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6. Primers and protocols for standardized detection of minimal residual disease in acute lymphoblastic leukemia using immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets Report of the BIOMED-1 CONCERTED ACTION: Investigation of minimal residual disease in acute leukemia

Author

Pongers-Willemse, MJ, Seriu, T, Stolz, F, d’Aniello, E, Gameiro, P, Pisa, P, Gonzalez, M, Bartram, CR, Panzer-Grümayer, ER, Biondi, A, Miguel, JF San, and van Dongen, JJM

Published
1999
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14. Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia

Author

Vijayakrishnan, J, Studd, J, Broderick, P, Kinnersley, B, Holroyd, A, Law, PJ, Kumar, R, Allan, JM, Harrison, CJ, Moorman, AV, Vora, A, Roman, E, Rachakonda, S, Kinsey, SE, Sheridan, E, Thompson, PD, Irving, JA, Koehler, R, Hoffmann, P, Nöthen, MM, Heilmann-Heimbach, S, Jöckel, KH, Easton, DF, Pharaoh, PDP, Dunning, AM, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Greaves, M, Zimmerman, M, Bartram, CR, Schrappe, M, Stanulla, M, Hemminki, K, Houlston, RS, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Olama, AAA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, YJ, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, The PRACTICAL Consortium, and Claessens, Frank

Subjects
Male, Oncogene Proteins, Fusion, Glycosyltransferases, Prognosis, Polymorphism, Single Nucleotide, HLA Antigens, Risk Factors, Child, Preschool, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Core Binding Factor Alpha 2 Subunit, Humans, Female, Genetic Predisposition to Disease, Child, Genome-Wide Association Study
Abstract

© 2018 The Author(s). Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology. ispartof: Nature Communications vol:9 issue:1 ispartof: location:England status: published

Published
2018

15. Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia (vol 9, 1340, 2018)

Author

Vijayakrishnan, J, Studd, J, Broderick, P, Kinnersley, B, Holroyd, A, Law, PJ, Kumar, R, Allan, JM, Harrison, CJ, Moorman, AV, Vora, A, Roman, E, Rachakonda, S, Kinsey, SE, Sheridan, E, Thompson, PD, Irving, JA, Koehler, R, Hoffmann, P, Noethen, MM, Heilmann-Heimbach, S, Joeckel, K-H, Easton, DF, Pharaoh, PDP, Dunning, AM, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Al Olama, AA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, John, EM, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Greaves, M, Zimmerman, M, Bartram, CR, Schrappe, M, Stanulla, M, Hemminki, K, Houlston, RS, Vijayakrishnan, J, Studd, J, Broderick, P, Kinnersley, B, Holroyd, A, Law, PJ, Kumar, R, Allan, JM, Harrison, CJ, Moorman, AV, Vora, A, Roman, E, Rachakonda, S, Kinsey, SE, Sheridan, E, Thompson, PD, Irving, JA, Koehler, R, Hoffmann, P, Noethen, MM, Heilmann-Heimbach, S, Joeckel, K-H, Easton, DF, Pharaoh, PDP, Dunning, AM, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Al Olama, AA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, John, EM, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Greaves, M, Zimmerman, M, Bartram, CR, Schrappe, M, Stanulla, M, Hemminki, K, and Houlston, RS

