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55. The genetic history of Greenlandic-European contact

Author

Waples, Ryan K., primary, Hauptmann, Aviaja L., additional, Seiding, Inge, additional, Jørsboe, Emil, additional, Jørgensen, Marit E., additional, Grarup, Niels, additional, Andersen, Mette K., additional, Larsen, Christina V.L., additional, Bjerregaard, Peter, additional, Hellenthal, Garrett, additional, Hansen, Torben, additional, Albrechtsen, Anders, additional, and Moltke, Ida, additional

Published
2021
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58. The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders

Author

Andersen, Mette K., Jørsboe, Emil, Skotte, Line, Hanghøj, Kristian, Sandholt, Camilla H., Moltke, Ida, Grarup, Niels, Kern, Timo, Mahendran, Yuvaraj, Søborg, Bolette, Bjerregaard, Peter, Larsen, Christina V. L., Dahl-Petersen, Inger K., Tiwari, Hemant K., Feenstra, Bjarke, Koch, Anders, Wiener, Howard W., Hopkins, Scarlett E., Pedersen, Oluf, Melbye, Mads, Boyer, Bert B., Jørgensen, Marit E., Albrechtsen, Anders, Hansen, Torben, Andersen, Mette K., Jørsboe, Emil, Skotte, Line, Hanghøj, Kristian, Sandholt, Camilla H., Moltke, Ida, Grarup, Niels, Kern, Timo, Mahendran, Yuvaraj, Søborg, Bolette, Bjerregaard, Peter, Larsen, Christina V. L., Dahl-Petersen, Inger K., Tiwari, Hemant K., Feenstra, Bjarke, Koch, Anders, Wiener, Howard W., Hopkins, Scarlett E., Pedersen, Oluf, Melbye, Mads, Boyer, Bert B., Jørgensen, Marit E., Albrechtsen, Anders, and Hansen, Torben

Abstract

The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,626 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup'ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population. We identified a common variant on chromosome 11, rs4936356, where the derived G-allele had a frequency of 24% in the stage 1 study population. The derived allele was genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p = 3.2x10-8), corresponding to 0.64 kg/m2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup'ik cohort (-0.09 SD, p = 0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p = 0.514). The association remained genome-wide significant in meta-analysis of the Arctic cohorts (-0.10 SD (0.02), p = 4.7x10-8). Moreover, the variant was associated with a leaner body type (weight, -1.68 (0.37) kg; waist circumference, -1.52 (0.33) cm; hip circumference, -0.85 (0.24) cm; lean mass, -0.84 (0.19) kg; fat mass and percent, -1.66 (0.33) kg and -1.39 (0.27) %; visceral adipose tissue, -0.30 (0.07) cm; subcutaneous adipose tissue, -0.16 (0.05) cm, all p<0.0002), lower insulin resistance (HOMA-IR, -0.12 (0.04), p = 0.00021), and favorable lipid levels (triglyceride, -0.05 (0.02) mmol/l, p = 0.025; HDL-cholesterol, 0.04 (0.01) mmol/l, p = 0.0015). In conclusion, we identified a novel variant, where the derived G-allele possibly associated with lower BMI in Arctic populations, and as a consequence also leaner body type, lo

Published
2020

59. High preharvest donor Foxp3 mRNA level predicts late relapse of acute lymphoblastic leukaemia after haematopoietic stem cell transplantation

Author

Jacobsen, Niels, primary, Frisch, Tina, additional, Keiding, Niels, additional, Heilmann, Carsten, additional, Sengeløv, Henrik, additional, Madsen, Hans O., additional, Marquart, Hanne, additional, Dickmeiss, Ebbe, additional, Andersen, Mette K., additional, Christiansen, Claus B., additional, and Ryder, Lars P., additional

Published
2021
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62. Paediatric B-cell precursor acute lymphoblastic leukaemia with t(1;19)(q23;p13): clinical and cytogenetic characteristics of 47 cases from the Nordic countries treated according to NOPHO protocols

Author

Andersen, Mette K., Autio, Kirsi, Barbany, Gisela, Borgström, Georg, Cavelier, Lucia, Golovleva, Irina, Heim, Sverre, Heinonen, Kristina, Hovland, Randi, Johannsson, Johann H., Johansson, Bertil, Kjeldsen, Eigil, Nordgren, Ann, Palmqvist, Lars, and Forestier, Erik

Published
2011
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64. 246-OR: A Loss-of-Function Mutation in the Sucrase-Isomaltase Gene Is Linked to a Markedly Healthier Metabolic Profile in Greenlanders

Author

JØRGENSEN, MARIT E., primary, ANDERSEN, METTE K., additional, SKOTTE, LINE, additional, JØRSBOE, EMIL, additional, GRARUP, NIELS, additional, BJERREGAARD, PETER, additional, SOBORG, BOLETTE, additional, PEDERSEN, OLUF, additional, FEENSTRA, BJARKE, additional, FÆRGEMAN, NILS J.K., additional, KOCH, ANDERS, additional, MOLTKE, IDA, additional, HANSEN, TORBEN, additional, and ALBRECHTSEN, ANDERS, additional

Published
2020
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65. The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders

Author

Andersen, Mette K., primary, Jørsboe, Emil, additional, Skotte, Line, additional, Hanghøj, Kristian, additional, Sandholt, Camilla H., additional, Moltke, Ida, additional, Grarup, Niels, additional, Kern, Timo, additional, Mahendran, Yuvaraj, additional, Søborg, Bolette, additional, Bjerregaard, Peter, additional, Larsen, Christina V. L., additional, Dahl-Petersen, Inger K., additional, Tiwari, Hemant K., additional, Feenstra, Bjarke, additional, Koch, Anders, additional, Wiener, Howard W., additional, Hopkins, Scarlett E., additional, Pedersen, Oluf, additional, Melbye, Mads, additional, Boyer, Bert B., additional, Jørgensen, Marit E., additional, Albrechtsen, Anders, additional, and Hansen, Torben, additional

Published
2020
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73. Nordic Guidelines for Germline Predisposition to Myeloid Neoplasms in Adults: Recommendations for Genetic Diagnosis, Clinical Management and Follow-up

Author

Baliakas, Panagiotis, Tesi, Bianca, Wartiovaara-Kautto, Ulla, Stray-Pedersen, Asbjørg, Friis, Lone Smidstrup, Dybedal, Ingunn, Hovland, Randi, Jahnukainen, Kirsi, Raaschou-Jensen, Klas, Ljungman, Per, Rustad, Cecilie F., Lautrup, Charlotte K., Kilpivaara, Outi, Kittang, Astrid Olsnes, Grønbæk, Kirsten, Cammenga, Jörg, Hellström-Lindberg, Eva, Andersen, Mette K., Baliakas, Panagiotis, Tesi, Bianca, Wartiovaara-Kautto, Ulla, Stray-Pedersen, Asbjørg, Friis, Lone Smidstrup, Dybedal, Ingunn, Hovland, Randi, Jahnukainen, Kirsi, Raaschou-Jensen, Klas, Ljungman, Per, Rustad, Cecilie F., Lautrup, Charlotte K., Kilpivaara, Outi, Kittang, Astrid Olsnes, Grønbæk, Kirsten, Cammenga, Jörg, Hellström-Lindberg, Eva, and Andersen, Mette K.

