Pita, G. (Guillermo)
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- 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]
- 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.
- Whole exome sequencing characterization of individuals presenting extreme phenotypes of high and low risk of developing tobacco-induced lung adenocarcinoma(2021) Patiño-García, A. (Ana); Guruceaga, E. (Elizabeth); Segura, V. (Víctor); Sanchez-Bayona, R. (Rodrigo); Andueza-Unanua, P. (Pilar); Tamayo-Uria, I. (Ibon); Serrano, G. (Guillermo); Fusco, J.P. (Juan Pablo); Pajares, M.J. (María José); Gurpide, A. (Alfonso); Ocón-De-Miguel, M.M. (María M.); Fernandez-Sanmamed, M. (Miguel); Rodriguez-Ruiz, M.E. (María Esperanza); Melero, I. (Ignacio); Lozano, M.D. (María Dolores); NO USAR de Andrea, C. E. (Carlos E.); Pita, G. (Guillermo); Gonzalez-Neira, A. (Anna); González, Á. (Álvaro); Zulueta, J. (Javier); Montuenga-Badia, L.M. (Luis M.); Pio, R. (Rubén); Perez-Gracia, J.L. (Jose Luis)Background: Tobacco is the main risk factor for developing lung cancer. Yet, some heavy smokers do not develop lung cancer at advanced ages while others develop it at young ages. Here, we assess for the first time the genetic background of these clinically relevant extreme phenotypes using whole exome sequencing (WES). Methods: We performed WES of germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age (extreme cases, n=50) or did not present lung adenocarcinoma or other tumors at an advanced age (extreme controls, n=50). We selected non-synonymous variants located in exonic regions and consensus splice sites of the genes that showed significantly different allelic frequencies between both cohorts. We validated our results in all the additional extreme cases (i.e., heavy smokers who developed lung adenocarcinoma at an early age) available from The Cancer Genome Atlas (TCGA). Results: The mean age for the extreme cases and controls was respectively 49.7 and 77.5 years. Mean tobacco consumption was 43.6 and 56.8 pack-years. We identified 619 significantly different variants between both cohorts, and we validated 108 of these in extreme cases selected from TCGA. Nine validated variants, located in relevant cancer related genes, such as PARP4, HLA-A or NQO1, among others, achieved statistical significance in the False Discovery Rate test. The most significant validated variant (P=4.48×10−5) was located in the tumor-suppressor gene ALPK2. Conclusions: We describe genetic variants associated with extreme phenotypes of high and low risk for the development of tobacco-induced lung adenocarcinoma. Our results and our strategy may help to identify high-risk subjects and to develop new therapeutic approaches.