Abstract

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

Published
2019

16. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author

Parsons, MT, Tudini, E, Li, H, Hahnen, E, Wappenschmidt, B, Feliubadalo, L, Aalfs, CM, Agata, S, Aittomaki, K, Alducci, E, Concepcion Alonso-Cerezo, M, Arnold, N, Auber, B, Austin, R, Azzollini, J, Balmana, J, Barbieri, E, Bartram, CR, Blanco, A, Bluemcke, B, Bonache, S, Bonanni, B, Borg, A, Bortesi, B, Brunet, J, Bruzzone, C, Bucksch, K, Cagnoli, G, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Capone, GL, Caputo, SM, Carnevali, I, Carrasco, E, Caux-Moncoutier, V, Cavalli, P, Cini, G, Clarke, EM, Concolino, P, Cops, EJ, Cortesi, L, Couch, FJ, Darder, E, de la Hoya, M, Dean, M, Debatin, I, Del Valle, J, Delnatte, C, Derive, N, Diez, O, Ditsch, N, Domchek, SM, Dutrannoy, V, Eccles, DM, Ehrencrona, H, Enders, U, Evans, DG, Farra, C, Faust, U, Felbor, U, Feroce, I, Fine, M, Foulkes, WD, Galvao, HC, Gambino, G, Gehrig, A, Gensini, F, Gerdes, A-M, Germani, A, Giesecke, J, Gismondi, V, Gomez, C, Garcia, EBG, Gonzalez, S, Grau, E, Grill, S, Gross, E, Guerrieri-Gonzaga, A, Guillaud-Bataille, M, Gutierrez-Enriquez, S, Haaf, T, Hackmann, K, Hansen, TV, Harris, M, Hauke, J, Heinrich, T, Hellebrand, H, Herold, KN, Honisch, E, Horvath, J, Houdayer, C, Huebbel, V, Iglesias, S, Izquierdo, A, James, PA, Janssen, LA, Jeschke, U, Kaulfuss, S, Keupp, K, Kiechle, M, Koelbl, A, Krieger, S, Kruse, TA, Kvist, A, Lalloo, F, Larsen, M, Lattimore, VL, Lautrup, C, Ledig, S, Leinert, E, Lewis, AL, Lim, J, Loeffler, M, Lopez-Fernandez, A, Lucci-Cordisco, E, Maass, N, Manoukian, S, Marabelli, M, Matricardi, L, Meindl, A, Michelli, RD, Moghadasi, S, Moles-Fernandez, A, Montagna, M, Montalban, G, Monteiro, AN, Montes, E, Mori, L, Moserle, L, Mueller, CR, Mundhenke, C, Naldi, N, Nathanson, KL, Navarro, M, Nevanlinna, H, Nichols, CB, Niederacher, D, Nielsen, HR, Ong, K-R, Pachter, N, Palmero, E, Papi, L, Pedersen, IS, Peissel, B, Perez-Segura, P, Pfeifer, K, Pineda, M, Pohl-Rescigno, E, Poplawski, NK, Porfirio, B, Quante, AS, Ramser, J, Reis, RM, Revillion, F, Rhiem, K, Riboli, B, Ritter, J, Rivera, D, Rofes, P, Rump, A, Salinas, M, Sanchez de Abajo, AM, Schmidt, G, Schoenwiese, U, Seggewiss, J, Solanes, A, Steinemann, D, Stiller, M, Stoppa-Lyonnet, D, Sullivan, KJ, Susman, R, Sutter, C, Tavtigian, S, Teo, SH, Teule, A, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tornero, E, Torngren, T, Torres-Esquius, S, Toss, A, Trainer, AH, Tucker, KM, van Asperen, CJ, van Mackelenbergh, MT, Varesco, L, Vargas-Parra, G, Varon, R, Vega, A, Velasco, A, Vesper, A-S, Viel, A, Vreeswijk, MPG, Wagner, SA, Waha, A, Walker, LC, Walters, RJ, Wang-Gohrke, S, Weber, BHF, Weichert, W, Wieland, K, Wiesmueller, L, Witzel, I, Woeckel, A, Woodward, ER, Zachariae, S, Zampiga, V, Zeder-Goss, C, Lazaro, C, De Nicolo, A, Radice, P, Engel, C, Schmutzler, RK, Goldgar, DE, Spurdle, AB, Parsons, MT, Tudini, E, Li, H, Hahnen, E, Wappenschmidt, B, Feliubadalo, L, Aalfs, CM, Agata, S, Aittomaki, K, Alducci, E, Concepcion Alonso-Cerezo, M, Arnold, N, Auber, B, Austin, R, Azzollini, J, Balmana, J, Barbieri, E, Bartram, CR, Blanco, A, Bluemcke, B, Bonache, S, Bonanni, B, Borg, A, Bortesi, B, Brunet, J, Bruzzone, C, Bucksch, K, Cagnoli, G, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Capone, GL, Caputo, SM, Carnevali, I, Carrasco, E, Caux-Moncoutier, V, Cavalli, P, Cini, G, Clarke, EM, Concolino, P, Cops, EJ, Cortesi, L, Couch, FJ, Darder, E, de la Hoya, M, Dean, M, Debatin, I, Del Valle, J, Delnatte, C, Derive, N, Diez, O, Ditsch, N, Domchek, SM, Dutrannoy, V, Eccles, DM, Ehrencrona, H, Enders, U, Evans, DG, Farra, C, Faust, U, Felbor, U, Feroce, I, Fine, M, Foulkes, WD, Galvao, HC, Gambino, G, Gehrig, A, Gensini, F, Gerdes, A-M, Germani, A, Giesecke, J, Gismondi, V, Gomez, C, Garcia, EBG, Gonzalez, S, Grau, E, Grill, S, Gross, E, Guerrieri-Gonzaga, A, Guillaud-Bataille, M, Gutierrez-Enriquez, S, Haaf, T, Hackmann, K, Hansen, TV, Harris, M, Hauke, J, Heinrich, T, Hellebrand, H, Herold, KN, Honisch, E, Horvath, J, Houdayer, C, Huebbel, V, Iglesias, S, Izquierdo, A, James, PA, Janssen, LA, Jeschke, U, Kaulfuss, S, Keupp, K, Kiechle, M, Koelbl, A, Krieger, S, Kruse, TA, Kvist, A, Lalloo, F, Larsen, M, Lattimore, VL, Lautrup, C, Ledig, S, Leinert, E, Lewis, AL, Lim, J, Loeffler, M, Lopez-Fernandez, A, Lucci-Cordisco, E, Maass, N, Manoukian, S, Marabelli, M, Matricardi, L, Meindl, A, Michelli, RD, Moghadasi, S, Moles-Fernandez, A, Montagna, M, Montalban, G, Monteiro, AN, Montes, E, Mori, L, Moserle, L, Mueller, CR, Mundhenke, C, Naldi, N, Nathanson, KL, Navarro, M, Nevanlinna, H, Nichols, CB, Niederacher, D, Nielsen, HR, Ong, K-R, Pachter, N, Palmero, E, Papi, L, Pedersen, IS, Peissel, B, Perez-Segura, P, Pfeifer, K, Pineda, M, Pohl-Rescigno, E, Poplawski, NK, Porfirio, B, Quante, AS, Ramser, J, Reis, RM, Revillion, F, Rhiem, K, Riboli, B, Ritter, J, Rivera, D, Rofes, P, Rump, A, Salinas, M, Sanchez de Abajo, AM, Schmidt, G, Schoenwiese, U, Seggewiss, J, Solanes, A, Steinemann, D, Stiller, M, Stoppa-Lyonnet, D, Sullivan, KJ, Susman, R, Sutter, C, Tavtigian, S, Teo, SH, Teule, A, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tornero, E, Torngren, T, Torres-Esquius, S, Toss, A, Trainer, AH, Tucker, KM, van Asperen, CJ, van Mackelenbergh, MT, Varesco, L, Vargas-Parra, G, Varon, R, Vega, A, Velasco, A, Vesper, A-S, Viel, A, Vreeswijk, MPG, Wagner, SA, Waha, A, Walker, LC, Walters, RJ, Wang-Gohrke, S, Weber, BHF, Weichert, W, Wieland, K, Wiesmueller, L, Witzel, I, Woeckel, A, Woodward, ER, Zachariae, S, Zampiga, V, Zeder-Goss, C, Lazaro, C, De Nicolo, A, Radice, P, Engel, C, Schmutzler, RK, Goldgar, DE, and Spurdle, AB

Abstract

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

Published
2019

17. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort

Author

Waszak, SM, Northcott, PA, Buchhalter, I, Robinson, GW, Sutter, C, Groebner, S, Grund, KB, Brugières, L, Jones, DTW, Pajtler, KW, Morrissy, AS, Kool, M, Sturm, D, Chavez, L, Ernst, A, Brabetz, S, Hain, M, Zichner, T, Segura-Wang, M, Weischenfeldt, J, Rausch, T, Mardin, BR, Zhou, X, Baciu, C, Lawerenz, C, Chan, JA, Varlet, P, Guerrini-Rousseau, L, Fults, DW, Grajkowska, W, Hauser, P, Jabado, N, Ra, YS, Zitterbart, K, Shringarpure, SS, De La Vega, FM, Bustamante, CD, Ng, HK, Perry, A, MacDonald, TJ, Hernáiz Driever, P, Bendel, AE, Bowers, DC, McCowage, G, Chintagumpala, MM, Cohn, R, Hassall, T, Fleischhack, G, Eggen, T, Wesenberg, F, Feychting, M, Lannering, B, Schüz, J, Johansen, C, Andersen, TV, Röösli, M, Kuehni, CE, Grotzer, M, Kjaerheim, K, Monoranu, CM, Archer, TC, Duke, E, Pomeroy, SL, Shelagh, R, Frank, S, Sumerauer, D, Scheurlen, W, Ryzhova, MV, Milde, T, Kratz, CP, Samuel, D, Zhang, J, Solomon, DA, Marra, M, Eils, R, Bartram, CR, von Hoff, K, Rutkowski, S, Ramaswamy, V, Gilbertson, RJ, Korshunov, A, Taylor, MD, Lichter, P, Malkin, D, Gajjar, A, Korbel, JO, Pfister, SM, Waszak, SM, Northcott, PA, Buchhalter, I, Robinson, GW, Sutter, C, Groebner, S, Grund, KB, Brugières, L, Jones, DTW, Pajtler, KW, Morrissy, AS, Kool, M, Sturm, D, Chavez, L, Ernst, A, Brabetz, S, Hain, M, Zichner, T, Segura-Wang, M, Weischenfeldt, J, Rausch, T, Mardin, BR, Zhou, X, Baciu, C, Lawerenz, C, Chan, JA, Varlet, P, Guerrini-Rousseau, L, Fults, DW, Grajkowska, W, Hauser, P, Jabado, N, Ra, YS, Zitterbart, K, Shringarpure, SS, De La Vega, FM, Bustamante, CD, Ng, HK, Perry, A, MacDonald, TJ, Hernáiz Driever, P, Bendel, AE, Bowers, DC, McCowage, G, Chintagumpala, MM, Cohn, R, Hassall, T, Fleischhack, G, Eggen, T, Wesenberg, F, Feychting, M, Lannering, B, Schüz, J, Johansen, C, Andersen, TV, Röösli, M, Kuehni, CE, Grotzer, M, Kjaerheim, K, Monoranu, CM, Archer, TC, Duke, E, Pomeroy, SL, Shelagh, R, Frank, S, Sumerauer, D, Scheurlen, W, Ryzhova, MV, Milde, T, Kratz, CP, Samuel, D, Zhang, J, Solomon, DA, Marra, M, Eils, R, Bartram, CR, von Hoff, K, Rutkowski, S, Ramaswamy, V, Gilbertson, RJ, Korshunov, A, Taylor, MD, Lichter, P, Malkin, D, Gajjar, A, Korbel, JO, and Pfister, SM