Published
2019
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74. Nordic Guidelines for Germline Predisposition to Myeloid Neoplasms in Adults:Recommendations for Genetic Diagnosis, Clinical Management and Follow-up

Author

Baliakas, Panagiotis, Tesi, Bianca, Wartiovaara-kautto, Ulla, Stray-pedersen, Asbj⊘rg, Friis, Lone Smidstrup, Dybedal, Ingunn, Hovland, Randi, Jahnukainen, Kirsi, Raaschou-Jensen, Klas, Ljungman, Per, Rustad, Cecilie F., Lautrup, Charlotte K., Kilpivaara, Outi, Kittang, Astrid Olsnes, Grønbæk, Kirsten, Cammenga, Jörg, Hellström-lindberg, Eva, Andersen, Mette K., Baliakas, Panagiotis, Tesi, Bianca, Wartiovaara-kautto, Ulla, Stray-pedersen, Asbj⊘rg, Friis, Lone Smidstrup, Dybedal, Ingunn, Hovland, Randi, Jahnukainen, Kirsi, Raaschou-Jensen, Klas, Ljungman, Per, Rustad, Cecilie F., Lautrup, Charlotte K., Kilpivaara, Outi, Kittang, Astrid Olsnes, Grønbæk, Kirsten, Cammenga, Jörg, Hellström-lindberg, Eva, and Andersen, Mette K.

Published
2019

75. Global microRNA profiling of metastatic conjunctival melanoma

Author

Mikkelsen, Lauge H, Andersen, Mette K, Andreasen, Simon, Larsen, Ann-Cathrine, Tan, Qihua, Toft, Peter B, Wadt, Karin, Heegaard, Steffen, Mikkelsen, Lauge H, Andersen, Mette K, Andreasen, Simon, Larsen, Ann-Cathrine, Tan, Qihua, Toft, Peter B, Wadt, Karin, and Heegaard, Steffen

Abstract

This study aimed to investigate the microRNA (miRNA) profile in primary tumors from conjunctival melanoma with and without subsequent metastatic spread along with their coupled distant metastases to identify miRNAs likely to be involved in metastatic progression. This observational study included 13 patients with metastatic conjunctival melanoma (follow-up: 1-39 years) treated at a Danish referral center. Twenty-five patients with nonmetastatic conjunctival melanoma (follow-up: 5-17 years) were included for comparison. Global miRNA profiling was performed with the Affymetrix GeneChip 4.1 microarray. Taqman qPCR arrays were used for validation. Significant differentially expressed miRNAs were defined as having a false discovery rate of less than 0.05. Primary conjunctival melanoma with and without subsequent metastatic spread clustered separately according to miRNA expression, and 15 miRNAs were found to have significant differential expression. Six miRNAs (hsa-miR-4528, hsa-miR-1270, hsa-miR-1290, hsa-mir-548f-4, hsa-mir-4278, and hsa-miR-34a-3p) were downregulated and nine miRNAs were upregulated (hsa-mir-575, hsa-miR-527, hsa-miR-518a-5p, hsa-miR-6759-5p, hsa-miR-8078, hsa-mir-4501, hsa-mir-622, hsa-mir-4698, and hsa-mir-4654) in primary conjunctival melanoma with subsequent metastatic spread. A comparison of primary conjunctival melanoma with their pair-matched metastases identified six significant differentially expressed miRNAs (hsa-miR-1246 and hsa-miR-302d-5p, hsa-mir-6084, hsa-miR-184, hsa-mir-658, and hsa-mir-4427). qPCR confirmed downregulation of hsa-miR-184 in the distant metastases when compared with the corresponding primary tumor. Primary conjunctival melanoma with and without subsequent metastatic spread separated clearly on the miRNA level when profiled with microarray-based methods. qPCR was able to replicate expression levels of one miRNA (hsa-miR-184) that was downregulated in metastases when compared with corresponding primary tumors.

Published
2019

77. Nordic Guidelines for Germline Predisposition to Myeloid Neoplasms in Adults: Recommendations for Genetic Diagnosis, Clinical Management and Follow-up

Author

Baliakas, Panagiotis, primary, Tesi, Bianca, additional, Wartiovaara-Kautto, Ulla, additional, Stray-Pedersen, Asbjørg, additional, Friis, Lone Smidstrup, additional, Dybedal, Ingunn, additional, Hovland, Randi, additional, Jahnukainen, Kirsi, additional, Raaschou-Jensen, Klas, additional, Ljungman, Per, additional, Rustad, Cecilie F., additional, Lautrup, Charlotte K., additional, Kilpivaara, Outi, additional, Kittang, Astrid Olsnes, additional, Grønbæk, Kirsten, additional, Cammenga, Jörg, additional, Hellström-Lindberg, Eva, additional, and Andersen, Mette K., additional

Published
2019
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78. Estimating narrow-sense heritability from genome-wide data in admixed populations

Author

Athanasiadis, Georgios, primary, Speed, Doug, additional, Andersen, Mette K., additional, Appel, Emil V. R., additional, Grarup, Niels, additional, Brandslund, Ivan, additional, Jørgensen, Marit Eika, additional, Lytken Larsen, Christina Viskum, additional, Bjerregaard, Peter, additional, Hansen, Torben, additional, and Albrechtsen, Anders, additional

Published
2019
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80. Long-Term Metastatic Risk after Biopsy of Posterior Uveal Melanoma

Author

Bagger, Mette, Smidt-Nielsen, Isabel, Andersen, Mette K., Jensen, Peter K., Heegaard, Steffen, Andersen, Klaus K., Friis, Søren, Kiilgaard, Jens F., Bagger, Mette, Smidt-Nielsen, Isabel, Andersen, Mette K., Jensen, Peter K., Heegaard, Steffen, Andersen, Klaus K., Friis, Søren, and Kiilgaard, Jens F.

