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9. Mutational Characterization of Cutaneous Melanoma Supports Divergent Pathways Model for Melanoma Development

Author

Millan-Esteban D, Pena-Chilet M, Garcia-Casado Z, Manrique-Silva E, Requena C, Banuls J, Lopez-Guerrero J, Rodriguez-Hernandez A, Traves V, Dopazo J, Viros A, Kumar R, and Nagore E

Subjects
melanoma, etiopathogeny, mutations, neoplasms
Abstract

Simple Summary The divergent pathway model established at least two approaches for melanoma development. One was related to a propensity to melanocytic proliferation (nevogenic), and the other was associated with an accumulation of solar damage (CSD). We conducted a retrospective study to examine whether this model had a molecular support using sequencing and bioinformatic tools on a set of cutaneous melanomas corresponding to these two groups. We found that the nevogenic melanomas were associated with mutations in BRAF, while the CSD melanomas were associated with mutations in NF1, ROS1, GNA11, and RAC1. We concluded that nevogenic and CSD melanomas constitute two different biological entities. According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being BRAF. The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included NF1, ROS1, GNA11, and RAC1. We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.

Published
2021

14. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author

Landi MT, Bishop DT, MacGregor S, Machiela MJ, Stratigos AJ, Ghiorzo P, Brossard M, Calista D, Choi J, Fargnoli MC, Zhang T, Rodolfo M, Trower AJ, Menin C, Martinez J, Hadjisavvas A, Song L, Stefanaki I, Scolyer R, Yang R, Goldstein AM, Potrony M, Kypreou KP, Pastorino L, Queirolo P, Pellegrini C, Cattaneo L, Zawistowski M, Gimenez-Xavier P, Rodriguez A, Elefanti L, Manoukian S, Rivoltini L, Smith BH, Loizidou MA, Del Regno L, Massi D, Mandala M, Khosrotehrani K, Akslen LA, Amos CI, Andresen PA, Avril MF, Azizi E, Soyer HP, Bataille V, Dalmasso B, Bowdler LM, Burdon KP, Chen WV, Codd V, Craig JE, Debniak T, Falchi M, Fang S, Friedman E, Simi S, Galan P, Garcia-Casado Z, Gillanders EM, Gordon S, Green A, Gruis NA, Hansson J, Harland M, Harris J, Helsing P, Henders A, Hocevar M, Höiom V, Hunter D, Ingvar C, Kumar R, Lang J, Lathrop GM, Lee JE, Li X, Lubinski J, Mackie RM, Malt M, Malvehy J, McAloney K, Mohamdi H, Molven A, Moses EK, Neale RE, Novakovic S, Nyholt DR, Olsson H, Orr N, Fritsche LG, Puig-Butille JA, Qureshi AA, Radford-Smith GL, Randerson-Moor J, Requena C, Rowe C, Samani NJ, Sanna M, Schadendorf D, Schulze HJ, Simms LA, Smithers M, Song F, Swerdlow AJ, van der Stoep N, Kukutsch NA, Visconti A, Wallace L, Ward SV, Wheeler L, Sturm RA, Hutchinson A, Jones K, Malasky M, Vogt A, Zhou W, Pooley KA, Elder DE, Han J, Hicks B, Hayward NK, Kanetsky PA, Brummett C, Montgomery GW, Olsen CM, Hayward C, Dunning AM, Martin NG, Evangelou E, Mann GJ, Long G, Pharoah PDP, Easton DF, Barrett JH, Cust AE, Abecasis G, Duffy DL, Whiteman DC, Gogas H, De Nicolo A, Tucker MA, Newton-Bishop JA, GenoMEL Consortium, Q-MEGA and QTWIN Investigators, ATHENS Melanoma Study Group, 23andMe, SDH Study Group, IBD Investigators, Essen-Heidelberg Investigators, AMFS Investigators, MelaNostrum Consortium, Peris K, Chanock SJ, Demenais F, Brown KM, Puig S, Nagore E, Shi J, Iles MM, and Law MH

Abstract

Meta-analysis of 36,760 cases and 375,188 controls identifies 54 loci associated with susceptibility to cutaneous melanoma. Further analysis combining nevus count and hair color GWAS results provide insights into the genetic architecture of melanoma. Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 x 10(-8)) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Published
2020

15. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author

Landi, M.T. Bishop, D.T. MacGregor, S. Machiela, M.J. Stratigos, A.J. Ghiorzo, P. Brossard, M. Calista, D. Choi, J. Fargnoli, M.C. Zhang, T. Rodolfo, M. Trower, A.J. Menin, C. Martinez, J. Hadjisavvas, A. Song, L. Stefanaki, I. Scolyer, R. Yang, R. Goldstein, A.M. Potrony, M. Kypreou, K.P. Pastorino, L. Queirolo, P. Pellegrini, C. Cattaneo, L. Zawistowski, M. Gimenez-Xavier, P. Rodriguez, A. Elefanti, L. Manoukian, S. Rivoltini, L. Smith, B.H. Loizidou, M.A. Del Regno, L. Massi, D. Mandala, M. Khosrotehrani, K. Akslen, L.A. Amos, C.I. Andresen, P.A. Avril, M.-F. Azizi, E. Soyer, H.P. Bataille, V. Dalmasso, B. Bowdler, L.M. Burdon, K.P. Chen, W.V. Codd, V. Craig, J.E. Dębniak, T. Falchi, M. Fang, S. Friedman, E. Simi, S. Galan, P. Garcia-Casado, Z. Gillanders, E.M. Gordon, S. Green, A. Gruis, N.A. Hansson, J. Harland, M. Harris, J. Helsing, P. Henders, A. Hočevar, M. Höiom, V. Hunter, D. Ingvar, C. Kumar, R. Lang, J. Lathrop, G.M. Lee, J.E. Li, X. Lubiński, J. Mackie, R.M. Malt, M. Malvehy, J. McAloney, K. Mohamdi, H. Molven, A. Moses, E.K. Neale, R.E. Novaković, S. Nyholt, D.R. Olsson, H. Orr, N. Fritsche, L.G. Puig-Butille, J.A. Qureshi, A.A. Radford-Smith, G.L. Randerson-Moor, J. Requena, C. Rowe, C. Samani, N.J. Sanna, M. Schadendorf, D. Schulze, H.-J. Simms, L.A. Smithers, M. Song, F. Swerdlow, A.J. van der Stoep, N. Kukutsch, N.A. Visconti, A. Wallace, L. Ward, S.V. Wheeler, L. Sturm, R.A. Hutchinson, A. Jones, K. Malasky, M. Vogt, A. Zhou, W. Pooley, K.A. Elder, D.E. Han, J. Hicks, B. Hayward, N.K. Kanetsky, P.A. Brummett, C. Montgomery, G.W. Olsen, C.M. Hayward, C. Dunning, A.M. Martin, N.G. Evangelou, E. Mann, G.J. Long, G. Pharoah, P.D.P. Easton, D.F. Barrett, J.H. Cust, A.E. Abecasis, G. Duffy, D.L. Whiteman, D.C. Gogas, H. De Nicolo, A. Tucker, M.A. Newton-Bishop, J.A. Peris, K. Chanock, S.J. Demenais, F. Brown, K.M. Puig, S. Nagore, E. Shi, J. Iles, M.M. Law, M.H. GenoMEL Consortium Q-MEGA QTWIN Investigators ATHENS Melanoma Study Group 23andMe The SDH Study Group IBD Investigators Essen-Heidelberg Investigators AMFS Investigators MelaNostrum Consortium

Abstract

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10−8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis. © 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Published
2020

17. The JAK2 V617F mutation identifies a subgroup of MDS patients with isolated deletion 5q and a proliferative bone marrow

Author

Ingram, W, Lea, N C, Cervera, J, Germing, U, Fenaux, P, Cassinat, B, Kiladjian, J J, Varkonyi, J, Antunovic, P, Westwood, N B, Arno, M J, Mohamedali, A, Gaken, J, Kontou, T, Czepulkowski, B H, Twine, N A, Tamaska, J, Csomer, J, Benedek, S, Gattermann, N, Zipperer, E, Giagounidis, A, Garcia-Casado, Z, Sanz, G, and Mufti, G J

Published
2006
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19. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Author

