Browsing by Author "Gomez, Fernando"
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Item Association of genetic variants at TOX3, 2q35 and 8q24 with the risk of familial and early-onset breast cancer in a South-American population(Springer, 2014) Elematore, Isabel; Gonzalez-Hormazabal, Patricio; Reyes, José; Blanco, Rafael; Bravo, Teresa; Peralta, Octavio; Gomez, Fernando; Waugh, Enrique; Margarit, Sonia; Ibañez, Gladys; Romero, Carmen; Pakomio, Janara; Roizen, Gigia; Gabriella, Di Capua; Jara, LilianRecent Genome-Wide Association Studies have identified several single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) among women of Asian, European, and African-American ancestry. Nevertheless, the contribution of these variants in the South American population is unknown. Furthermore, there is little information about the effect of these risk alleles in women with early BC diagnosis. In the present study, we evaluated the association between rs3803662 (TOX3, also known as TNRC9), rs13387042 (2q35), and rs13281615 (8q24) with BC risk in 344 Chilean BRCA1/2-negative BC cases and in 801 controls. Two SNPs, rs3803662 and rs13387042, were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC. The risk of BC increased in a dose-dependent manner with the number of risk alleles (P-trend < 0.0001 and 0.0091, respectively). The odds ratios for BC in familial BC and in early-onset non-familial BC were 3.76 (95%CI 1.02-13.84, P = 0.046) and 8.0 (95%CI 2.20-29.04, P = 0.002), respectively, for the maximum versus minimum number of risk alleles. These results indicate an additive effect of the TOX3 rs3803662 and 2q35 rs13387042 alleles for BC risk. We also evaluated the interaction between rs3803662 and rs13387042 SNPs. We observed an additive interaction only in non-familial early-onset BC cases (AP = 0.72 (0.28-1.16), P = 0.001). No significant association was observed for rs13281615 (8q24) with BC risk in women from the Chilean population. The strongly increased risk associated with the combination of low-penetrance risk alleles supports the polygenic inheritance model of BC.Item Association of genetic variants at TOX3, 2q35 and 8q24 with the risk of familial and early-onset breast cancer in a South-American population(2014) Elematore, Isabel; Gonzalez-Hormazabal, Patricio; Reyes, Jose M.; Blanco, Rafael; Bravo, Teresa; Peralta, Octavio; Gomez, Fernando; Waugh, Enrique; Margarit, Sonia; Ibañez, Gladys; Romero, Carmen; Pakomio, Janara; Roizen, Gigia; Di Capua, Gabriella A.; Jara, LilianAbstract Recent Genome-Wide Association Studies have identified several single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) among women of Asian, European, and African-American ancestry.Nevertheless, the contribution of these variants in the South American population is unknown. Furthermore, there is little information about the effect of these risk alleles in women with early BC diagnosis. In the present study, we evaluated the association between rs3803662 (TOX3, also known as TNRC9), rs13387042 (2q35), and rs13281615 (8q24) with BC risk in 344 Chilean BRCA1/2-negative BC cases and in 801 controls. Two SNPs, rs3803662 and rs13387042, were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC. The risk of BC increased in a dose-dependent manner with the number of risk alleles (P-trend \0.0001 and 0.0091, respectively). The odds ratios for BC in familial BC and in early-onset non-familial BC were 3.76 (95 %CI 1.02–13.84, P = 0.046) and 8.0 (95 %CI 2.20–29.04, P = 0.002), respectively, for the maximum versus minimum number of risk alleles. These results indicate an additive effect of the TOX3 rs3803662 and 2q35 rs13387042 alleles for BC risk. We also evaluated the interaction between rs3803662 and rs13387042 SNPs. We observed an additive interaction only in non-familial early-onset BC cases (AP = 0.72 (0.28–1.16), P = 0.001). No significant association was observed for rs13281615 (8q24) with BC risk in women from the Chilean population. The strongly increased risk associated with the combination of low-penetrance risk alleles supports the polygenic inheritance model of BC.Item Genetic variants in FGFR2 and MAP3K1 are associated