Abstract

Background: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. Methods: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MB WNT ), SHH (MB SHH ), group 3 (MB Group3 ), and group 4 (MB Group4 ). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. Findings: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we co

Published
2018

18. Reduced-Intensity delayed intensification in standard-Risk pediatric acute lymphoblastic leukemia defined by undetectable minimal residual disease: Results of an international randomized trial (AIEOP-BFM ALL 2000)

Author

Schrappe, M, Bleckmann, K, Zimmermann, M, Biondi, A, Möricke, A, Locatelli, F, Cario, G, Rizzari, C, Attarbaschi, A, Valsecchi, M, Bartram, C, Barisone, E, Niggli, F, Niemeyer, C, Testi, A, Mann, G, Ziino, O, Schäfer, B, Panzer-Grümayer, R, Beier, R, Parasole, R, Göhring, G, Ludwig, W, Casale, F, Schlegel, P, Basso, G, Conter, V, Valsecchi, MG, Bartram, CR, Testi, AM, Ludwig, WD, Schlegel, PG, Schrappe, M, Bleckmann, K, Zimmermann, M, Biondi, A, Möricke, A, Locatelli, F, Cario, G, Rizzari, C, Attarbaschi, A, Valsecchi, M, Bartram, C, Barisone, E, Niggli, F, Niemeyer, C, Testi, A, Mann, G, Ziino, O, Schäfer, B, Panzer-Grümayer, R, Beier, R, Parasole, R, Göhring, G, Ludwig, W, Casale, F, Schlegel, P, Basso, G, Conter, V, Valsecchi, MG, Bartram, CR, Testi, AM, Ludwig, WD, and Schlegel, PG

Abstract

Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8-year rate of disease-free survival (6 SE) was 89.2 6 1.3% and 92.3 6 1.2% (P = .04); cumulative incidence of relapse, 8.7 6 1.2% and 6.4 6 1.1% (P = .09); and overall survival, 96.1 6 0.8% and 98.0 6 0.6% (P = .06). Patients with ETV6-RUNX1–positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 6 0.5% and 0.6 6 0.4% for P-III and P-II, respectively (P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity o

Published
2018

21. Molekulargenetischer Nachweis minimaler Resterkrankung (minimal residual disease, MRD) bei Kindern mit akuter lymphoblastischer Leukämie

Author

Koehler R and Bartram Cr

Subjects
Oncology, medicine.medical_specialty, Treatment response, Text mining, business.industry, hemic and lymphatic diseases, Lymphoblastic Leukemia, Internal medicine, Pediatrics, Perinatology and Child Health, Medicine, business, Minimal residual disease
Abstract

The treatment of acute lymphoblastic leukemia (ALL) in childhood and adolescence achieves nowadays cure rates of more than 80%. The detection of minimal residual disease (MRD) via molecular genetic methods provides - in comparison with conventional clinical and biological parameters - much more sensitive approaches to monitor individual treatment response. Here we will discuss the molecular background and technical developments in the framework of the BFM-study group.

Published
2013
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24. Carnosinase Gene—Is It Responsible for Diabetic Nephropathy?

Author

Janssen B, Hohenadel D, Brinkkoetter P, Peters V, Rind N, Fischer C, Rychlik I, Cerna M, Romzova M, de Heer E, Baelde H, Bakker SJ, Zirie M, Rondeau E, Mathieson P, Saleem MA, Meyer J, Ko[Combining Diaeresis]ppel H, Sauerhoefer S, Bartram CR, Nawroth P, Hammes HP, Yard BA, Zschokke J, and van der Woude FJ

Subjects
Nephrology, General Medicine
Published
2005
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25. Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: A case-control study

Author

Johnson, N, Dudbridge, F, Orr, N, Gibson, L, Jones, ME, Schoemaker, MJ, Folkerd, EJ, Haynes, BP, Hopper, JL, Southey, MC, Dite, GS, Apicella, C, Schmidt, MK, Broeks, A, Van't Veer, LJ, Atsma, F, Muir, K, Lophatananon, A, Fasching, PA, Beckmann, MW, Ekici, AB, Renner, SP, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Guénel, P, Truong, T, Cordina, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, R, Zamora, MP, Perez, JIA, Benitez, J, Bernstein, L, Anton-Culver, H, Ziogas, A, Dur, CC, Brenner, H, Müller, H, Arndt, V, Dieffenbach, AK, Meindl, A, Heil, J, Bartram, CR, Schmutzler, RK, Brauch, H, Justenhoven, C, Ko, YD, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Matsuo, K, Dörk, T, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Chenevix-Trench, G, Beesley, J, Wu, AH, Van den Berg, D, Tseng, CC, and Lambrechts, D

Abstract

© 2014 Johnson et al. Introduction: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. Methods: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. Results: We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (Ptrend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (Ptrend = 0.005) but not cases (Ptrend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (Phet = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; Ptrend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; Ptrend = 0.29). Conclusions: To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.

Published
2014
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26. Glucocorticoid withdrawal - heterozygous carriers of congenital adrenal hyperplasia at risk?

Author

Hinderhofer K, Wolfgang Holter, Bartram Cr, Helmuth-Günther Dörr, Brackmann F, and Thorsten Langer

Subjects
Male, medicine.medical_specialty, Hydrocortisone, DNA Mutational Analysis, Iatrogenic Disease, Genetic Counseling, Dexamethasone, Adrenocorticotropic Hormone, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Congenital adrenal hyperplasia, Genetic Predisposition to Disease, Adrenal Hyperplasia, Congenital, business.industry, Genetic Carrier Screening, Sequence Analysis, DNA, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Adrenogenital Syndrome, Substance Withdrawal Syndrome, Endocrinology, Child, Preschool, Pediatrics, Perinatology and Child Health, Prednisone, Steroid 21-Hydroxylase, business, Glucocorticoid, medicine.drug
Published
2012

29. Concurrent deIetions of IKZF1 and PAX5, CDKN2A, CDKN2B or PAR1 (IKZF1plus) confer a very poor prognosis in pediatric acute lymphoblastic leukemia

Author

Dagdan, E, primary, Zaliova, M, additional, Zimmermann, M, additional, Dörge, P, additional, Möricke, A, additional, Teigler-Schlegel, A, additional, Koehler, R, additional, Bartram, CR, additional, Alten, J, additional, Schewe, D, additional, Kratz, C, additional, Houlston, RS, additional, Schrappe, M, additional, Cario, G, additional, and Stanulla, M, additional