Landi, M.T. Bishop, D.T. MacGregor, S. Machiela, M.J. Stratigos, A.J. Ghiorzo, P. Brossard, M. Calista, D. Choi, J. Fargnoli, M.C. Zhang, T. Rodolfo, M. Trower, A.J. Menin, C. Martinez, J. Hadjisavvas, A. Song, L. Stefanaki, I. Scolyer, R. Yang, R. Goldstein, A.M. Potrony, M. Kypreou, K.P. Pastorino, L. Queirolo, P. Pellegrini, C. Cattaneo, L. Zawistowski, M. Gimenez-Xavier, P. Rodriguez, A. Elefanti, L. Manoukian, S. Rivoltini, L. Smith, B.H. Loizidou, M.A. Del Regno, L. Massi, D. Mandala, M. Khosrotehrani, K. Akslen, L.A. Amos, C.I. Andresen, P.A. Avril, M.-F. Azizi, E. Soyer, H.P. Bataille, V. Dalmasso, B. Bowdler, L.M. Burdon, K.P. Chen, W.V. Codd, V. Craig, J.E. Dębniak, T. Falchi, M. Fang, S. Friedman, E. Simi, S. Galan, P. Garcia-Casado, Z. Gillanders, E.M. Gordon, S. Green, A. Gruis, N.A. Hansson, J. Harland, M. Harris, J. Helsing, P. Henders, A. Hočevar, M. Höiom, V. Hunter, D. Ingvar, C. Kumar, R. Lang, J. Lathrop, G.M. Lee, J.E. Li, X. Lubiński, J. Mackie, R.M. Malt, M. Malvehy, J. McAloney, K. Mohamdi, H. Molven, A. Moses, E.K. Neale, R.E. Novaković, S. Nyholt, D.R. Olsson, H. Orr, N. Fritsche, L.G. Puig-Butille, J.A. Qureshi, A.A. Radford-Smith, G.L. Randerson-Moor, J. Requena, C. Rowe, C. Samani, N.J. Sanna, M. Schadendorf, D. Schulze, H.-J. Simms, L.A. Smithers, M. Song, F. Swerdlow, A.J. van der Stoep, N. Kukutsch, N.A. Visconti, A. Wallace, L. Ward, S.V. Wheeler, L. Sturm, R.A. Hutchinson, A. Jones, K. Malasky, M. Vogt, A. Zhou, W. Pooley, K.A. Elder, D.E. Han, J. Hicks, B. Hayward, N.K. Kanetsky, P.A. Brummett, C. Montgomery, G.W. Olsen, C.M. Hayward, C. Dunning, A.M. Martin, N.G. Evangelou, E. Mann, G.J. Long, G. Pharoah, P.D.P. Easton, D.F. Barrett, J.H. Cust, A.E. Abecasis, G. Duffy, D.L. Whiteman, D.C. Gogas, H. De Nicolo, A. Tucker, M.A. Newton-Bishop, J.A. Peris, K. Chanock, S.J. Demenais, F. Brown, K.M. Puig, S. Nagore, E. Shi, J. Iles, M.M. Law, M.H. GenoMEL Consortium Q-MEGA QTWIN Investigators ATHENS Melanoma Study Group 23andMe The SDH S and Landi, M.T. Bishop, D.T. MacGregor, S. Machiela, M.J. Stratigos, A.J. Ghiorzo, P. Brossard, M. Calista, D. Choi, J. Fargnoli, M.C. Zhang, T. Rodolfo, M. Trower, A.J. Menin, C. Martinez, J. Hadjisavvas, A. Song, L. Stefanaki, I. Scolyer, R. Yang, R. Goldstein, A.M. Potrony, M. Kypreou, K.P. Pastorino, L. Queirolo, P. Pellegrini, C. Cattaneo, L. Zawistowski, M. Gimenez-Xavier, P. Rodriguez, A. Elefanti, L. Manoukian, S. Rivoltini, L. Smith, B.H. Loizidou, M.A. Del Regno, L. Massi, D. Mandala, M. Khosrotehrani, K. Akslen, L.A. Amos, C.I. Andresen, P.A. Avril, M.-F. Azizi, E. Soyer, H.P. Bataille, V. Dalmasso, B. Bowdler, L.M. Burdon, K.P. Chen, W.V. Codd, V. Craig, J.E. Dębniak, T. Falchi, M. Fang, S. Friedman, E. Simi, S. Galan, P. Garcia-Casado, Z. Gillanders, E.M. Gordon, S. Green, A. Gruis, N.A. Hansson, J. Harland, M. Harris, J. Helsing, P. Henders, A. Hočevar, M. Höiom, V. Hunter, D. Ingvar, C. Kumar, R. Lang, J. Lathrop, G.M. Lee, J.E. Li, X. Lubiński, J. Mackie, R.M. Malt, M. Malvehy, J. McAloney, K. Mohamdi, H. Molven, A. Moses, E.K. Neale, R.E. Novaković, S. Nyholt, D.R. Olsson, H. Orr, N. Fritsche, L.G. Puig-Butille, J.A. Qureshi, A.A. Radford-Smith, G.L. Randerson-Moor, J. Requena, C. Rowe, C. Samani, N.J. Sanna, M. Schadendorf, D. Schulze, H.-J. Simms, L.A. Smithers, M. Song, F. Swerdlow, A.J. van der Stoep, N. Kukutsch, N.A. Visconti, A. Wallace, L. Ward, S.V. Wheeler, L. Sturm, R.A. Hutchinson, A. Jones, K. Malasky, M. Vogt, A. Zhou, W. Pooley, K.A. Elder, D.E. Han, J. Hicks, B. Hayward, N.K. Kanetsky, P.A. Brummett, C. Montgomery, G.W. Olsen, C.M. Hayward, C. Dunning, A.M. Martin, N.G. Evangelou, E. Mann, G.J. Long, G. Pharoah, P.D.P. Easton, D.F. Barrett, J.H. Cust, A.E. Abecasis, G. Duffy, D.L. Whiteman, D.C. Gogas, H. De Nicolo, A. Tucker, M.A. Newton-Bishop, J.A. Peris, K. Chanock, S.J. Demenais, F. Brown, K.M. Puig, S. Nagore, E. Shi, J. Iles, M.M. Law, M.H. GenoMEL Consortium Q-MEGA QTWIN Investigators ATHENS Melanoma Study Group 23andMe The SDH S

Abstract

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10−8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis. © 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Published
2020

21. Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk

Author

Rachakonda S, Kong H, Srinivas N, Garcia-Casado Z, Requena C, Fallah M, Heidenreich B, Planelles D, Traves V, Schadendorf D, Nagore E, and Kumar R