Abstract

Purpose: Biopsy of posterior uveal melanoma continues to be intensely debated in terms of the clinical benefits and safety profile. Although several studies have reported a low frequency of ocular complications after tumor biopsy, the potential long-term risk of iatrogenic dissemination remains unresolved. The purpose of this study was to assess the risk of metastatic disease after biopsy of posterior uveal melanoma. Design: Retrospective nationwide cohort study linking clinical and histopathologic records to pathology, cancer, and mortality registries. Participants: All patients with posterior uveal melanoma treated in Denmark between January 1985 and December 2016. Methods: For each patient, we recorded detailed information on age, gender, tumor characteristics, and diagnostic and therapeutic measures, including tumor biopsy, if any, and the primary treating hospital. Absolute risk of melanoma-specific death was presented by cumulative incidence curves that accounted for competing risks. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and melanoma-specific mortality of patients who underwent biopsy during primary treatment compared with nonbiopsied patients through November 1, 2017. Fine and Gray risk regression was used as a sensitivity analysis to evaluate the impact of competing risks. Main Outcome Measures: All-cause and melanoma-specific mortality. Results: Among 1637 patients, 567 (35%) underwent biopsy during primary treatment. At diagnosis, biopsied patients exhibited better prognostic characteristics, including smaller tumor size (P < 0.001) and younger age (P < 0.001), than nonbiopsied patients. In the adjusted analyses, we observed no apparent differences in all-cause mortality (HR, 1.07; 95% CI, 0.89–1.26; P = 0.47) or melanoma-specific mortality (HR, 1.11; 95% CI, 0.89–1.39; P = 0.35) among biopsied patients compared with nonbiopsied patients. Conclusions: All

Published
2018

81. Putative new childhood leukemia cancer predisposition syndrome caused by germline bi-allelic missense mutations in DDX41

Author

Diness, Birgitte R., Risom, Lotte, Frandsen, Thomas L., Hansen, Bente, Andersen, Mette K., Schmiegelow, Kjeld, Wadt, Karin A.W., Diness, Birgitte R., Risom, Lotte, Frandsen, Thomas L., Hansen, Bente, Andersen, Mette K., Schmiegelow, Kjeld, and Wadt, Karin A.W.

Abstract

DDX41 has recently been identified as a new autosomal dominantly inherited cancer predisposition syndrome causing increased risk of adult onset acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We report for the first time compound heterozygote germline missense DDX41 mutations located in the DEAD-box domain, identified in two siblings by exome sequencing. Both siblings have slight dysmorphic findings, psychomotor delays and intellectual disability, and one developed blastic plasmacytoid dendritic cell neoplasm (BPDCN) at age five. RNA-sequencing of bone marrow showed DDX41 expression including both mutations. However, the allele fraction of p.Pro321Leu accounted for 96% in the RNA-sequencing indicating this mutation to be the more significant variant. Exome sequencing of the leukemic blasts identified no additional known driver mutations. There is no pattern indicating autosomal dominantly inherited cancer predisposition in the family, but the father has sarcoidosis, which has been associated with heterozygous DDX41 mutation. We propose that bi-allelic mutations in DDX41 could potentially be a new cancer predisposition syndrome associated with delayed psychomotor development.

Published
2018

82. First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes

Author

Cousminer, Diana L., Ahlqvist, Emma, Mishra, Rajashree, Andersen, Mette K., Chesi, Alessandra, Hawa, Mohammad I., Davis, Asa, Hodge, Kenyaita M., Bradfield, Jonathan P., Zhou, Kaixin, Guy, Vanessa C., Akerlund, Mikael, Wod, Mette, Fritsche, Lars G., Vestergaard, Henrik, Snyder, James, Højlund, Kurt, Linneberg, Allan, Karajamaki, Annemari, Brandslund, Ivan, Kim, Cecilia E., Witte, Daniel, Sorgjerd, Elin Pettersen, Brillon, David J., Pedersen, Oluf, Beck-Nielsen, Henning, Grarup, Niels, Pratley, Richard E., Rickels, Michael R., Vella, Adrian, Ovalle, Fernando, Melander, Olle, Harris, Ronald I., Varvel, Stephen, Grill, Valdemar E. R., Hakonarson, Hakon, Froguel, Philippe, Lonsdale, John T., Mauricio, Didac, Schloot, Nanette C., Khunti, Kamlesh, Greenbaum, Carla J., Asvold, Bjorn Olav, Yderstraede, Knud B., Pearson, Ewan R., Schwartz, Stanley, Voight, Benjamin F., Hansen, Torben, Tuomi, Tiinamaija, Boehm, Bernhard O., Groop, Leif, Leslie, R. David, Grant, Struan F. A., Cousminer, Diana L., Ahlqvist, Emma, Mishra, Rajashree, Andersen, Mette K., Chesi, Alessandra, Hawa, Mohammad I., Davis, Asa, Hodge, Kenyaita M., Bradfield, Jonathan P., Zhou, Kaixin, Guy, Vanessa C., Akerlund, Mikael, Wod, Mette, Fritsche, Lars G., Vestergaard, Henrik, Snyder, James, Højlund, Kurt, Linneberg, Allan, Karajamaki, Annemari, Brandslund, Ivan, Kim, Cecilia E., Witte, Daniel, Sorgjerd, Elin Pettersen, Brillon, David J., Pedersen, Oluf, Beck-Nielsen, Henning, Grarup, Niels, Pratley, Richard E., Rickels, Michael R., Vella, Adrian, Ovalle, Fernando, Melander, Olle, Harris, Ronald I., Varvel, Stephen, Grill, Valdemar E. R., Hakonarson, Hakon, Froguel, Philippe, Lonsdale, John T., Mauricio, Didac, Schloot, Nanette C., Khunti, Kamlesh, Greenbaum, Carla J., Asvold, Bjorn Olav, Yderstraede, Knud B., Pearson, Ewan R., Schwartz, Stanley, Voight, Benjamin F., Hansen, Torben, Tuomi, Tiinamaija, Boehm, Bernhard O., Groop, Leif, Leslie, R. David, and Grant, Struan F. A.

Published
2018

85. Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers

Author

Nielsen, Stine N., Eriksson, Frank, Rosthoej, Susanne, Andersen, Mette K., Forestier, Erik, Hasle, Henrik, Hjalgrim, Lisa L., Aasberg, Ann, Abrahamsson, Jonas, Heyman, Mats, Jónsson, Ólafur G., Pruunsild, Kaie, Vaitkeviciené, Goda E., Vettenranta, Kim, Schmiegelow, Kjeld, Nielsen, Stine N., Eriksson, Frank, Rosthoej, Susanne, Andersen, Mette K., Forestier, Erik, Hasle, Henrik, Hjalgrim, Lisa L., Aasberg, Ann, Abrahamsson, Jonas, Heyman, Mats, Jónsson, Ólafur G., Pruunsild, Kaie, Vaitkeviciené, Goda E., Vettenranta, Kim, and Schmiegelow, Kjeld

Abstract

Background: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. Procedure: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]. Results: After median 9.5 years (interquartile range, 5.4-15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06-0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02-0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69-5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54-3.76, P = 0.47). Conclusions: The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.