Published
2014
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31. Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)

Author

Chan, KYK, Hein, R, Maranian, M, Hopper, JL, Kapuscinski, MK, Southey, MC, Park, DJ, Schmidt, MK, Broeks, A, Hogervorst, FBL, Bueno-de-Mesquit, HB, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, IDS, Peto, J, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Marmee, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Cordina-Duverger, E, Menegaux, F, Truong, T, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, RL, Arias Perez, JI, Pilar Zamora, M, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Clarke, CA, Brenner, H, Mueller, H, Arndt, V, Stegmaier, C, Rahman, N, Seal, S, Turnbull, C, Renwick, A, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Brauch, H, Hamann, U, Ko, Y-D, Wang-Gohrke, S, Doerk, T, Schuermann, P, Karstens, JH, Hillemanns, P, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Zalutsky, IV, Antonenkova, NN, Bermisheva, M, Prokovieva, D, Farahtdinova, A, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, J, Chen, X, Beesley, J, Lambrechts, D, Zhao, H, Neven, P, Wildiers, H, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Manoukian, S, Barile, M, Couch, FJ, Olson, JE, Wang, X, Fredericksen, Z, Giles, GG, Baglietto, L, McLean, CA, Severi, G, Offit, K, Robson, M, Gaudet, MM, Vijai, J, Alnaes, GG, Kristensen, V, Borresen-Dale, A-L, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Figueroa, JD, Garcia-Closas, M, Lissowska, J, Sherman, ME, Hooning, M, Martens, JWM, Seynaeve, C, Collee, M, Hall, P, Humpreys, K, Czene, K, Liu, J, Cox, A, Brock, IW, Cross, SS, Reed, MWR, Ahmed, S, Ghoussaini, M, Pharoah, PDP, Kang, D, Yoo, K-Y, Noh, D-Y, Jakubowska, A, Jaworska, K, Durda, K, Zlowocka, E, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Shen, C-Y, Yu, J-C, Hsu, H-M, Hou, M-F, Orr, N, Schoemaker, M, Ashworth, A, Swerdlow, A, Trentham-Dietz, A, Newcomb, PA, Titus, L, Egan, KM, Chenevix-Trench, G, Antoniou, AC, Humphreys, MK, Morrison, J, Chang-Claude, J, Easton, DF, Dunning, AM, Chan, KYK, Hein, R, Maranian, M, Hopper, JL, Kapuscinski, MK, Southey, MC, Park, DJ, Schmidt, MK, Broeks, A, Hogervorst, FBL, Bueno-de-Mesquit, HB, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, IDS, Peto, J, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Marmee, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Cordina-Duverger, E, Menegaux, F, Truong, T, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, RL, Arias Perez, JI, Pilar Zamora, M, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Clarke, CA, Brenner, H, Mueller, H, Arndt, V, Stegmaier, C, Rahman, N, Seal, S, Turnbull, C, Renwick, A, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Brauch, H, Hamann, U, Ko, Y-D, Wang-Gohrke, S, Doerk, T, Schuermann, P, Karstens, JH, Hillemanns, P, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Zalutsky, IV, Antonenkova, NN, Bermisheva, M, Prokovieva, D, Farahtdinova, A, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, J, Chen, X, Beesley, J, Lambrechts, D, Zhao, H, Neven, P, Wildiers, H, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Manoukian, S, Barile, M, Couch, FJ, Olson, JE, Wang, X, Fredericksen, Z, Giles, GG, Baglietto, L, McLean, CA, Severi, G, Offit, K, Robson, M, Gaudet, MM, Vijai, J, Alnaes, GG, Kristensen, V, Borresen-Dale, A-L, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Figueroa, JD, Garcia-Closas, M, Lissowska, J, Sherman, ME, Hooning, M, Martens, JWM, Seynaeve, C, Collee, M, Hall, P, Humpreys, K, Czene, K, Liu, J, Cox, A, Brock, IW, Cross, SS, Reed, MWR, Ahmed, S, Ghoussaini, M, Pharoah, PDP, Kang, D, Yoo, K-Y, Noh, D-Y, Jakubowska, A, Jaworska, K, Durda, K, Zlowocka, E, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Shen, C-Y, Yu, J-C, Hsu, H-M, Hou, M-F, Orr, N, Schoemaker, M, Ashworth, A, Swerdlow, A, Trentham-Dietz, A, Newcomb, PA, Titus, L, Egan, KM, Chenevix-Trench, G, Antoniou, AC, Humphreys, MK, Morrison, J, Chang-Claude, J, Easton, DF, and Dunning, AM

Abstract

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of

Published
2012

32. 11q13 is a susceptibility locus for hormone receptor positive breast cancer

Author

Lambrechts, D, Truong, T, Justenhoven, C, Humphreys, MK, Wang, J, Hopper, JL, Dite, GS, Apicella, C, Southey, MC, Schmidt, MK, Broeks, A, Cornelissen, S, van Hien, R, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Milne, RL, Pilar Zamora, M, Arias Perez, JI, Benitez, J, Hamann, U, Ko, Y-D, Bruening, T, Chang-Claude, J, Eilber, U, Hein, R, Nickels, S, Flesch-Janys, D, Wang-Gohrke, S, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Chenevix-Trench, G, Beesley, J, Chen, X, Menegaux, F, Cordina-Duverger, E, Shen, C-Y, Yu, J-C, Wu, P-E, Hou, M-F, Andrulis, IL, Selander, T, Glendon, G, Mulligan, AM, Anton-Culver, H, Ziogas, A, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Jones, M, Orr, N, Ashworth, A, Swerdlow, A, Severi, G, Baglietto, L, Giles, G, Southey, M, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Yesilyurt, BT, Neven, P, Paridaens, R, Wildiers, H, Brenner, H, Mueller, H, Arndt, V, Stegmaier, C, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Cox, A, Brock, IW, Elliott, G, Cross, SS, Fasching, PA, Schulz-Wendtland, R, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, IDS, Peto, J, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Doerk, T, Schuermann, P, Bremer, M, Hillemanns, P, Bogdanova, NV, Antonenkova, NN, Rogov, YI, Karstens, JH, Khusnutdinova, E, Bermisheva, M, Prokofieva, D, Gancev, S, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Nordestgaard, BG, Bojesen, SE, Lanng, C, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Radice, P, Peterlongo, P, Manoukian, S, Bernard, L, Couch, FJ, Olson, JE, Wang, X, Fredericksen, Z, Alnaes, GG, Kristensen, V, Borresen-Dale, A-L, Devilee, P, Tollenaar, RAEM, Seynaeve, CM, Hooning, MJ, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Sherman, ME, Hall, P, Liu, J, Czene, K, Kang, D, Yoo, K-Y, Noh, D-Y, Lindblom, A, Margolin, S, Dunning, AM, Pharoah, PDP, Easton, DF, Guenel, P, Brauch, H, Lambrechts, D, Truong, T, Justenhoven, C, Humphreys, MK, Wang, J, Hopper, JL, Dite, GS, Apicella, C, Southey, MC, Schmidt, MK, Broeks, A, Cornelissen, S, van Hien, R, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Milne, RL, Pilar Zamora, M, Arias Perez, JI, Benitez, J, Hamann, U, Ko, Y-D, Bruening, T, Chang-Claude, J, Eilber, U, Hein, R, Nickels, S, Flesch-Janys, D, Wang-Gohrke, S, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Chenevix-Trench, G, Beesley, J, Chen, X, Menegaux, F, Cordina-Duverger, E, Shen, C-Y, Yu, J-C, Wu, P-E, Hou, M-F, Andrulis, IL, Selander, T, Glendon, G, Mulligan, AM, Anton-Culver, H, Ziogas, A, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Jones, M, Orr, N, Ashworth, A, Swerdlow, A, Severi, G, Baglietto, L, Giles, G, Southey, M, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Yesilyurt, BT, Neven, P, Paridaens, R, Wildiers, H, Brenner, H, Mueller, H, Arndt, V, Stegmaier, C, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Cox, A, Brock, IW, Elliott, G, Cross, SS, Fasching, PA, Schulz-Wendtland, R, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, IDS, Peto, J, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Doerk, T, Schuermann, P, Bremer, M, Hillemanns, P, Bogdanova, NV, Antonenkova, NN, Rogov, YI, Karstens, JH, Khusnutdinova, E, Bermisheva, M, Prokofieva, D, Gancev, S, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Nordestgaard, BG, Bojesen, SE, Lanng, C, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Radice, P, Peterlongo, P, Manoukian, S, Bernard, L, Couch, FJ, Olson, JE, Wang, X, Fredericksen, Z, Alnaes, GG, Kristensen, V, Borresen-Dale, A-L, Devilee, P, Tollenaar, RAEM, Seynaeve, CM, Hooning, MJ, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Sherman, ME, Hall, P, Liu, J, Czene, K, Kang, D, Yoo, K-Y, Noh, D-Y, Lindblom, A, Margolin, S, Dunning, AM, Pharoah, PDP, Easton, DF, Guenel, P, and Brauch, H