Subjects
TERT, melanoma, telomere length, promoter mutations
Abstract

Telomere repeats at chromosomal ends, critical for genomic integrity, undergo age-dependent attrition and telomere length has been associated with different disorders including cancers. In this study, based on 1469 patients and 1158 healthy controls, we show a statistically significant (P =6x10(-10)) association between increased telomere length and melanoma risk. Mendelian randomization, using 5 telomere length-associated polymorphisms, ruled out confounding factors or reverse causality and showed association between increased telomere length and melanoma risk with odds ratio of 2.66 (95% confidence interval: 2.07-3.25). Age-dependent telomere attrition was faster in melanoma cases than controls (P =.01). The carriers of a highly penetrant germline -57A>C TERT promoter mutation, in a previously reported melanoma family, had longer telomeres than the noncarriers. The mutation causes increased TERT and telomerase levels through creation of a binding motif for E-twenty six (ETS) transcription factors and the carriers develop melanoma with an early age of onset and rapid progression to metastasis. In analogy, we hypothesize that increased telomere length in melanoma patients reflects stochastic increased telomerase levels due to common genetic variation. Paradoxically, we observed shorter telomeres (P =1x10(-5)) in primary tumors from unrelated melanoma patients with (121) than without (170) somatic TERT promoter mutations that similar to the germline mutation, also create binding motifs for ETS transcription factors. However, the age-dependent telomere attrition was faster in tumors with the TERT promoter mutations than in those without such mutations. Besides a robust association between increased telomere length and risk, our data show a perturbed telomere homeostasis in melanoma.

Published
2018

25. TERT promoter mutations in melanoma survival

Author

Nagore E, Heidenreich B, Rachakonda S, Garcia-Casado Z, Requena C, Soriano V, Frank C, Traves V, Quecedo E, Sanjuan-Gimenez J, Hemminki K, Landi MT, and Kumar R

Subjects
melanoma-specific survival, disease-free survival, melanoma, BRAF mutations, TERT promoter mutations
Abstract

Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at-risk primary melanoma patients. In this study, we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. Tumors from 300 patients with stage I/II melanoma were sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression-free and melanoma-specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease-free and melanoma-specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease-free survival was 2.3 (95% CI 1.2-4.4) and for melanoma-specific survival 5.8 (95% CI 1.9-18.3). The effect of the mutations on melanoma-specific survival in noncarriers of variant allele of the polymorphism was significant (HR 4.5, 95% CI 1.4-15.2) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.3, 95% CI 0.1-0.9). The data in this study provide preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter.

Published
2016

29. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma

Author

Shi, J, Yang, Xr, Ballew, B, Rotunno, M, Calista, D, Fargnoli, Mc, Ghiorzo, P, Bressac De Paillerets, B, Nagore, E, Avril, Mf, Caporaso, Ne, Mcmaster, Ml, Cullen, M, Wang, Z, Zhang, X, Bruno, W, Pastorino, L, Queirolo, P, Banuls Roca, J, Garcia Casado, Z, Vaysse, A, Mohamdi, H, Riazalhosseini, Y, Foglio, M, Jouenne, F, Hua, X, Hyland, Pl, Yin, J, Vallabhaneni, H, Chai, W, Minghetti, P, Pellegrini, C, Ravichandran, S, Eggermont, A, Lathrop, M, Peris, Ketty, Scarra, Gb, Landi, G, Savage, Sa, Sampson, Jn, He, J, Yeager, M, Goldin, Lr, Demenais, F, Chanock, Sj, Tucker, Ma, Goldstein, Am, Liu, Y, Landi, Mt, Peris, Ketty (ORCID:0000-0002-5237-0463), Shi, J, Yang, Xr, Ballew, B, Rotunno, M, Calista, D, Fargnoli, Mc, Ghiorzo, P, Bressac De Paillerets, B, Nagore, E, Avril, Mf, Caporaso, Ne, Mcmaster, Ml, Cullen, M, Wang, Z, Zhang, X, Bruno, W, Pastorino, L, Queirolo, P, Banuls Roca, J, Garcia Casado, Z, Vaysse, A, Mohamdi, H, Riazalhosseini, Y, Foglio, M, Jouenne, F, Hua, X, Hyland, Pl, Yin, J, Vallabhaneni, H, Chai, W, Minghetti, P, Pellegrini, C, Ravichandran, S, Eggermont, A, Lathrop, M, Peris, Ketty, Scarra, Gb, Landi, G, Savage, Sa, Sampson, Jn, He, J, Yeager, M, Goldin, Lr, Demenais, F, Chanock, Sj, Tucker, Ma, Goldstein, Am, Liu, Y, Landi, Mt, and Peris, Ketty (ORCID:0000-0002-5237-0463)

Abstract

Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.

Published
2014

32. The JAK2 V617F mutation identifies a subgroup of MDS patients with isolated deletion 5q and a proliferative bone marrow [14]

Author

Ingram, W., Lea, N.C., Cervera, J., Germing, U., Fenaux, P., Cassinat, B., Kiladjian, J.J., Varkonyi, J., Antunovic, Petar, Westwood, N.B., Arno, M.J., Mohamedali, A., Gaken, J., Kontou, T., Czepulkowski, B.H., Twine, N.A., Tamaska, J., Csomer, J., Benedek, S., Gattermann, N., Zipperer, E., Giagounidis, A., Garcia-Casado, Z., Sanz, G., Mufti, G.J., Ingram, W., Lea, N.C., Cervera, J., Germing, U., Fenaux, P., Cassinat, B., Kiladjian, J.J., Varkonyi, J., Antunovic, Petar, Westwood, N.B., Arno, M.J., Mohamedali, A., Gaken, J., Kontou, T., Czepulkowski, B.H., Twine, N.A., Tamaska, J., Csomer, J., Benedek, S., Gattermann, N., Zipperer, E., Giagounidis, A., Garcia-Casado, Z., Sanz, G., and Mufti, G.J.