with the risk of familial and early-onset breast cancer in a south-american population(Springer, 2013) Jara, Lilian; Gonzalez-Hormazabal, Patricio; Cerceño, Kerube; Di Capua, Gabriella; Jose, Reyes; Blanco, Rafael; Bravo, Teresa; Peralta, Octavio; Gomez, Fernando; Waugh, Enrique; Margarit, Sonia; Ibañez, Gladys; Romero, Carmen; Pakomio, Janara; Roizen, GigiaGenome-Wide Association Studies have identified several loci associated with breast cancer (BC) in populations of different ethnic origins. One of the strongest associations was found in the FGFR2 gene, and MAP3K1 has been proposed as a low-penetrance BC risk factor. In this study, we evaluated the associations among FGFR2 SNPs rs2981582, rs2420946, and rs1219648; and MAP3K1 rs889312, with BC risk in 351 BRCA1/2-negative Chilean BC cases and 802 controls. All the SNPs studied were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC, in a dose-dependent manner. Subjects with 3 risk alleles were at a significantly increased risk of BC compared with subjects with 0-2 risk alleles, in both familial BC and early-onset non-familial BC (OR = 1.47, 95 % CI 1.04-2.07, P = 0.026 and OR = 2.04 95 % CI 1.32-3.24, P < 0.001, respectively). In the haplotype analysis, the FGFR2 rs2981582 T / rs2420946 T / rs1219648 G haplotype (ht2) was associated with a significantly increased BC risk compared with the rs2981582 C / rs2420946 C / rs1219648 A haplotype in familial BC and in non-familial early-onset BC (OR = 1.32, 95 % CI 1.06-1.65, P = 0.012; OR = 1.46, 95 % CI 1.11-1.91, P = 0.004, respectively). When the FGFR2 ht2 and MAP3K1 rs889312 were evaluated as risk alleles, the risk of BC increased in a dose-dependent manner as the number of risk alleles increased (P trend <0.0001), indicating an additive effect. Nevertheless, there is no evidence of an interaction between FGFR2 ht2 and the MAP3K1 rs889312 C allele. These findings suggest that genetic variants in the FGFR2 and MAP3K1 genes may contribute to genetic susceptibility to BC.Item The BARD1 Cys557Ser variant and risk of familial breast cancer in a South-American population(Springer, 2012) Gonzalez-Hormazabal, Patricio; Reyes, Jose; Blanco, Rafael; Bravo, Teresa; Carrera, Ignacio; Peralta, Octavio; Gomez, Fernando; Waugh, Enrique; Margarit, Sonia; Ibañez, Gladys; Santos, Jose; Jara, LilianSince the discovery of the BRCA1 and BRCA2 genes, much work has been carried out to identify further breast cancer (BC) susceptibility genes. BARD1 (BRCA1-associated ring domain) was originally identified as a BRCA1-interacting protein but has also been described in tumor-suppressive functions independent of BRCA1. Some association studies have suggested that the BARD1 Cys557Ser variant might be associated with increased risk of BC, but others have failed to confirm this finding. To date, this variant has not been analyzed in Spanish or South-American populations. In this study, using a case–control design, we analyzed the C-terminal Cys557Ser change in 322 Chilean BC cases with no mutations in BRCA1 or BRCA2 and in 570 controls in order to evaluate its possible association with BC susceptibility. BARD1 Cys557Ser was associated with an increased BC risk (P = 0.04, OR = 3.4 [95 % CI 1.2–10.2]) among cases belonging to families with a strong family history of BC. No difference between single cases affected with age <50 years at diagnosis (n = 117) and controls was observed for carriers of Cys/Ser genotype. It is likely that this variant is not involved in BC risk in this group of women. We also analyzed a possible interaction between BARD1 557Ser/XRCC3 241Met variants considering the role of both genes in the maintenance of genome integrity. The combined genotype Cys/Ser-carrier with the XRCC3 241Met allele was associated with an increased BC risk (P = 0.02, OR = 5.01 [95 % CI 1.36–18.5]) among women belonging to families with at least three BC and/or ovarian cancer cases. Our results suggest that BARD1 557Ser and XRCC3 241Met may play roles in BC risk in women with a strong family history of BC. Nevertheless there is no evidence of an interaction between the two SNPs. These findings should be confirmed by other studies and in