Published
2017
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86. Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers

Author

Nielsen, Stine N., primary, Eriksson, Frank, additional, Rosthoej, Susanne, additional, Andersen, Mette K., additional, Forestier, Erik, additional, Hasle, Henrik, additional, Hjalgrim, Lisa L., additional, Aasberg, Ann, additional, Abrahamsson, Jonas, additional, Heyman, Mats, additional, Jónsson, Ólafur G., additional, Pruunsild, Kaie, additional, Vaitkeviciené, Goda E., additional, Vettenranta, Kim, additional, and Schmiegelow, Kjeld, additional

Published
2017
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87. Addressing the room for improvement in management of acute promyelocytic leukemia.

Author

Nørgaard, Jan M., Mølle, Ingolf, Kjeldsen, Eigil, Østgård, Lene S.G., Kristensen, Jørgen S., Medeiros, Bruno C., Friis, Lone S., Nielsen, Ove J., Severinsen, Marianne T., Marcher, Claus W., Møller, Peter, Schoellkopf, Claudia, Preiss, Birgitte S., and Andersen, Mette K.

Subjects
ACUTE promyelocytic leukemia, DISSEMINATED intravascular coagulation, ACUTE leukemia, MULTIPLE organ failure, EARLY death, THERAPEUTICS, DEATH rate
Abstract

Acute promyelocytic leukemia (APL) is highly curable. To achieve high cure rates, targeted therapy with retinoic acid (ATRA) must be started promptly at time of suspected diagnosis. Early death rates (EDRs, ≤30 days from diagnosis) differ markedly in patients treated on clinical trials compared to the general population. Objectives and methods: We used the comprehensive Danish National Acute Leukemia Registry (DNLR) to investigate the incidence, treatment, EDR, and long‐term clinical outcome in APL between 2000 and 2014. Results: Twenty‐two of 41 deaths occurring in 122 APL patients were EDs which were primarily caused by intracranial hemorrhage, disseminated intravascular coagulation (DIC), sepsis, and multiorgan failure. The overall EDR was 18.0%, whereas clinical trial participants had an EDR of 6.7%. Fifteen patients recruited to the NCRI AML17 APL trial from 2010 to 2013 were younger and had decreased mortality (HR 0.18, CI 0.04‐0.86, P = 0.02) compared to contemporarily treated patients (n = 15) not recruited to a clinical trial. Performance status, leukemia origin, and Sanz‐score were independent prognostic variables. Conclusions: The very low EDR for on‐trial patients is not observed in the general cohort of APL patients. Diagnostic awareness emerges as the greatest clinical challenge in management of APL. [ABSTRACT FROM AUTHOR]

Published
2019
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88. Targeted Sequencing of Diagnostic Samples Correlated to Clinical Outcome: Data from the Nordic Mantle Cell Lymphoma (MCL2 and MCL3) Studies with Long-Term Follow-up

Author

Eskelund, Christian Winther, primary, Hansen, Jakob W, additional, Westman, Maj Karoline, additional, Freiburghaus, Catja, additional, Ek, Sara, additional, Pedersen, Lone B, additional, Andersen, Mette K, additional, Räty, Riikka, additional, Kolstad, Arne, additional, Jerkeman, Mats, additional, Brown, Peter de Nully, additional, Geisler, Christian H, additional, and Groenbaek, Kirsten, additional

Published
2016
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90. The Prognostic Effect of American Joint Committee on Cancer Staging and Genetic Status in Patients With Choroidal and Ciliary Body Melanoma

Author

Bagger, Mette, Andersen, Morten T, Andersen, Klaus K, Heegaard, Steffen, Andersen, Mette K, Kiilgaard, Jens F, Bagger, Mette, Andersen, Morten T, Andersen, Klaus K, Heegaard, Steffen, Andersen, Mette K, and Kiilgaard, Jens F

Abstract

PURPOSE: To evaluate the prognostic effect of a combination of American Joint Committee on Cancer (AJCC) staging (7th edition) and genetic status in patients with posterior uveal melanoma.METHODS: A consecutive cohort of 153 patients with posterior uveal melanoma treated at Copenhagen University Hospital from January 1, 2009 through December 31, 2012 was followed until October 2014. Survival, AJCC stage, and cytogenetic data were registered. The AJCC stage was available for all patients, and cytogenetic information for chromosomes 3 and 8 was available for 139 patients. The individual and joint prognostic effects of AJCC staging and cytogenetic changes were evaluated by cumulative incidence curves and Cox proportional hazard models.RESULTS: An overall 5-year survival rate of 62% (95% confidence interval [CI]: 0.50-0.73) was observed. A normal genetic status of chromosomes 3 and 8, as found in 42 patients (30%), minimized the additional prognostic effect of AJCC staging. The frequency of tumors with normal genetic status decreased with increasing AJCC stage. Both AJCC stage III (hazard ratio [HR]: 11.0, 95% CI: 1.4-85.6) and abnormal copy number of chromosomes 3 (HR: 6.3, 95% CI: 1.4-28.3) and 8 (HR: 2.8, 95% CI: 1.03-7.8) were identified as significant predictors of a poor prognosis in the multivariate Cox regression analysis.CONCLUSIONS: Identification of a normal genetic status of chromosomes 3 and 8 minimized the prognostic effect of AJCC staging, while a combination of genetic status and AJCC staging provided the most accurate prediction of survival in patients with an abnormal chromosomal status.

Published
2015

91. Genetic Aspects of Latent Autoimmune Diabetes in Adults: A Mini-Review

Author

Andersen, Mette K. and Hansen, Torben

Abstract

Diabetes is a multifactorial disease, caused by a complex interplay between environmental and genetic risk factors. Genetic determinants of particularly Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D) have been studied extensively, whereas well-powered studies of Latent Autoimmune Diabetes in Adults (LADA) are lacking. So far available studies support a clear genetic overlap between LADA and T1D, however, with smaller effect sizes of the T1D-risk variants in LADA as compared to T1D. A genetic overlap between LADA and T2D is less clear. However, recent studies, including large numbers of LADA patients, provide different lines of evidence to support a genetic overlap between T2D and LADA. The genetic predisposition to LADA is yet to be explored in a study design, like a genome- wide association study, which allows for analyses of the genetic predisposition independently of prior hypothesis about potential candidate genes. This type of study may facilitate the discovery of risk variants associated with LADA independently of T1D and T2D, and is central in order to determine if LADA should be considered as an independent diabetic subtype. Extended knowledge about the genetic predisposition to LADA may also facilitate stratification of the heterogeneous group of LADA patients, which may assist the choice of treatment. This mini-review summarizes current knowledge of the genetics of LADA, and discusses the perspectives for future studies.