Abstract

[No abstract available]

Published
2006
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37. 428 Involvement of molecular factors in the prognosis of prostate cancer patients treated with radical prostatectomy according to status of the TMPRSS2-ERG fusion gene

Author

Rubio-Briones, J., primary, Fernandez-Serra, A., additional, Calatrava, A., additional, Casanova, J., additional, Rubio-Martinez, L., additional, Gomez-Ferrer, A., additional, Collado, A., additional, Ramirez, M., additional, Garcia-Casado, Z., additional, Dominguez-Scrig, J., additional, Iborra, I., additional, Solsona, E., additional, and Lopez-Guerrero, J.A., additional

Published
2012
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38. Corroboration of polymorphisms in the aromatase (CYP19A1) gene with response to neoadjuvant therapy with letrozole in postmenopausal women with stages II-II ER/PgR-positive breast cancer

Author

Lopez-Guerrero, J. A., primary, Garcia-Casado, Z., additional, Guerrero-Zotano, A. L., additional, Calatrava, A., additional, Ruiz-Sauri, A., additional, Fernandez-Serra, A., additional, Ruiz, A., additional, Llombart-Bosch, A., additional, Guillem-Porta, V., additional, and Llombart-Cussac, A., additional

Published
2007
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41. Validación externa de los ARNm: FXYD3y KRT20como biomarcadores predictivos de la presencia de micrometástasis en ganglios de pacientes con tumor vesical infiltrante

Author

Ramírez-Backhaus, M., Fernández-Serra, A., Rubio-Briones, J., Cruz Garcia, P., Calatrava, A., Garcia Casado, Z., Casanova Salas, I., Rubio, L., Solsona, E., and López-Guerrero, J.A.

Abstract

Recientes estudios han propuesto que los ARNm FXYD3 y KRT20 cuantificados por qrtPCR en material parafinado podrían ser biomarcadores capaces de detectar los ganglios portadores de micrometástasis que se escapaban al análisis convencional por hematoxilina-eosina (HE). Se decidió hacer un estudio de validación en ganglios de pacientes a los que se les practicó una cistectomía radical.

Published
2015
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42. Distribution of MC1 R variants among melanoma subtypes: p. R163 Q is associated with lentigo maligna melanoma in a Mediterranean population.

Author

Puig‐Butillé, J.A., Carrera, C., Kumar, R., Garcia‐Casado, Z., Badenas, C., Aguilera, P., Malvehy, J., Nagore, E., and Puig, S.

Subjects
MELANOMA, SKIN tumors, TUMORS, HUMAN skin color, CANCER research
Abstract

Background Cutaneous melanoma tumour is classified into clinicohistopathological subtypes that may be associated with different genetic and host factors. Variation in the MC1R gene is one of the main factors of risk variation in sporadic melanoma. The relationship between MC1R variants and the risk of developing a specific subtype of melanoma has not been previously explored. Objectives To analyse whether certain MC1R variants are associated with particular melanoma subtypes with specific clinicohistopathological features. Methods An association study was performed between MC1R gene variants and clinicopathological subtypes of primary melanoma derived from 1679 patients. Results We detected 53 MC1 R variants (11 synonymous and 42 nonsynonymous). Recurrent nonsynonymous variants were p. V60L (30·0%), p. V92 M (11·7%), p. D294 H (9·4%), p. R151 C (8·8%), p. R160 W (6·2%), p. R163 Q (4·2%) p. R142 H (3·3%), p.I155 T (3·8%), p. V122 M (1·5%) and p. D84 E (1·0%). Melanoma subtypes showed differences in the total number of MC1 R variants ( P = 0·028) and the number of red hair colour variants ( P = 0·035). Furthermore, an association between p. R163 Q and lentigo maligna melanoma was detected under a dominant model of heritance (odds ratio 2·16, 95% confidence interval 1·07-4·37; P = 0·044). No association was found between p. R163 Q and Fitzpatrick skin phototype, eye colour or skin colour, indicating that the association was independent of the role of MC1 R in pigmentation. No association was observed between MC1 R polymorphisms and other melanoma subtypes. Conclusions Our findings suggest that certain MC1 R variants could increase melanoma risk due to their impact on pathways other than pigmentation, and may therefore be linked to specific melanoma subtypes. [ABSTRACT FROM AUTHOR]

Published
2013
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46. PROBABILITY MODEL FOR PREDICTING BRCA1 AND BRCA2 MUTATIONS IN SPANISH FAMILIES WITH BREAST CANCER

Author

Diez, O., Rue, M., Balmana, J., Gadea, N., Bosch, N., Grana, B., Gutierrez-Enriquez, S., Romero, A., Perez-Segura, P., Diaz-Rubio, E., Caldes, T., La Hoya, M., Alonso, C., Ramon Y Cajal, T., Baiget, M., Lasa, A., Blanco, A., Santamarina, M., Fachal, L., Vega, A., Infante, M., Duran, M., Eladio Andrés Velasco, Chirivella, I., Osorio, A., Benitez, J., Esteban-Cardenosa, E., Bolufer, P., Segura, A., Brunet, J., Sanchez-Heras, B., Andres, R., Torres, A., Martnez Duenas, E., and Garcia-Casado, Z.

