Benitez, J. (Javier)
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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.
- De novo erythroleukemia chromosome features include multiple rearrangements, with special involvement of chromosomes 11 and 19(Wiley-Blackwell, 2003) Cigudosa, J.C. (Juan Cruz); Urioste, M. (Miguel); Benitez, J. (Javier); Alvarez, S. (Sara); Sole, F. (Francesc); Cervera, J.V. (Jose V.); Nimer, S.D. (Stephen D.); Martinez-Ramirez, A. (Angel); Sanz, M.A. (Miguel A.); Calasanz-Abinzano, M.J. (Maria Jose); Salido, M. (Marta); MacGrogan, D. (Donald); Arranz, E. (Eva); Odero, M.D. (Maria Dolores)Erythroid leukemia (ERL or AML-M6) is an uncommon subtype of acute myeloid leukemia, the clinical, morphological, and genetic behavior of which needs further characterization. We analyzed a homogeneous group of 23 de novo AML-M6 patients whose bone marrow cells showed complex karyotypes. We also analyzed eight leukemia cell lines with erythroid phenotype, performing detailed molecular cytogenetic analyses, including spectral karyotyping (SKY) in all samples. The main features are: (1) A majority of patients (56%) had hypodiploidy. Loss of genetic material was the most common genetic change, especially monosomies of chromosome 7 or 18, and deletions of chromosome arm 5q. Taken together, 87% of the cases displayed aberrations involving chromosome 5 or 8. (2) We describe a novel, cryptic, and recurrent translocation, t(11;19)(p11.2;q13.1). Another translocation, t(12;21)(p11.2;q11.2), was found to be recurrent in a patient with ERL and in the K562 cell line. (3) MLL gene rearrangements were detected in 20% of cases (three translocations and three amplifications) and, overall, we defined 52 rearrangements (excluding deletions) with a mean of 2.3 translocations per patient. (4) Of the structural aberrations, 21% involved chromosomes 11 and 19. Most of the rearrangements were unbalanced; only 13 reciprocal translocations were observed. The general picture of chromosomal aberrations in cell lines did not reflect what occurred in patient samples. However, both primary samples and cell lines shared three common breakpoints at 19q13.1, 20q11.2, and 21q11.2. This is the first molecular cytogenetic description of the karyotype abnormalities present in patients with ERL. It should assist in the identification of genes involved in erythroleukemogenesis.
- 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]