Published
2019
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92. Additional aberrations of the ETV6 and RUNX1 genes have no prognostic impact in 229 t(12;21)(p13;q22)-positive B-cell precursor acute lymphoblastic leukaemias treated according to the NOPHO-ALL-2000 protocol

Author

Barbany, Gisela, Andersen, Mette K., Autio, Kirsti, Borgström, Georg, Franco, Lucia Cavalier, Golovleva, Irina, Heim, Sverre, Heinonen, Kristina, Hovland, Randi, Johansson, Bertil, Johannsson, Johann H., Kjeldsen, Eigil, Nordgren, Ann, Palmqvist, Lars, and Forestier, Erik

Published
2012
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93. High Early Death Rate With Excellent Survival Beyond Day 30 in Acute Promyelocytic Leukemia confirmed in unselected patients: Results of a Population-based Registry Study

Author

Nørgaard, Jan M., Østgård, Lene Sofie Granfeldt, Kjeldsen, Eigil, Holm, Mette S., Andersen, Mette K., Nielsen, Ove J., Kjeldsen, Lars, Kallenbach, Maria, Severinsen, Marianne Tang, Johansen, Preben, Friis, Lone Smidstrup, Weber, Duruta, Kerndrup, Gitte Birk, Preiss, Birgitte Strange, Jensen, Morten K., Dufva, Inge Høgh, Timshel, Susanne, and Brown, Peter

Published
2012

94. Paediatric B-cell precursor acute lymphoblastic leukaemia with t(1;19)(q23;p13):Clinical and cytogenetic characteristics of 47 cases from the Nordic countries treated according to NOPHO protocols

Author

Andersen, Mette K., Autio, Kirsi, Barbany, Gisela, Borgström, Georg, Cavelier, Lucia, Golovleva, Irina, Heim, Sverre, Heinonen, Kristina, Hovland, Randi, Johannsson, Johann H., Johansson, Bertil, Kjeldsen, Eigil, Nordgren, Ann, Palmqvist, Lars, and Forestier, Erik

Subjects
PBX1, Paediatric, Acute lymphoblastic leukaemia, T(1, 19), TCF3
Abstract

The translocation t(1;19)(q23;p13)/der(19)t(1;19) is a risk stratifying aberration in childhood B-cell precursor acute lymphoblastic leukaemia (BCP ALL) in the Nordic countries. We have identified 47 children/adolescents with t(1;19)/der(19)t(1;19)-positive BCP ALL treated on two successive Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols between 1992 and 2007 and have reviewed the clinical and cytogenetic characteristics of these cases, comprising 1·8% of all cases. The translocation was balanced in 15 cases (32%) and unbalanced in 29 cases (62%). The most common additional chromosome abnormalities were del(9p), i(9q), del(6q), and del(13q). The median age was 7years, the median white blood cell (WBC) count was 16×10 9/l, and the female/male ratio was 1·2. The predicted event-free survival (EFS) at 5 and 10years was 0·79, whereas the predicted overall survival (OS) at 5 and 10years was 0·85 and 0·82, respectively. Nine patients had a bone marrow relapse after a median of 23months; no patient had a central nervous system relapse. Additional cytogenetic abnormalities, age, gender, WBC count or whether the t(1;19) was balanced or unbalanced did not influence EFS or OS. Compared to cases with t(12,21) and high hyperdiploidy, EFS was similar, but overall survival was worse in patients with t(1;19)/der(19)t(1;19) (P=0·004).

Published
2011
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96. Clinical and cytogenetic features of a population-based consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias: rare T-cell receptor gene rearrangements are associated with poor outcome

Author

Karrman, Kristina, Forestier, Erik, Heyman, Mats, Andersen, Mette K, Autio, Kirsi, Blennow, Elisabeth, Borgström, Georg, Ehrencrona, Hans, Golovleva, Irina, Heim, Sverre, Heinonen, Kristiina, Hovland, Randi, Johannsson, Johann H, Kerndrup, Gitte, Nordgren, Ann, Palmqvist, Lars, Johansson, Bertil, Nordic Society of, Pediatric Hematology, Oncology, Swedish, Cytogenetic Leukemia Study Group, and NOPHO, Leukemia Cytogenetic Study Group

Subjects
Male, Cancer Research, medicine.medical_specialty, Adolescent, T cell, Population, Receptors, Antigen, T-Cell, Kaplan-Meier Estimate, Biology, Gene Rearrangement, T-Lymphocyte, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Gastroenterology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, White blood cell, Internal medicine, Genetics, medicine, Humans, education, Child, Kaplan-Meiers Estimate, 030304 developmental biology, Proportional Hazards Models, Chromosome Aberrations, 0303 health sciences, education.field_of_study, Hematology, Chi-Square Distribution, Genetic heterogeneity, Incidence (epidemiology), T-cell receptor, Gene rearrangement, Prognosis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Child, Preschool, Immunology, Cytogenetic Analysis, Multivariate Analysis, Female
Abstract

Udgivelsesdato: 2009-Sep Clinical characteristics and cytogenetic aberrations were ascertained and reviewed in a population-based consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias (T-ALLs) diagnosed between 1992 and 2006 in the Nordic countries. Informative karyotypic results were obtained in 249 (87%) cases, of which 119 (48%) were cytogenetically abnormal. Most (62%) of the aberrant T-ALLs were pseudodiploid. Structural changes were more common than numerical ones; 86% displayed at least one structural abnormality and 41% at least one numerical anomaly. The most frequent abnormalities were T-cell receptor (TCR) gene rearrangements (20%) [TCR;11p13 (10%), TCR;10q24 (3%), TCR;other (8%)], del(9p) (17%), +8 (14%), del(6q) (12%), and 11q23 rearrangements (6%). The TCR;other group comprised the rare rearrangements t(X;14)(p11;q11), t(X;7)(q22;q34), t(1;14)(p32;q11), ins(14;5)(q11;q?q?), inv(7)(p15q34), t(8;14)(q24;q11), t(7;11)(q34;p15), and t(12;14)(p13;q11). The clinical characteristics of this Nordic patient cohort agreed well with previous larger series, with a median age of 9.0 years, male predominance (male/female ratio 3.1), median white blood cell (WBC) count of 66.5 x 10(9)/l, and a high incidence of mediastinal mass and central nervous system involvement (59% and 9.5%, respectively). These features did not differ significantly among the various genetic subgroups. 5-year event-free survival (EFS) and overall survival for all patients were 0.61 (+/-0.03) and 0.67 (+/-0.03), respectively. In a multivariate analysis, two factors affected negatively the EFS, namely a WBC count of > or =200 x 10(9)/l (P < 0.001) and the presence of rare TCR rearrangements (P = 0.001). In conclusion, in this large series of childhood T-ALLs from the Nordic countries, the cytogenetic findings were not associated with risk of therapy failure with the exception of the TCR;other group. However, further prospective and collaborative investigations of this genetically heterogeneous entity are needed to confirm these results.