Abstract

A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.

Published
2012

33. 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

Author

Warren, H, Dudbridge, F, Fletcher, O, Orr, N, Johnson, N, Hopper, JL, Apicella, C, Southey, MC, Mahmoodi, M, Schmidt, MK, Broeks, A, Cornelissen, S, Braaf, LM, Muir, KR, Lophatananon, A, Chaiwerawattana, A, Wiangnon, S, Fasching, PA, Beckmann, MW, Ekici, AB, Schulz-Wendtland, R, Sawyer, EJ, Tomlinson, I, Kerin, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Guenel, P, Therese, T, Laurent-Puig, P, Mulot, C, Bojesen, SE, Nielsen, SF, Flyger, H, Nordestgaard, BG, Milne, RL, Benitez, J, Arias-Perez, J-I, Pilar Zamora, M, Anton-Culver, H, Ziogas, A, Bernstein, L, Dur, CC, Brenner, H, Mueller, H, Arndt, V, Langheinz, A, Meindl, A, Golatta, M, Bartram, CR, Schmutzler, RK, Brauch, H, Justenhoven, C, Bruening, T, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Doerk, T, Schuermann, P, Bremer, M, Hillemanns, P, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, N, Antonenkova, N, Rogov, Y, Bermisheva, M, Prokofyeva, D, Zinnatullina, G, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, V-M, Hartikainen, JM, Kataja, V, Chenevix-Trench, G, Beesley, J, Chen, X, Lambrechts, D, Smeets, A, Paridaens, R, Weltens, C, Flesch-Janys, D, Buck, K, Behrens, S, Peterlongo, P, Bernard, L, Manoukian, S, Radice, P, Couch, FJ, Vachon, C, Wang, X, Olson, J, Giles, G, Baglietto, L, McLean, CA, Severi, G, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Mulligan, AM, Weerasooriya, N, Devilee, P, Tollenaar, RAEM, Martens, JWM, Seynaeve, CM, Hooning, MJ, Hollestelle, A, Jager, A, Tilanus-Linthorst, MMA, Hall, P, Czene, K, Liu, J, Li, J, Cox, A, Cross, SS, Brock, IW, Reed, MWR, Pharoah, P, Blows, FM, Dunning, AM, Ghous-saini, M, Ashworth, A, Swerdlow, A, Jones, M, Schoemaker, M, Easton, DF, Humphreys, M, Wang, Q, Peto, J, dos-Santos-Silva, I, Warren, H, Dudbridge, F, Fletcher, O, Orr, N, Johnson, N, Hopper, JL, Apicella, C, Southey, MC, Mahmoodi, M, Schmidt, MK, Broeks, A, Cornelissen, S, Braaf, LM, Muir, KR, Lophatananon, A, Chaiwerawattana, A, Wiangnon, S, Fasching, PA, Beckmann, MW, Ekici, AB, Schulz-Wendtland, R, Sawyer, EJ, Tomlinson, I, Kerin, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Guenel, P, Therese, T, Laurent-Puig, P, Mulot, C, Bojesen, SE, Nielsen, SF, Flyger, H, Nordestgaard, BG, Milne, RL, Benitez, J, Arias-Perez, J-I, Pilar Zamora, M, Anton-Culver, H, Ziogas, A, Bernstein, L, Dur, CC, Brenner, H, Mueller, H, Arndt, V, Langheinz, A, Meindl, A, Golatta, M, Bartram, CR, Schmutzler, RK, Brauch, H, Justenhoven, C, Bruening, T, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Doerk, T, Schuermann, P, Bremer, M, Hillemanns, P, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, N, Antonenkova, N, Rogov, Y, Bermisheva, M, Prokofyeva, D, Zinnatullina, G, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, V-M, Hartikainen, JM, Kataja, V, Chenevix-Trench, G, Beesley, J, Chen, X, Lambrechts, D, Smeets, A, Paridaens, R, Weltens, C, Flesch-Janys, D, Buck, K, Behrens, S, Peterlongo, P, Bernard, L, Manoukian, S, Radice, P, Couch, FJ, Vachon, C, Wang, X, Olson, J, Giles, G, Baglietto, L, McLean, CA, Severi, G, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Mulligan, AM, Weerasooriya, N, Devilee, P, Tollenaar, RAEM, Martens, JWM, Seynaeve, CM, Hooning, MJ, Hollestelle, A, Jager, A, Tilanus-Linthorst, MMA, Hall, P, Czene, K, Liu, J, Li, J, Cox, A, Cross, SS, Brock, IW, Reed, MWR, Pharoah, P, Blows, FM, Dunning, AM, Ghous-saini, M, Ashworth, A, Swerdlow, A, Jones, M, Schoemaker, M, Easton, DF, Humphreys, M, Wang, Q, Peto, J, and dos-Santos-Silva, I

Abstract

BACKGROUND: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). METHODS: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls). RESULTS: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29)] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors. CONCLUSIONS: This study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer. IMPACT: The findings further support the view that genetic susceptibility varies according to tumor subtype.