47. A polymorphism at the 3'-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole.

Author

Garcia-Casado Z, Guerrero-Zotano A, Llombart-Cussac A, Calatrava A, Fernandez-Serra A, Ruiz-Simon A, Gavila J, Climent MA, Almenar S, Cervera-Deval J, Campos J, Albaladejo CV, Llombart-Bosch A, Guillem V, Lopez-Guerrero JA, Garcia-Casado, Zaida, Guerrero-Zotano, Angel, Llombart-Cussac, Antonio, Calatrava, Ana, and Fernandez-Serra, Antonio

Abstract

Background: Aromatase (CYP19A1) regulates estrogen biosynthesis. Polymorphisms in CYP19A1 have been related to the pathogenesis of breast cancer (BC). Inhibition of aromatase with letrozole constitutes the best option for treating estrogen-dependent BC in postmenopausal women. We evaluate a series of polymorphisms of CYP19A1 and their effect on response to neoadjuvant letrozole in early BC.Methods: We analyzed 95 consecutive postmenopausal women with stage II-III ER/PgR [+] BC treated with neoadjuvant letrozole. Response to treatment was measured by radiology at 4th month by World Health Organization (WHO) criteria. Three polymorphisms of CYP19A1, one in exon 7 (rs700519) and two in the 3'-UTR region (rs10046 and rs4646) were evaluated on DNA obtained from peripheral blood.Results: Thirty-five women (36.8%) achieved a radiological response to letrozole. The histopathological and immunohistochemical parameters, including hormonal receptor status, were not associated with the response to letrozole. Only the genetic variants (AC/AA) of the rs4646 polymorphism were associated with poor response to letrozole (p = 0.03). Eighteen patients (18.9%) reported a progression of the disease. Those patients carrying the genetic variants (AC/AA) of rs4646 presented a lower progression-free survival than the patients homozygous for the reference variant (p = 0.0686). This effect was especially significant in the group of elderly patients not operated after letrozole induction (p = 0.009).Conclusions: Our study reveals that the rs4646 polymorphism identifies a subgroup of stage II-III ER/PgR [+] BC patients with poor response to neoadjuvant letrozole and poor prognosis. Testing for the rs4646 polymorphism could be a useful tool in order to orientate the treatment in elderly BC patients. [ABSTRACT FROM AUTHOR]

Published
2010
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48. Laboratory Cross-Comparison and Ring Test Trial for Tumor BRCA Testing in a Multicenter Epithelial Ovarian Cancer Series: The BORNEO GEICO 60-0 Study