Published
2009
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98. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Author

Couch, Fergus J., Wang, Xianshu, McGuffog, Lesley, Lee, Andrew, Olswold, Curtis, Kuchenbaecker, Karoline B., Soucy, Penny, Fredericksen, Zachary, Barrowdale, Daniel, Dennis, Joe, Gaudet, Mia M., Dicks, Ed, Kosel, Matthew, Healey, Sue, Sinilnikova, Olga M., Lee, Adam, Bacot, Francois, Vincent, Daniel, Hogervorst, Frans B. L., Peock, Susan, Stoppa-Lyonnet, Dominique, Jakubowska, Anna, Radice, Paolo, Schmutzler, Rita Katharina, Domchek, Susan M., Piedmonte, Marion, Singer, Christian F., Friedman, Eitan, Thomassen, Mads, Hansen, Thomas V. O., Neuhausen, Susan L., Szabo, Csilla I., Blanco, Ignacio, Greene, Mark H., Karlan, Beth Y., Garber, Judy, Phelan, Catherine M., Weitzel, Jeffrey N., Montagna, Marco, Olah, Edith, Andrulis, Irene L., Godwin, Andrew K., Yannoukakos, Drakoulis, Goldgar, David E., Caldes, Trinidad, Nevanlinna, Heli, Osorio, Ana, Terry, Mary Beth, Daly, Mary B., van Rensburg, Elizabeth J., Hamann, Ute, Ramus, Susan J., Toland, Amanda Ewart, Caligo, Maria A., Olopade, Olufunmilayo I., Tung, Nadine, Claes, Kathleen, Beattie, Mary S., Southey, Melissa C., Imyanitov, Evgeny N., Tischkowitz, Marc, Janavicius, Ramunas, John, Esther M., Kwong, Ava, Diez, Orland, Balmana, Judith, Barkardottir, Rosa B., Arun, Banu K., Rennert, Gad, Teo, Soo-Hwang, Ganz, Patricia A., Campbell, Ian, van der Hout, Annemarie H., van Deurzen, Carolien H. M., Seynaeve, Caroline, Garcia, Encarna B. Gomez, van Leeuwen, Flora E., Meijers-Heijboer, Hanne E. J., Gille, Johannes J. P., Ausems, Margreet G. E. M., Blok, Marinus J., Ligtenberg, Marjolijn J. L., Rookus, Matti A., Devilee, Peter, Verhoef, Senno, van Os, Theo A. M., Wijnen, Juul T., Frost, Debra, Ellis, Steve, Fineberg, Elena, Platte, Radka, Evans, D. Gareth, Izatt, Louise, Eeles, Rosalind A., Adlard, Julian, Eccles, Diana M., Cook, Jackie, Brewer, Carole, Douglas, Fiona, Hodgson, Shirley, Morrison, Patrick J., Side, Lucy E., Donaldson, Alan, Houghton, Catherine, Rogers, Mark T., Dorkins, Huw, Eason, Jacqueline, Gregory, Helen, McCann, Emma, Murray, Alex, Calender, Alain, Hardouin, Agnes, Berthet, Pascaline, Delnatte, Capucine, Nogues, Catherine, Lasset, Christine, Houdayer, Claude, Leroux, Dominique, Rouleau, Etienne, Prieur, Fabienne, Damiola, Francesca, Sobol, Hagay, Coupier, Isabelle, Venat-Bouvet, Laurence, Castera, Laurent, Gauthier-Villars, Marion, Leone, Melanie, Pujol, Pascal, Mazoyer, Sylvie, Bignon, Yves-Jean, Zlowocka-Perlowska, Elzbieta, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska, Katarzyna, Huzarski, Tomasz, Spurdle, Amanda B., Viel, Alessandra, Peissel, Bernard, Bonanni, Bernardo, Melloni, Giulia, Ottini, Laura, Papi, Laura, Varesco, Liliana, Tibiletti, Maria Grazia, Peterlongo, Paolo, Volorio, Sara, Manoukian, Siranoush, Pensotti, Valeria, Arnold, Norbert, Engel, Christoph, Deissler, Helmut, Gadzicki, Dorothea, Gehrig, Andrea, Kast, Karin, Rhiem, Kerstin, Meindl, Alfons, Niederacher, Dieter, Ditsch, Nina, Plendl, Hansjoerg, Preisler-Adams, Sabine, Engert, Stefanie, Sutter, Christian, Varon-Mateeva, Raymonda, Wappenschmidt, Barbara, Weber, Bernhard H. F., Arver, Brita, Stenmark-Askmalm, Marie, Loman, Niklas, Rosenquist, Richard, Einbeigi, Zakaria, Nathanson, Katherine L., Rebbeck, Timothy R., Blank, Stephanie V., Cohn, David E., Rodriguez, Gustavo C., Small, Laurie, Friedlander, Michael, Bae-Jump, Victoria L., Fink-Retter, Anneliese, Rappaport, Christine, Gschwantler-Kaulich, Daphne, Pfeiler, Georg, Tea, Muy-Kheng, Lindor, Noralane M., Kaufman, Bella, Paluch, Shani Shimon, Laitman, Yael, Skytte, Anne-Bine, Gerdes, Anne-Marie, Pedersen, Inge Sokilde, Moeller, Sanne Traasdahl, Kruse, Torben A., Jensen, Uffe Birk, Vijai, Joseph, Sarrel, Kara, Robson, Mark, Kauff, Noah, Mulligan, Anna Marie, Glendon, Gord, Ozcelik, Hilmi, Ejlertsen, Bent, Nielsen, Finn C., Jonson, Lars, Andersen, Mette K., Ding, Yuan Chun, Steele, Linda, Foretova, Lenka, Teule, Alex, Lazaro, Conxi, Brunet, Joan, Angel Pujana, Miquel, Mai, Phuong L., Loud, Jennifer T., Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Narod, Steven A., Herzog, Josef, Sand, Sharon R., Tognazzo, Silvia, Agata, Simona, Vaszko, Tibor, Weaver, Joellen, Stavropoulou, Alexandra V., Buys, Saundra S., Romero, Atocha, de la Hoya, Miguel, Aittomaki, Kristiina, Muranen, Taru A., Duran, Mercedes, Chung, Wendy K., Lasa, Adriana, Dorfling, Cecilia M., Miron, Alexander, Benitez, Javier, Senter, Leigha, Huo, Dezheng, Chan, Salina B., Sokolenko, Anna P., Chiquette, Jocelyne, Tihomirova, Laima, Friebel, Tara M., Agnarsson, Bjarni A., Lu, Karen H., Lejbkowicz, Flavio, James, Paul A., Hall, Per, Dunning, Alison M., Tessier, Daniel, Cunningham, Julie, Slager, Susan L., Wang, Chen, Hart, Steven, Stevens, Kristen, Simard, Jacques, Pastinen, Tomi, Pankratz, Vernon