Gonzalez-Neira, A. (Anna)
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- Genomic characterization of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced lung cancer(2018) Pajares, M.J. (María José); Gil-Bazo, I. (Ignacio); Patiño-García, A. (Ana); Pio, R. (Rubén); Lozano, M.D. (María Dolores); Alonso, R. (Rosario); Casanova, C. (Ciro); Perez-Gracia, J.L. (Jose Luis); Benitez, J. (Javier); Rodriguez-Ruiz, M.E. (María Esperanza); Agudo, A. (Antonio); Baz-Dávila, R. (Rebeca); Bou-i-Sala, N. (Núria); Lopez-Picazo, J.M. (José M.); Fusco, J.P. (Juan Pablo); Torres, J.P. (Juan P.) de; Gurpide, A. (Alfonso); Andueza, M.P. (Maria P.); Montuenga-Badia, L.M. (Luis M.); Melero, I. (Ignacio); Ardanaz, E. (Eva); González, Á. (Álvaro); Gonzalez-Neira, A. (Anna); Alvarez, N. (Nuria); Fernandez-Sanmamed, M. (Miguel); Zulueta, J. (Javier); Pita, G. (Guillermo)Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n=3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (p(combined)=5.66x10(-5); ORcombined=2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (p(combined)=1.02x10(-4); ORcombined=2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10D mRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p=0.01 and p<0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I-II NSCLC (p=0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco-induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco-induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC.
- SLC7A8 coding for LAT2 is associated with early disease progression in osteosarcoma and transports doxorubicin(2022) Patiño-García, A. (Ana); Bont, E.S.J.M. (Eveline S. J. M.) de; Versleijen-Jonkers, Y.M.H. (Yvonne M. H.); Loo, D. M. W. M. (D. Maroeska W. M.) to; Nagabushan, S. (Sumanth); Coenen, M. J. H. (Marieke J. H.); Schreuder, H.W.B. (Hendrik W. B.); Vos, H.I. (Hanneke I.); Gelderblom, H. (Hans); Caron, H. (Huib); Nijhoff, G.J. (G. Jan); Brunner, H.G. (Han G.); Koenderink, J.B. (Jan B.); Flucke, U. (Uta); Hagleitner, M.M. (Melanie M.); Graaf, W.T.A. (Winette T. A.); McCowage, G. (Geoff); Hurkmans, E.G.E. (Evelien); Guchelaar, H. J. (Henk-Jan); Saletta, F. (Federica); Muradjan, G. (Grigor); Windsor, R. (Rachael); Kremer, L.C.M. (Leontien C. M.); Hillebrandt-Roeffen, M.H.S. (Melissa H. S.); Cleton-Jansen, A.M. (Anne-Marie); Gonzalez-Neira, A. (Anna); Catchpoole, D. (Daniel); Groothuismink, J.M. (Johanne M.); Heuvel, J.J.M.W. (Jeroen J. M. W.) van den; Touw, D.J. (Daan J.)Background: Despite (neo) adjuvant chemotherapy with cisplatin, doxorubicin and methotrexate, some patients with primary osteosarcoma progress during first-line systemic treatment and have a poor prognosis. In this study, we investigated whether patients with early disease progression (EDP), are characterized by a distinctive pharmacogenetic profile. Methods and Findings: Germline DNA from 287 Dutch high-grade osteosarcoma patients was genotyped using the DMET Plus array (containing 1,936 genetic markers in 231 drug metabolism and transporter genes). Associations between genetic variants and EDP were assessed using logistic regression models and associated variants (p < 0.05) were validated in independent cohorts of 146 (Spain and United Kingdom) and 28 patients (Australia). In the association analyses, EDP was significantly associated with an SLC7A8 locus and was independently validated (meta-analysis validation cohorts: OR 0.19 [0.06-0.55], p = 0.002). The functional relevance of the top hits was explored by immunohistochemistry staining and an in vitro transport models. SLC7A8 encodes for the L-type amino acid transporter 2 (LAT2). Transport assays in HEK293 cells overexpressing LAT2 showed that doxorubicin, but not cisplatin and methotrexate, is a substrate for LAT2 (p < 0.0001). Finally, SLC7A8 mRNA expression analysis and LAT2 immunohistochemistry of osteosarcoma tissue showed that the lack of LAT2 expression is a prognostic factor of poor prognosis and reduced overall survival in patients without metastases (p = 0.0099 and p = 0.14, resp.). Conclusion: This study identified a novel locus in SLC7A8 to be associated with EDP in osteosarcoma. Functional studies indicate LAT2-mediates uptake of doxorubicin, which could give new opportunities to personalize treatment of osteosarcoma patients.
- Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility.(Nature Research, 2018) Machiela, M.J. (Mitchell J.); Wyatt, K. (Kathleen); Bhatia, S. (Smita); Patiño-García, A. (Ana); Armstrong, G.T. (Gregory T.); Zaidi, S. (Sakina); Cox, D.G. (David G.); Zhou, W. (Weiyin); Grünewald, T.G.P. (Thomas G. P.); Tirode, F. (Franck); Hartmann, W. (Wolfgang); Dirksen, U. (Uta); Kirchner, T. (Thomas); Kulozik, A. (Andreas E.); Khan, J. (Javed); Hoover, R.N. (Robert N.); Laurence, V. (Valérie); Freedman, N.D. (Neal D.); Kontny, U. (Udo); Alonso, J. (Javier); Delattre, O. (Olivier); Surdez, D. (Didier); Mirabeau, O. (Olivier); Pierron, G. (Gaelle); Manning, M. (Michelle); Grossetete-Lalami, S. (Sandrine); Mirabello, L. (Lisa); Burdett, L. (Laurie); Leisenring, W.M. (Wendy M.); Ballet, S. (Stelly); Strauch, K. (Konstantin); Kovar, H. (Heinrich); Gaspar, N. (Nathalie); Dagnall, C. (Casey); Kriebel, J. (Jennifer); Chanock, S.J. (Stephen J.); Michon, J. (Jean); Metzler, M. (Markus); Jones, K. (Krisitine); Reynaud, S. (Stephanie); Corradini, N. (Nadege); Picci, P. (Piero); Morton, L.M. (Lindsay M.); Karlins, E. (Eric); Rubio, R.A. (Rebeca Alba); Meitinger, T. (Thomas); Lapouble, E. (Eve); Yeager, M. (Meredith); Bérard, P.M. (Perrine Marec); Robison, L.L. (Leslie L.); Tucker, M. (Margaret); Gonzalez-Neira, A. (Anna); Rothman, N. (Nathaniel)Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.
- El interés de la audiencia española en la política televisada: de los debates electorales al "politainment"(Servicio de Publicaciones de la Universidad de Navarra, 2020) Quintas-Froufe, N. (Natalia); Conde-Vázquez, E. (Erika); Gonzalez-Neira, A. (Anna)Televised politics have become an essential focal point in the planning of the electoral campaigns of any political party. Television is the main source of information during electoral processes and politainment programs have become decisive engagements for candidates. This paper carries out a diachronic analysis of the evolution of the audience of Spanish televised debates in order to verify whether this format is worn out. The sample includes ten electoral debates between presidential candidates held before April 2019. In addition, it focuses on the integration of other platforms in the broadcasting and viewing of the electoral debate, e.g. Twitter. The results of this research show the interest of the Spanish audience in this format, from the first broadcast in 1993 up until today, turning them into real television milestones. Likewise, the candidates have also increased their presence on television through other entertainment formats in order to show furthermore human and emotional facets to the electorate. This recent media exposure of political leaders has also been followed by the Spanish citizens.
- Effect of ABCB1 and ABCC3 Polymorphisms on Osteosarcoma Survival after Chemotherapy: A Pharmacogenetic Study(Public Library of Science, 2011) Caronia, D. (Daniela); Patiño-García, A. (Ana); Zalacain, M. (Marta); Benitez, J. (Javier); Perez-Martinez, A. (Antonio); Sierrasesumaga, L. (Luis); Molina, B. (Blanca); Moreno, L.T. (Leticia Tais); Colmenero, I. (Isabel); Gonzalez-Neira, A. (Anna); Pita, G. (Guillermo)Standard treatment for osteosarcoma patients consists of a combination of cisplatin, adriamycin, and methotrexate before surgical resection of the primary tumour, followed by postoperative chemotherapy including vincristine and cyclophosphamide. Unfortunately, many patients still relapse or suffer adverse events. We examined whether common germline polymorphisms in chemotherapeutic transporter and metabolic pathway genes of the drugs used in standard osteosarcoma treatment may predict treatment response. METHODOLOGY/PRINCIPAL FINDINGS: In this study we screened 102 osteosarcoma patients for 346 Single Nucleotide Polymorphisms (SNPs) and 2 Copy Number Variants (CNVs) in 24 genes involved in the metabolism or transport of cisplatin, adriamycin, methotrexate, vincristine, and cyclophosphamide. We studied the association of the genotypes with tumour response and overall survival. We found that four SNPs in two ATP-binding cassette genes were significantly associated with overall survival: rs4148416 in ABCC3 (per-allele HR = 8.14, 95%CI = 2.73-20.2, p-value = 5.1x10(-)(5)), and three SNPs in ABCB1, rs4148737 (per-allele HR = 3.66, 95%CI = 1.85-6.11, p-value = 6.9x10(-)(5)), rs1128503 and rs10276036 (r(2) = 1, per-allele HR = 0.24, 95%CI = 0.11-0.47 p-value = 7.9x10(-)(5)). Associations with these SNPs remained statistically significant after correction for multiple testing (all corrected p-values [permutation test]