Author

Zaida Garcia-Casado, Ana Oaknin, Marta Mendiola, Gorka Alkorta-Aranburu, Jose Ramon Antunez-Lopez, Gema Moreno-Bueno, Jose Palacios, Alfonso Yubero, Raul Marquez, Alejandro Gallego, Ana Beatriz Sanchez-Heras, Jose Antonio Lopez-Guerrero, Cristina Perez-Segura, Pilar Barretina-Ginesta, Jesus Alarcon, Lydia Gaba, Antonia Marquez, Judit Matito, Juan Cueva, Isabel Palacio, Maria Iglesias, Angels Arcusa, Luisa Sanchez-Lorenzo, Eva Guerra-Alia, Ignacio Romero, Ana Vivancos, Institut Català de la Salut, [Garcia-Casado Z] Molecular Biology Department, Fundacion Instituto Valenciano de Oncologia, Valencia, Spain. [Oaknin A] Medical Oncology Department, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Mendiola M] Instituto de Investigacion Biomedica del Hospital La Paz (IdiPAZ), Madrid, Spain. Centro de Investigacion Biomedica en Red de Cáncer (CIBERONC) Instituto de Salud Carlos III, Madrid, Spain. [Alkorta-Aranburu G] CIMA LAB Diagnostics/Universidad de Navarra, Pamplona, Spain. [Antunez-Lopez JR] Molecular Biology Department, Hospital Clinico Universitario Santiago, Santiago, Spain. [Moreno-Bueno G] Centro de Investigacion Biomedica en Red de Cáncer (CIBERONC) Instituto de Salud Carlos III, Madrid, Spain. Fundacion MD Anderson, Madrid, Spain. Departamento de Bioquímica, Instituto de Investigaciones Biomedicas ‘Alberto Sols. Conexion Cancer (UAM-CSIC), Universidad Autonoma de Madrid (UAM), IdiPAZ, Madrid, Spain, Vall d'Hebron Barcelona Hospital Campus, AstraZeneca, [Garcia-Casado, Zaida] Fdn Inst Valenciano Oncol, Mol Biol Dept, Valencia 46009, Spain, [Antonio Lopez-Guerrero, Jose] Fdn Inst Valenciano Oncol, Mol Biol Dept, Valencia 46009, Spain, [Oaknin, Ana] Vall dHebron Inst Oncol, Med Oncol Dept, Barcelona 08035, Spain, [Mendiola, Marta] Inst Invest Biomed Hosp La Paz IdiPAZ, Madrid 28029, Spain, [Mendiola, Marta] Inst Salud Carlos III, Ctr Invest Biomed Red Canc CIBERONC, Madrid 28029, Spain, [Moreno-Bueno, Gema] Inst Salud Carlos III, Ctr Invest Biomed Red Canc CIBERONC, Madrid 28029, Spain, [Palacios, Jose] Inst Salud Carlos III, Ctr Invest Biomed Red Canc CIBERONC, Madrid 28029, Spain, [Alkorta-Aranburu, Gorka] Univ Navarra, CIMA LAB Diagnost, Pamplona 31008, Spain, [Ramon Antunez-Lopez, Jose] Hosp Clin Univ Santiago, Mol Biol Dept, Santiago 15706, Spain, [Moreno-Bueno, Gema] Fdn MD Anderson, Madrid 28033, Spain, [Marquez, Raul] Fdn MD Anderson, Madrid 28033, Spain, [Moreno-Bueno, Gema] Univ Autonoma Madrid UAM, Inst Invest Biomed Alberto Sols Conex Canc UAM CS, Dept Bioquim, IdiPAZ, Madrid 28029, Spain, [Palacios, Jose] Hosp Univ Ramon Y Cajal, Pathol Dept, Madrid 28034, Spain, [Palacios, Jose] Alcala Univ, Fac Med, Madrid 28801, Spain, [Palacios, Jose] Inst Ramon Y Cajal Hlth Res IRYCIS, Madrid 28034, Spain, [Yubero, Alfonso] Hosp Clin Univ Lozano Blesa, Med Oncol Dept, Zaragoza 50009, Spain, [Gallego, Alejandro] Hosp Univ La Paz, Med Oncol Dept, Madrid 28029, Spain, [Beatriz Sanchez-Heras, Ana] Hosp Gen Univ Elche, Med Oncol Dept, Elche 03203, Spain, [Antonio Lopez-Guerrero, Jose] Univ Catolica Valencia, Valencia 46001, Spain, [Antonio Lopez-Guerrero, Jose] Unidad Mixta Invest Canc IVO CIPF, Valencia 46009, Spain, [Perez-Segura, Cristina] Hosp St Pau & Santa Tecla, Med Oncol Dept, Tarragona 43003, Spain, [Barretina-Ginesta, Pilar] Inst Catala dOncol Girona, Med Oncol Dept, Girona 17007, Spain, [Alarcon, Jesus] Hosp Univ Son Espases, Med Oncol Dept, Palma De Mallorca 07120, Spain, [Gaba, Lydia] Hosp Clin Barcelona, Med Oncol Dept, Barcelona 08036, Spain, [Marquez, Antonia] Reg & Virgen Victoria Univ Hosp, Med Oncol Interctr Unit, IBIMA, Malaga 29010, Spain, [Matito, Judit] Vall dHebron Inst Oncol VHIO, Canc Genom Lab, Barcelona 08035, Spain, [Vivancos, Ana] Vall dHebron Inst Oncol VHIO, Canc Genom Lab, Barcelona 08035, Spain, [Cueva, Juan] Hosp Clin Univ Santiago, Med Oncol Dept, Santiago 15706, Spain, [Palacio, Isabel] Hosp Univ Cent Asturias, Med Oncol Dept, Oviedo 33011, Spain, [Iglesias, Maria] Hosp Univ Son LLatzer, Med Oncol Dept, Palma De Mallorca 07198, Spain, [Arcusa, Angels] Hosp Terrassa, Med Oncol Dept, Terrassa 08227, Spain, [Sanchez-Lorenzo, Luisa] Clin Univ Navarra, Med Oncol Dept, Pamplona 31008, Spain, [Guerra-Alia, Eva] Hosp Univ Ramon Y Cajal, Med Oncol Dept, Madrid 28034, Spain, [Romero, Ignacio] Inst Valenciano Oncol, Med Oncol Dept, Valencia 46009, Spain, and Astra Zeneca Farmaceutica Spain SA

Subjects
Standards, Germline, Survival, Medicine (miscellaneous), Ovaris - Càncer - Aspectes genètics, Guidelines, neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas [ENFERMEDADES], Sequence variants, Association, Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Genetic Testing [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Somatic mutations, Ovarian cancer, Other subheadings::Other subheadings::/genetics [Other subheadings], Chemotherapy, Joint-consensus-recommendation, Ring Test Trial, Otros calificadores::Otros calificadores::/genética [Otros calificadores], Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms [DISEASES], Cromosomes humans - Anomalies - Diagnòstic, diagnóstico::técnicas y procedimientos diagnósticos::técnicas de laboratorio clínico::pruebas genéticas [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], College, BRCA mutations, BRCA testing, ovarian cancer, NGS
Abstract

