EPHA genes, 5 genes involved in paclitaxel pharmacokinetics, and 30 Charcot-Marie-Tooth genes, in 228 cancer patients with no/low neuropathy or high-grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/gene-based analyses were used to compare variant frequencies among neuropathy groups, and Cox regression models were used to analyze neuropathy along treatment.Results: Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy. Low-frequency nonsynonymous variants in EPHA6 were present exclusively in patients with high neuropathy, and all affected the ligand-binding domain of the protein. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency nonsynonymous variant carriers [HR, 14.60; 95% confidence interval (CI), 2.33-91.62; P = 0.0042], and an independent cohort confirmed an increased neuropathy risk (HR, 2.07; 95% CI, 1.14-3.77; P = 0.017). Combining the series gave an estimated 2.5-fold higher risk of neuropathy (95% CI, 1.46-4.31; P = 9.1 × 10-4).Conclusions: This first study sequencing EPHA genes revealed that low-frequency variants in EPHA6, EPHA5, and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHA's neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs. Clin Cancer Res; 23(5); 1227-35. ©2016 AACR.Publication Whole-exome sequencing reveals defective CYP3A4 variants predictive of paclitaxel dose-limiting neuropathy.(American Association for Cancer Research (AACR), 2015-01-15) Apellániz-Ruiz, María; Lee, Mi-Young; Sánchez-Barroso, Lara; Gutiérrez-Gutiérrez, Gerardo; Calvo, Isabel; García-Estévez, Laura; Sereno, María; García-Donás, Jesús; Castelo, Beatriz; Guerra, Eva; Leandro-García, Luis J; Cascón, Alberto; Johansson, Inger; Robledo Batanero, Mercedes; Ingelman-Sundberg, Magnus; Rodriguez Antona, Cristina; Ministerio de Economía y Competitividad (España); The Swedish Research Council; The Swedish Cancer Foundation; Karolinska Institutet; Fundación La CaixaPURPOSE Paclitaxel, a widely used chemotherapeutic drug, can cause peripheral neuropathies leading to dose reductions and treatment suspensions and decreasing the quality of life of patients. It has been suggested that genetic variants altering paclitaxel pharmacokinetics increase neuropathy risk, but the major causes of interindividual differences in susceptibility to paclitaxel toxicity remain unexplained. We carried out a whole-exome sequencing (WES) study to identify genetic susceptibility variants associated with paclitaxel neuropathy. EXPERIMENTAL DESIGN Blood samples from 8 patients with severe paclitaxel-induced peripheral neuropathy were selected for WES. An independent cohort of 228 cancer patients with complete paclitaxel neuropathy data was used for variant screening by DHPLC and association analysis. HEK293 cells were used for heterologous expression and characterization of two novel CYP3A4 enzymes. RESULTS WES revealed 2 patients with rare CYP3A4 variants, a premature stop codon (CYP3A4*20 allele) and a novel missense variant (CYP3A4*25, p.P389S) causing reduced enzyme expression. Screening for CYP3A4 variants in the independent cohort revealed three additional CYP3A4*20 carriers, and two patients with missense variants exhibiting diminished enzyme activity (CYP3A4*8 and the novel CYP3A4*27 allele, p.L475V). Relative to CYP3A4 wild-type patients, those carrying CYP3A4 defective variants had more severe neuropathy (2- and 1.3-fold higher risk of neuropathy for loss-of-function and missense variants, respectively, P = 0.045) and higher probability of neuropathy-induced paclitaxel treatment modifications (7- and 3-fold higher risk for loss-of-function and missense variants, respectively, P = 5.9 × 10(-5)). CONCLUSION This is the first description of a genetic marker associated with paclitaxel treatment modifications caused by neuropathy. CYP3A4 defective variants may provide a basis for paclitaxel treatment individualization.