S., Offit, Kenneth, Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., Couch, Fergus J., Wang, Xianshu, McGuffog, Lesley, Lee, Andrew, Olswold, Curtis, Kuchenbaecker, Karoline B., Soucy, Penny, Fredericksen, Zachary, Barrowdale, Daniel, Dennis, Joe, Gaudet, Mia M., Dicks, Ed, Kosel, Matthew, Healey, Sue, Sinilnikova, Olga M., Lee, Adam, Bacot, Francois, Vincent, Daniel, Hogervorst, Frans B. L., Peock, Susan, Stoppa-Lyonnet, Dominique, Jakubowska, Anna, Radice, Paolo, Schmutzler, Rita Katharina, Domchek, Susan M., Piedmonte, Marion, Singer, Christian F., Friedman, Eitan, Thomassen, Mads, Hansen, Thomas V. O., Neuhausen, Susan L., Szabo, Csilla I., Blanco, Ignacio, Greene, Mark H., Karlan, Beth Y., Garber, Judy, Phelan, Catherine M., Weitzel, Jeffrey N., Montagna, Marco, Olah, Edith, Andrulis, Irene L., Godwin, Andrew K., Yannoukakos, Drakoulis, Goldgar, David E., Caldes, Trinidad, Nevanlinna, Heli, Osorio, Ana, Terry, Mary Beth, Daly, Mary B., van Rensburg, Elizabeth J., Hamann, Ute, Ramus, Susan J., Toland, Amanda Ewart, Caligo, Maria A., Olopade, Olufunmilayo I., Tung, Nadine, Claes, Kathleen, Beattie, Mary S., Southey, Melissa C., Imyanitov, Evgeny N., Tischkowitz, Marc, Janavicius, Ramunas, John, Esther M., Kwong, Ava, Diez, Orland, Balmana, Judith, Barkardottir, Rosa B., Arun, Banu K., Rennert, Gad, Teo, Soo-Hwang, Ganz, Patricia A., Campbell, Ian, van der Hout, Annemarie H., van Deurzen, Carolien H. M., Seynaeve, Caroline, Garcia, Encarna B. Gomez, van Leeuwen, Flora E., Meijers-Heijboer, Hanne E. J., Gille, Johannes J. P., Ausems, Margreet G. E. M., Blok, Marinus J., Ligtenberg, Marjolijn J. L., Rookus, Matti A., Devilee, Peter, Verhoef, Senno, van Os, Theo A. M., Wijnen, Juul T., Frost, Debra, Ellis, Steve, Fineberg, Elena, Platte, Radka, Evans, D. Gareth, Izatt, Louise, Eeles, Rosalind A., Adlard, Julian, Eccles, Diana M., Cook, Jackie, Brewer, Carole, Douglas, Fiona, Hodgson, Shirley, Morrison, Patrick J., Side, Lucy E., Donaldson, Alan, Houghton, Catherine, Rogers, Mark T., Dorkins, Huw, Eason, Jacqueline, Gregory, Helen, McCann, Emma, Murray, Alex, Calender, Alain, Hardouin, Agnes, Berthet, Pascaline, Delnatte, Capucine, Nogues, Catherine, Lasset, Christine, Houdayer, Claude, Leroux, Dominique, Rouleau, Etienne, Prieur, Fabienne, Damiola, Francesca, Sobol, Hagay, Coupier, Isabelle, Venat-Bouvet, Laurence, Castera, Laurent, Gauthier-Villars, Marion, Leone, Melanie, Pujol, Pascal, Mazoyer, Sylvie, Bignon, Yves-Jean, Zlowocka-Perlowska, Elzbieta, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska, Katarzyna, Huzarski, Tomasz, Spurdle, Amanda B., Viel, Alessandra, Peissel, Bernard, Bonanni, Bernardo, Melloni, Giulia, Ottini, Laura, Papi, Laura, Varesco, Liliana, Tibiletti, Maria Grazia, Peterlongo, Paolo, Volorio, Sara, Manoukian, Siranoush, Pensotti, Valeria, Arnold, Norbert, Engel, Christoph, Deissler, Helmut, Gadzicki, Dorothea, Gehrig, Andrea, Kast, Karin, Rhiem, Kerstin, Meindl, Alfons, Niederacher, Dieter, Ditsch, Nina, Plendl, Hansjoerg, Preisler-Adams, Sabine, Engert, Stefanie, Sutter, Christian, Varon-Mateeva, Raymonda, Wappenschmidt, Barbara, Weber, Bernhard H. F., Arver, Brita, Stenmark-Askmalm, Marie, Loman, Niklas, Rosenquist, Richard, Einbeigi, Zakaria, Nathanson, Katherine L., Rebbeck, Timothy R., Blank, Stephanie V., Cohn, David E., Rodriguez, Gustavo C., Small, Laurie, Friedlander, Michael, Bae-Jump, Victoria L., Fink-Retter, Anneliese, Rappaport, Christine, Gschwantler-Kaulich, Daphne, Pfeiler, Georg, Tea, Muy-Kheng, Lindor, Noralane M., Kaufman, Bella, Paluch, Shani Shimon, Laitman, Yael, Skytte, Anne-Bine, Gerdes, Anne-Marie, Pedersen, Inge Sokilde, Moeller, Sanne Traasdahl, Kruse, Torben A., Jensen, Uffe Birk, Vijai, Joseph, Sarrel, Kara, Robson, Mark, Kauff, Noah, Mulligan, Anna Marie, Glendon, Gord, Ozcelik, Hilmi, Ejlertsen, Bent, Nielsen, Finn C., Jonson, Lars, Andersen, Mette K., Ding, Yuan Chun, Steele, Linda, Foretova, Lenka, Teule, Alex, Lazaro, Conxi, Brunet, Joan, Angel Pujana, Miquel, Mai, Phuong L., Loud, Jennifer T., Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Narod, Steven A., Herzog, Josef, Sand, Sharon R., Tognazzo, Silvia, Agata, Simona, Vaszko, Tibor, Weaver, Joellen, Stavropoulou, Alexandra V., Buys, Saundra S., Romero, Atocha, de la Hoya, Miguel, Aittomaki, Kristiina, Muranen, Taru A., Duran, Mercedes, Chung, Wendy K., Lasa, Adriana, Dorfling, Cecilia M., Miron, Alexander, Benitez, Javier, Senter, Leigha, Huo, Dezheng, Chan, Salina B., Sokolenko, Anna P., Chiquette, Jocelyne, Tihomirova, Laima, Friebel, Tara M., Agnarsson, Bjarni A., Lu, Karen H., Lejbkowicz, Flavio, James, Paul A., Hall, Per, Dunning, Alison M., Tessier, Daniel, Cunningham, Julie, Slager, Susan L., Wang, Chen, Hart, Steven, Stevens, Kristen, Simard, Jacques, Pastinen, Tomi, Pankratz, Vernon S., Offit, Kenneth, Easton, Douglas F., Chenevix-Trench, Georgia, and Antoniou, Antonis C.