Germline and tumor BRCA testing constitutes a valuable tool for clinical decision-making in the management of epithelial ovarian cancer (EOC) patients. Tissue testing is able to identify both germline (g) and somatic (s) BRCA variants, but tissue preservation methods and the widespread implementation of NGS represent pre-analytical and analytical challenges that need to be managed. This study was carried out on a multicenter prospective GEICO cohort of EOC patients with known gBRCA status in order to determine the inter-laboratory reproducibility of tissue sBRCA testing. The study consisted of two independent experimental approaches, a bilateral comparison between two reference laboratories (RLs) testing 82 formalin-paraffin-embedded (FFPE) EOC samples each, and a Ring Test Trial (RTT) with five participating clinical laboratories (CLs) evaluating the performance of tissue BRCA testing in a total of nine samples. Importantly, labs employed their own locally adopted next-generation sequencing (NGS) analytical approach. BRCA mutation frequency in the RL sub-study cohort was 23.17%: 12 (63.1%) germline and 6 (31.6%) somatic. Concordance between the two RLs with respect to BRCA status was 84.2% (gBRCA 100%). The RTT study distributed a total of nine samples (three commercial synthetic human FFPE references, three FFPE, and three OC DNA) among five CLs. The median concordance detection rate among them was 64.7% (range: 35.3–70.6%). Analytical discrepancies were mainly due to the minimum variant allele frequency thresholds, bioinformatic pipeline filters, and downstream variant interpretation, some of them with consequences of clinical relevance. Our study demonstrates a wide range of concordance in the identification and interpretation of BRCA sequencing data, highlighting the relevance of establishing standard criteria for detecting, interpreting, and reporting BRCA variants., This research was funded by Astra Zéneca Farmacéutica Spain SA (Grant Number GEICO60-0).

Published
2022

49. Open-label phase II clinical trial of orteronel (TAK-700) in metastatic or advanced non-resectable granulosa cell ovarian tumors: the Greko II study (GETHI2013-01).

Author

Garcia-Donas J, Garrigos L, Lainez N, Santaballa A, Redondo A, Cueva JF, Rubio MJ, Prieto M, Lopez-Guerrero JA, Garcia-Casado Z, Barquin A, Grande E, Alia EG, Sevillano E, Bover I, Grazioso TP, Sanchez-Escribano R, Hurtado A, Navarro P, and Rodriguez-Moreno JF

Abstract

Background: Granulosa cell ovarian tumors (GCTs) are a rare neoplasia characterized by a pathognomonic mutation in the FOXL2 gene. In vitro studies have demonstrated an overactivation of hormone activity due to this alteration. Thus, we aimed to determine the activity of orteronel, a CYP17 inhibitor, in advanced disease., Methods: We designed a multicentric open-label phase II clinical trial. Eligible patients were adult woman with advanced or unresectable GCTs. Primary objective was clinical benefit rate, defined as the average of patients with radiological response plus stable disease longer than 6 months., Results: From October 1, 2014 to May 20, 2016, ten patients were included in six participating institutions members of the GETTHI group. The study was terminated early due to a low recruitment rate. Up to 40% (CI 95% [9.6-70.4%]) cases presented a disease stabilization longer than 6 months and two of them, longer than 12 months. One patient continued on treatment at database closure 29 months after inclusion in the trial. No patient reached partial or complete response by RECIST criteria on the independent radiological review. The drug was well tolerated with nausea as the only grade 3 adverse event in one case., Conclusion: Low accrual led to an early interruption of the study. However, orteronel achieved a promising clinical benefit rate that supports further development of new hormonotherapies in this tumor., Gov Identifier: NCT02101684., Competing Interests: Declarations. Conflict of interest: Jesus Garcia-Donas, corresponding author, has received research funding from Gilead Inc, Pfizer Inc, Merck Inc, Bristol-Myers Squibb, AstraZeneca, Novartis, MSD Inc, Roche Inc, Astellas Inc, Novartis Inc, and Exelixis Inc. He has acted as a speaker for Gilead Inc, Pfizer Inc, Merck Inc, Bristol-Myers Squibb, AstraZeneca, Novartis, Glaxo Smithkline Inc, and MSD Inc. He has served as a scientific advisor for Pfizer Inc, Merck Inc, Bristol-Myers Squibb, AstraZeneca, Novartis, and MSD Inc. Enrique Grande has received honoraria for speaker engagements, advisory roles or funding of continuous medical education from Adacap, AMGEN, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, Guardant Health, HRA-Pharma, IPSEN, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, and Thermo Fisher Scientific. EG has received research grants from Pfizer, Astra Zeneca, Astellas, and Lexicon Pharmaceuticals. AR has received honoraria for speaker engagements, advisory roles or funding of continuous medical education from Astellas, Bristol Myers Squibb, IPSEN, Pfizer, and MSD. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: All participants provided informed consent prior to their participation., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Published
2024
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