Published
2012

34. Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)

Author

Hein, R, Maranian, M, Hopper, JL, Kapuscinski, MK, Southey, MC, Park, DJ, Schmidt, Marjanka K, Broeks, A, Hogervorst, FBL, Bueno-de-Mesquit, HB, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, ID, Peto, J, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Marmee, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Cordina-Duverger, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, RL, Perez, JIA, Zamora, MP, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Clarke, CA, Brenner, H, Muller, H, Arndt, V, Stegmaier, C, Rahman, N, Seal, S, Turnbull, C, Renwick, A, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Brauch, H, Hamann, U, Ko, YD, Wang-Gohrke, S, Dork, T, Schurmann, P, Karstens, JH, Hillemanns, P, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Zalutsky, IV, Antonenkova, NN, Bermisheva, M, Prokovieva, D, Farahtdinova, A, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, J, Chen, XQ, Beesley, J, Lambrechts, D, Zhao, H (Hui), Neven, P, Wildiers, H, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Manoukian, S, Barile, M, Couch, FJ, Olson, JE, Wang, XS, Fredericksen, Z, Giles, GG, Baglietto, L, McLean, CA, Severi, G, Offit, K, Robson, M, Gaudet, MM, Vijai, J, Alnaes, GG, Kristensen, V, Borresen-Dale, AL, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Figueroa, JD, Garcia-Closas, M, Lissowska, J, Sherman, ME, Hooning, M, Martens, John, Seynaeve, Caroline, Collee, M, Hall, P, Humpreys, K, Czene, K, Liu, JJ, Cox, A, Brock, IW, Cross, SS, Reed, MWR, Ahmed, S (Shahana), Ghoussaini, M, Pharoah, PDP, Kang, D, Yoo, KY, Noh, DY, Jakubowska, A, Jaworska, K, Durda, K, Zlowocka, E, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Shen, CY, Yu, JC, Hsu, HM, Hou, MF, Orr, N, Schoemaker, M, Ashworth, A, Swerdlow, A, Trentham-Dietz, A, Newcomb, PA, Titus, L, Egan, KM, Chenevix-Trench, G, Antoniou, AC, Humphreys, MK, Morrison, J, Chang-Claude, J, Easton, DF, Dunning, AM, Truong, T, Hein, R, Maranian, M, Hopper, JL, Kapuscinski, MK, Southey, MC, Park, DJ, Schmidt, Marjanka K, Broeks, A, Hogervorst, FBL, Bueno-de-Mesquit, HB, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, ID, Peto, J, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Marmee, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Cordina-Duverger, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, RL, Perez, JIA, Zamora, MP, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Clarke, CA, Brenner, H, Muller, H, Arndt, V, Stegmaier, C, Rahman, N, Seal, S, Turnbull, C, Renwick, A, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Brauch, H, Hamann, U, Ko, YD, Wang-Gohrke, S, Dork, T, Schurmann, P, Karstens, JH, Hillemanns, P, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Zalutsky, IV, Antonenkova, NN, Bermisheva, M, Prokovieva, D, Farahtdinova, A, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, J, Chen, XQ, Beesley, J, Lambrechts, D, Zhao, H (Hui), Neven, P, Wildiers, H, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Manoukian, S, Barile, M, Couch, FJ, Olson, JE, Wang, XS, Fredericksen, Z, Giles, GG, Baglietto, L, McLean, CA, Severi, G, Offit, K, Robson, M, Gaudet, MM, Vijai, J, Alnaes, GG, Kristensen, V, Borresen-Dale, AL, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Figueroa, JD, Garcia-Closas, M, Lissowska, J, Sherman, ME, Hooning, M, Martens, John, Seynaeve, Caroline, Collee, M, Hall, P, Humpreys, K, Czene, K, Liu, JJ, Cox, A, Brock, IW, Cross, SS, Reed, MWR, Ahmed, S (Shahana), Ghoussaini, M, Pharoah, PDP, Kang, D, Yoo, KY, Noh, DY, Jakubowska, A, Jaworska, K, Durda, K, Zlowocka, E, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Shen, CY, Yu, JC, Hsu, HM, Hou, MF, Orr, N, Schoemaker, M, Ashworth, A, Swerdlow, A, Trentham-Dietz, A, Newcomb, PA, Titus, L, Egan, KM, Chenevix-Trench, G, Antoniou, AC, Humphreys, MK, Morrison, J, Chang-Claude, J, Easton, DF, Dunning, AM, and Truong, T

Abstract

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6x10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8x10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2x10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8x10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8x10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3x10(-7), p(heterogeneity) = 5.1x10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.

Published
2012

35. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study

Author

Schrappe, M, Valsecchi, M, Bartram, C, Schrauder, A, Panzer Grümayer, R, Möricke, A, Parasole, R, Zimmermann, M, Dworzak, M, Buldini, B, Reiter, A, Basso, G, Klingebiel, T, Messina, C, Ratei, R, Cazzaniga, G, Köhler, R, Locatelli, F, Schäfer, B, Aricò, M, Welte, K, Van Dongen, J, Gadner, H, Biondi, A, Conter, V, Bartram, CR, Schäfer, BW, Van Dongen, JJ, Conter, V., VALSECCHI, MARIA GRAZIA, BIONDI, ANDREA, Schrappe, M, Valsecchi, M, Bartram, C, Schrauder, A, Panzer Grümayer, R, Möricke, A, Parasole, R, Zimmermann, M, Dworzak, M, Buldini, B, Reiter, A, Basso, G, Klingebiel, T, Messina, C, Ratei, R, Cazzaniga, G, Köhler, R, Locatelli, F, Schäfer, B, Aricò, M, Welte, K, Van Dongen, J, Gadner, H, Biondi, A, Conter, V, Bartram, CR, Schäfer, BW, Van Dongen, JJ, Conter, V., VALSECCHI, MARIA GRAZIA, and BIONDI, ANDREA

Abstract

The prognostic value of MRD in large series of childhood T-ALL has not yet been established. Trial AIEOP-BFM-ALL 2000 introduced standardized quantitative assessment of MRD for stratification, based on immunoglobulin and TCR gene rearrangements as polymerase chain reaction targets: Patients were considered MRD standard risk (MRD-SR) if MRD was negative at day 33 (time point 1 [TP1]) and day 78 (TP2), analyzed by at least 2 sensitive markers;MRDintermediate risk (MRDIR) if positive either at day 33 or 78 and < 10+3 at day 78; and MRD high risk (MRD-HR) if ≥ 10-3 at day 78. A total of 464 patients with T-ALL were stratified by MRD: 16% of them were MRD-SR, 63% MRD-IR, and 21% MRD-HR. Their 7-year event-free-survival (SE)was 91.1% (3.5%), 80.6% (2.3%), and 49.8% (5.1%) (P < .001), respectively. Negativity of MRD at TP1 was the most favorable prognostic factor. An excellent outcome was also obtained in 32% of patients turning MRD negative only at TP2, indicating that early (TP1) MRD levels were irrelevant if MRD at TP2 was negative (48% of all patients).MRD≥ 10+3 at TP2 constitutes the most important predictive factor for relapse in childhood T-ALL. The study is registered at http://www.clinicaltrials. gov; "Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With Acute Lymphoblastic Leukemia," protocol identification#NCT00430118 for BFM and #NCT00613457 for AIEOP. © 2011 by The American Society of Hematology.