other populations.Item Therapeutic alternatives for the treatment of type 1 hepatorenal syndrome: A Delphi technique-based consensus(Baishideng Publishing Group, 2016) Arab, Juan; Claro, Juan; Arancibia, Juan; Contreras, Jorge; Gomez, Fernando; Muñoz, Cristian; Nazal, Leyla; Roessler, Eric; Wolff, Rodrigo; Arrese, Marco; Benitez, CarlosAIM To propose several alternatives treatment of type 1 hepatorenal syndrome (HRS-1) what is the most severe expression of circulatory dysfunction on patients with portal hypertension. METHODS A group of eleven gastroenterologists and nephrologists performed a structured analysis of available literature. Each expert was designated to review and answer a question. They generated draft statements for evaluation by all the experts. Additional input was obtained from medical community. In order to reach consensus, a modified three-round Delphi technique method was used. According to United States Preventive Services Task Force criteria, the quality of the evidence and level of recommendation supporting each statement was graded. RESULTS Nine questions were formulated. The available evidence was evaluated considering its quality, number of patients included in the studies and the consistency of its results. The generated questions were answered by the expert panel with a high level of agreement. Thus, a therapeutic algorithm was generated. The role of terlipressin and norepinephrine was confirmed as the pharmacologic treatment of choice. On the other hand the use of the combination of octreotide, midodrine and albumin without vasoconstrictors was discouraged. The role of several other options was also evaluated and the available evidence was explored and discussed. Liver transplantation is considered the definitive treatment for HRS-1. The present consensus is an important effort that intends to organize the available strategies based on the available evidence in the literature, the quality of the evidence and the benefits, adverse effects and availability of the therapeutic tools described. CONCLUSION Based on the available evidence the expert panel was able to discriminate the most appropriate therapeutic alternatives for the treatment of HRS-1.Item Variants in DNA double-strand break repair genes and risk of familial breast cancer in a South American population(2010) Jara, Lilian; Dubois, Karen; Gaete, Daniel; de Mayo, Tomas; Ratkevicius, Nikalai; Bravo, Teresa; Margarit, Sonia; Blanco, Rafael; Gomez, Fernando; Waugh, Enrique; Peralta, Octavio; Reyes, Jose M.; Ibanez, Gladys; Gonzalez-Hormazabal, PatricioThe double-strand break (DSB) DNA repair pathway has been implicated in breast cancer (BC). RAD51 and its paralogs XRCC3 and RAD51D play an important role in the repair of DSB through homologous recombination (HR). Some polymorphisms including XRCC3-Thr241Met, RAD51-135G[C, and RAD51D-E233G have been found to confer increased BC susceptibility. In order to detect novel mutations that may contribute to BC susceptibility, 150 patients belonging to 150 Chilean BRCA1/2-negative families were screened for mutations in XRCC3. No mutations were detected in the XRCC3 gene. In addition, using a case–control design we studied the XRCC3-Thr241Met, and RAD51D-E233G polymorphisms in 267 BC cases and 500 controls to evaluate their possible association with BC susceptibility. The XRCC3 Met/Met genotype was associated with an increased BC risk (P = 0.003, OR = 2.44 [95%CI 1.34–4.43]). We did not find an association between E233G polymorphism and BC risk. We also analyzed the effect of combined genotypes among RAD51-135G[C, Thr241Met, and E233G polymorphisms on BC risk. No interaction was observed between Thr241Met and 135G[C. The combined genotype Thr/Met–E/G was associated with an increased BC risk among women who (a) have a family history of BC, (b) are BRCA1/2-negative, and (c) were \50 years at onset (n = 195) (P = 0.037, OR = 10.5 [95%CI 1.16–94.5]). Our results suggested that the variability of the DNA HR repair genes XRCC3 and RAD51D may play a role in BC risk, but this role may be underlined by a mutual interaction between these genes. These findings should be confirmed in other populations.