Published
2011

36. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study

Author

Conter, V, Bartram, C, Valsecchi, M, Schrauder, A, Panzer Grumayer, R, Moricke, A, Arico, M, Zimmermann, M, Mann, G, De Rossi, G, Stanulla, M, Locatelli, F, Basso, G, Niggli, F, Barisone, E, Henze, G, Ludwig, W, Haas, O, Cazzaniga, G, Koehler, R, Silvestri, D, Bradtke, J, Parasole, R, Beier, R, van Dongen, J, Biondi, A, Schrappe, M, Bartram, CR, Ludwig, WD, Haas, OA, van Dongen, JJ, Schrappe, M., VALSECCHI, MARIA GRAZIA, BIONDI, ANDREA, Conter, V, Bartram, C, Valsecchi, M, Schrauder, A, Panzer Grumayer, R, Moricke, A, Arico, M, Zimmermann, M, Mann, G, De Rossi, G, Stanulla, M, Locatelli, F, Basso, G, Niggli, F, Barisone, E, Henze, G, Ludwig, W, Haas, O, Cazzaniga, G, Koehler, R, Silvestri, D, Bradtke, J, Parasole, R, Beier, R, van Dongen, J, Biondi, A, Schrappe, M, Bartram, CR, Ludwig, WD, Haas, OA, van Dongen, JJ, Schrappe, M., VALSECCHI, MARIA GRAZIA, and BIONDI, ANDREA

Abstract

The Associazione Italiana di Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster Acute Lymphoblastic Leukemia (AIEOP-BFM ALL 2000) study has for the first time introduced standardized quantitative assessment of minimal residual disease (MRD) based on immunoglobulin and T-cell receptor gene rearrangements as polymerase chain reaction targets (PCR-MRD), at 2 time points (TPs), to stratify patients in a large prospective study. Patients with precursor B (pB) ALL (n = 3184) were considered MRD standard risk (MRD-SR) if MRD was already negative at day 33 (analyzed by 2 markers, with a sensitivity of at least 10-4); MRD high risk (MRD-HR) if 10-3 or more at day 78 and MRD intermediate risk (MRD-IR): others. MRD-SR patients were 42% (1348): 5-year event-free survival (EFS, standard error) is 92.3% (0.9). Fifty-two percent (1647) were MRD-IR: EFS 77.6% (1.3). Six percent of patients (189) were MRD-HR: EFS 50.1% (4.1; P < .001). PCR-MRD discriminated prognosis even on top of white blood cell count, age, early response to prednisone, and genotype. MRD response detected by sensitive quantitative PCR at 2 predefined TPs is highly predictive for relapse in childhood pB-ALL. The study is registered at http://clinicaltrials.gov: NCT00430118 for BFM and NCT00613457 for AIEOP. (Blood. 2010;115(16):3206-3214) © 2010 by The American Society of Hematology.

Published
2010

38. Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia

Author

Flohr, T, Schrauder, A, Cazzaniga, G, Panzer Grümayer, R, van der Velden, V, Fischer, S, Stanulla, M, Basso, G, Niggli, F, Schäfer, B, Sutton, R, Koehler, R, Zimmermann, M, Valsecchi, M, Gadner, H, Masera, G, Schrappe, M, van Dongen, J, Biondi, A, Bartram, C, International BFM Study, G, Niggli, FK, Schäfer, BW, van Dongen, JJ, Bartram, CR, International BFM Study Group, VALSECCHI, MARIA GRAZIA, MASERA, GIUSEPPE, BIONDI, ANDREA, Flohr, T, Schrauder, A, Cazzaniga, G, Panzer Grümayer, R, van der Velden, V, Fischer, S, Stanulla, M, Basso, G, Niggli, F, Schäfer, B, Sutton, R, Koehler, R, Zimmermann, M, Valsecchi, M, Gadner, H, Masera, G, Schrappe, M, van Dongen, J, Biondi, A, Bartram, C, International BFM Study, G, Niggli, FK, Schäfer, BW, van Dongen, JJ, Bartram, CR, International BFM Study Group, VALSECCHI, MARIA GRAZIA, MASERA, GIUSEPPE, and BIONDI, ANDREA

Abstract

Detection of minimal residual disease (MRD) is the most sensitive method to evaluate treatment response and one of the strongest predictors of outcome in childhood acute lymphoblastic leukemia (ALL). The 10-year update on the I-BFM-SG MRD study 91 demonstrates stable results (event-free survival), that is, standard risk group (MRD-SR) 93%, intermediate risk group (MRD-IR) 74%, and high risk group (MRD-HR) 16%. In multicenter trial AIEOP-BFM ALL 2000, patients were stratified by MRD detection using quantitative PCR after induction (TP1) and consolidation treatment (TP2). From 1 July 2000 to 31 October 2004, PCR target identification was performed in 3341 patients: 2365 (71%) patients had two or more sensitive targets (≥10-4), 671 (20%) patients revealed only one sensitive target, 217 (6%) patients had targets with lower sensitivity, and 88 (3%) patients had no targets. MRD-based risk group assignment was feasible in 2594 (78%) patients: 40% were classified as MRD-SR (two sensitive targets, MRD negativity at both time points), 8% as MRD-HR (MRD ≤10-3 at TP2), and 52% as MRD-IR. The remaining 823 patients were stratified according to clinical risk features: HR (n=108) and IR (n=715). In conclusion, MRD-PCR-based stratification using stringent criteria is feasible in almost 80% of patients in an international multicenter trial.

Published
2008

41. Empirische Mutationshäufigkeiten pathogener Keimbahnmutationen in BRCA1 und BRCA2: Ergebnisse des Deutschen Konsortiums Familiärer Brust- und Eierstockkrebs

Author

Kast, K, primary, Schmutzler, R, additional, Kiechle, M, additional, Bartram, CR, additional, Niederacher, D, additional, Arnold, N, additional, Grimm, T, additional, Bick, U, additional, Schlegelberger, B, additional, Janni, W, additional, Wieacker, P, additional, Briest, S, additional, Meindl, A, additional, and Engel, C, additional

Published
2013
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43. Optimization of PCR-based minimal residual disease diagnostics for childhood acute lymphoblastic leukemia in a multi-center setting

Author

Vandervelden, V, Panzergrumayer, E, Cazzaniga, G, Flohr, T, Sutton, R, Schrauder, A, Basso, G, Schrappe, M, Wijkhuijs, J, Konrad, M, Bartram, C, Masera, G, Biondi, A, van Dongen, J, vanderVelden, VH, PanzerGrumayer, ER, Wijkhuijs, JM, Bartram, CR, van Dongen, JJ, MASERA, GIUSEPPE, BIONDI, ANDREA, Vandervelden, V, Panzergrumayer, E, Cazzaniga, G, Flohr, T, Sutton, R, Schrauder, A, Basso, G, Schrappe, M, Wijkhuijs, J, Konrad, M, Bartram, C, Masera, G, Biondi, A, van Dongen, J, vanderVelden, VH, PanzerGrumayer, ER, Wijkhuijs, JM, Bartram, CR, van Dongen, JJ, MASERA, GIUSEPPE, and BIONDI, ANDREA

Abstract

Minimal residual disease (MRD) diagnostics is used for treatment stratification in childhood acute lymphoblastic leukemia. We aimed to identify and solve potential problems in multicenter MRD studies to achieve and maintain consistent results between the AIEOP/BFM ALL-2000 MRD laboratories. As the dot-blot hybridization method was replaced by the real-time quantitative polymerase chain reaction (RQ-PCR) method during the treatment protocol, special attention was given to the comparison of MRD data obtained by both methods and to the reproducibility of RQ-PCR data. Evaluation of all key steps in molecular MRD diagnostics identified several pitfalls that resulted in discordant MRD results. In particular, guidelines for RQ-PCR data interpretation appeared to be crucial for obtaining concordant MRD results. The experimental variation of the RQ-PCR was generally less than three-fold, but logically became larger at low MRD levels below the reproducible sensitivity of the assay (<10-4). Finally, MRD data obtained by dot-blot hybridization were comparable to those obtained by RQ-PCR analysis (r2=0.74). In conclusion, MRD diagnostics using RQ-PCR analysis of immunoglobulin/T-cell receptor gene rearrangements is feasible in multicenter studies but requires standardization; particularly strict guidelines for interpretation of RQ-PCR data are required. We further recommend regular quality control for laboratories performing MRD diagnostics in international treatment protocols.

Published
2007

46. High incidence and unique features of antigen receptor gene rearrangements in TEL-AML1-positive leukemias

Author

Hubner, S, Cazzaniga, G, Flohr, T, van der Velden, V, Konrad, M, Potschger, U, Basso, G, Schrappe, M, van Dongen, J, Bartram, C, Biondi, A, Panzer Grumayer, E, van der Velden, VHJ, van Dongen, JJM, Bartram, CR, Panzer Grumayer, ER, BIONDI, ANDREA, Hubner, S, Cazzaniga, G, Flohr, T, van der Velden, V, Konrad, M, Potschger, U, Basso, G, Schrappe, M, van Dongen, J, Bartram, C, Biondi, A, Panzer Grumayer, E, van der Velden, VHJ, van Dongen, JJM, Bartram, CR, Panzer Grumayer, ER, and BIONDI, ANDREA

Abstract

The t(12;21) translocation resulting in the TEL-AML1 gene fusion is found in 25% of childhood B-cell precursor (BCP) acute lymphoblastic leukemias (ALL). Since TEL-AML1 has been reported to induce cell cycle retardation and thus may influence somatic recombination, we analyzed 214 TEL-AML1-positive ALL by PCR for rearrangements of the immunoglobulin (Ig) and T-cell receptor (TCR) genes. As a control group, 174 childhood BCP ALL without a TEL-AML1 were used. The majority of TEL-AML1-positive leukemias had a higher number of Ig/TCR rearrangements than control ALL. They also had a more mature immunogenotype characterized by their high frequency of complete IGH, IGK-Kde, and TCRG rearrangements. While IGK-Kde and TCRG were more frequently rearranged on both alleles at higher age, IGH and TCRD rearrangements decreased in their incidence along with a decrease in biallelic IGH rearrangements. This suggests that the recombination process continues in these leukemias leading to ongoing rearrangements and possibly also deletions of antigen receptor genes. We here provide first evidence that somatic recombination of antigen receptor genes is affected by the TEL-AML1 fusion, and that further age-related differences are probably caused by the longer latency period of the prenatally initiated TEL-AML1-positive leukemias in older children.

Published
2004

48. Prävalenz pathogener Mutationen in den Genen BRCA1 und BRCA2 in verschiedenen Risikogruppen: Ergebnisse des Deutschen Konsortiums familiärer Brust- und Eierstockkrebs

Author

Kast, K, primary, Schmutzler, RK, additional, Distler, W, additional, Arnold, N, additional, Bartram, CR, additional, Bick, U, additional, Froster, UG, additional, Grimm, T, additional, Kreienberg, R, additional, Nestle-Krämling, C, additional, Schlegelberger, B, additional, Wieacker, P, additional, Meindl, A, additional, and Engel, C, additional

Published
2010
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49. Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL

Author

Willemse, MJ, Seriu, T, Hettinger, K, d' Aniello, E, Hop, Wim C.J., Panzer-Grümayer, ER, Biondi, A, Schrappe, M, Kamps, WA, Masera, G, Gadner, H, Riehm, H, Bartram, CR, Dongen, Jacques, Willemse, MJ, Seriu, T, Hettinger, K, d' Aniello, E, Hop, Wim C.J., Panzer-Grümayer, ER, Biondi, A, Schrappe, M, Kamps, WA, Masera, G, Gadner, H, Riehm, H, Bartram, CR, and Dongen, Jacques

Published
2002

50. MINIMAL REQUIREMENTS FOR THE DIAGNOSIS, CLASSIFICATION, AND EVALUATION OF THE TREATMENT OF CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA (ALL) IN THE BFM FAMILY COOPERATIVE GROUP

Author

VANDERDOESVANDENBERG, A, BARTRAM, CR, BASSO, G, BENOIT, YCM, BIONDI, A, DEBATIN, KM, HAAS, OA, HARBOTT, J, KAMPS, WA, KOLLER, U, LAMPERT, F, LUDWIG, WD, NIEMEYER, CM, and VANWERING, ER

Subjects
ELECTRON-MICROSCOPY, DIAGNOSIS, CLASSIFICATION, BFM-FAMILY, CHILDREN, ACUTE LYMPHOBLASTIC LEUKEMIA, CEREBROSPINAL-FLUID, GAMMA-CHAIN GENE, POOR-PROGNOSIS, hemic and lymphatic diseases, T-CELL RECEPTOR, TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE, TRANSLOCATION 4-11, MONOCLONAL-ANTIBODIES, BETA-CHAIN, ANTIGEN RECEPTOR
Abstract

Minimal requirements and their rationale for the diagnosis and the response to treatment in childhood acute lymphoblastic leukemia (ALL) were defined in the recently instituted "BFM-Family"-Group, in which the German, Austrian, Dutch, Italian, Belgian, French and Hungarian childhood leukemia study groups cooperate. ALL is defined as greater-than-or-equal-to 25% lymphoblasts in the bone marrow; for confirmation of the diagnosis and classification the criteria of the French-American-British (FAB) criteria are retained. For determination of the extent of the disease at diagnosis or relapse the criteria by the Rome Workshop [1986] are recommended: An obligatory panel of monoclonal antibodies for immunophenotyping was defined, as well as criteria for precursor B-ALL and T-ALL. Cytogenetic studies may support the diagnosis and subtyping, and are essential to identify certain patients with a high risk of treatment failure (f.i. t(9;22), t(4;11)). The role of molecular genetics for the diagnosis and the characterization of leukemia and the value of its clinical application needs further elucidation. Relapse was defined as recurrence of evident leukemia in the blood, bone marrow (greater-than-or-equal-to 25% lymphoblasts) or at any other site (to be confirmed by histological examination). Bone marrow involvement combined with extramedullary relapse was defined as greater-than-or-equal-to 5% lymphoblasts in the bone marrow.

Published
1992

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