Abstract

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Published
2013
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99. High modal number and triple trisomies are highly correlated favorable factors in childhood B-cell precursor high hyperdiploid acute lymphoblastic leukemia treated according to the NOPHO ALL 1992/2000 protocols

Author

Paulsson, Kajsa, Forestier, Erik, Andersen, Mette K., Autio, Kirsi, Barbany, Gisela, Borgstrom, Georg, Cavelier, Lucia, Golovleva, Irina, Heim, Sverre, Heinonen, Kristiina, Hovland, Randi, Johannsson, Johann H., Kjeldsen, Eigil, Nordgren, Ann, Palmqvist, Lars, Johansson, Bertil, Paulsson, Kajsa, Forestier, Erik, Andersen, Mette K., Autio, Kirsi, Barbany, Gisela, Borgstrom, Georg, Cavelier, Lucia, Golovleva, Irina, Heim, Sverre, Heinonen, Kristiina, Hovland, Randi, Johannsson, Johann H., Kjeldsen, Eigil, Nordgren, Ann, Palmqvist, Lars, and Johansson, Bertil

Abstract

Between 1992 and 2008, 713 high hyperdiploid acute lymphoblastic leukemias in children aged 1-15 years were diagnosed and treated according to the Nordic Society for Pediatric Hematology and Oncology acute lymphoblastic leukemia 1992/2000 protocols. Twenty (2.8%) harbored t(1;19), t(9; 22), der(11q23), or t(12; 21). The median age of patients with "classic" high hyperdiploidy was lower than that of patients with translocation-positive high hyperdiploidy (P<0.001). Cases with triple trisomies (+4, +10, +17), comprising 50%, had higher modal numbers than the triple trisomy-negative cases (P<0.0001). The probabilities of event-free survival and overall survival were lower for those with white blood cell counts 250x10(9)/L (P=0.017/P=0.009), >5% bone marrow blasts at day 29 (P=0.001/0.002), and for high-risk patients (P<0.001/P=0.003), whereas event-free, but not overall, survival, was higher for cases with gains of chromosomes 4 (P<0.0001), 6 (P<0.003), 17 (P=0.010), 18 (P=0.049), and 22 (P=0.040), triple trisomies (P=0.002), and modal numbers >53/55 (P=0.020/0.024). In multivariate analyses, modal number and triple trisomies were significantly associated with superior event-free survival in separate analyses with age and white blood cell counts. When including both modal numbers and triple trisomies, only low white blood cell counts were significantly associated with superior event-free survival (P=0.009). We conclude that high modal chromosome numbers and triple trisomies are highly correlated prognostic factors and that these two parameters identify the same subgroup of patients characterized by a particularly favorable outcome.

Published
2013
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100. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Author

University of Helsinki, Department of Obstetrics and Gynecology, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Medicum, Couch, Fergus J., Wang, Xianshu, McGuffog, Lesley, Lee, Andrew, Olswold, Curtis, Kuchenbaecker, Karoline B., Soucy, Penny, Fredericksen, Zachary, Barrowdale, Daniel, Dennis, Joe, Gaudet, Mia M., Dicks, Ed, Kosel, Matthew, Healey, Sue, Sinilnikova, Olga M., Lee, Adam, Bacot, Francois, Vincent, Daniel, Hogervorst, Frans B.L., Peock, Susan, Stoppa-Lyonnet, Dominique, Jakubowska, Anna, Radice, Paolo, Schmutzler, Rita Katharina, Domchek, Susan M., Piedmonte, Marion, Singer, Christian F., Friedman, Eitan, Thomassen, Mads, Hansen, Thomas V.O., Neuhausen, Susan L., Szabo, Csilla I., Blanco, Ignacio, Greene, Mark H., Karlan, Beth Y., Garber, Judy, Phelan, Catherine M., Weitzel, Jeffrey N., Montagna, Marco, Olah, Edith, Andrulis, Irene L., Godwin, Andrew K., Yannoukakos, Drakoulis, Goldgar, David E., Caldes, Trinidad, Nevanlinna, Heli, Osorio, Ana, Terry, Mary Beth, Daly, Mary B., Van Rensburg, Elizabeth J., Hamann, Ute, Ramus, Susan J., Toland, Amanda Ewart, Caligo, Maria A., Olopade, Olufunmilayo I., Tung, Nadine, Claes, Kathleen, Beattie, Mary S., Southey, Melissa C., Imyanitov, Evgeny N., Tischkowitz, Marc, Janavicius, Ramunas, John, Esther M., Kwong, Ava, Diez, Orland, Balmana, Judith, Barkardottir, Rosa B., Arun, Banu K., Rennert, Gad, Teo, Soo-Hwang, Ganz, Patricia A., Campbell, Ian, Van der Hout, Annemarie H., Van Deurzen, Carolien H.M., Seynaeve, Caroline, Garcia, Encarna B. Gomez, Van Leeuwen, Flora E., Meijers-Heijboer, Hanne E.J., Gille, Johannes J.P., Ausems, Margreet G.E.M., Blok, Marinus J., Ligtenberg, Marjolijn J.L., Rookus, Matti A., Devilee, Peter, Verhoef, Senno, Van Os, Theo A.M., Wijnen, Juul T., Frost, Debra, Ellis, Steve, Fineberg, Elena, Platte, Radka, Evans, D. Gareth, Izatt, Louise, Eeles, Rosalind A., Adlard, Julian, Eccles, Diana M., Cook, Jackie, Brewer, Carole, Douglas, Fiona, Hodgson, Shirley, Morrison, Patrick J., Side, Lucy E., Donaldson, Alan, Houghton, Catherine, Rogers, Mark T., Dorkins, Huw, Eason, Jacqueline, Gregory, Helen, McCann, Emma, Murray, Alex, Calender, Alain, Hardouin, Agnes, Berthet, Pascaline, Delnatte, Capucine, Nogues, Catherine, Lasset, Christine, Houdayer, Claude, Leroux, Dominique, Rouleau, Etienne, Prieur, Fabienne, Damiola, Francesca, Sobol, Hagay, Coupier, Isabelle, Venat-Bouvet, Laurence, Castera, Laurent, Gauthier-Villars, Marion, Leone, Melanie, Pujol, Pascal, Mazoyer, Sylvie, Bignon, Yves-Jean, Zlowocka-Perlowska, Elzbieta, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska, Katarzyna, Huzarski, Tomasz, Spurdle, Amanda B., Viel, Alessandra, Peissel, Bernard, Bonanni, Bernardo, Melloni, Giulia, Ottini, Laura, Papi, Laura, Varesco, Liliana, Tibiletti, Maria Grazia, Peterlongo, Paolo, Volorio, Sara, Manoukian, Siranoush, Pensotti, Valeria, Arnold, Norbert, Engel, Christoph, Deissler, Helmut, Gadzicki, Dorothea, Gehrig, Andrea, Kast, Karin, Rhiem, Kerstin, Meindl, Alfons, Niederacher, Dieter, Ditsch, Nina, Plendl, Hansjoerg, Preisler-Adams, Sabine, Engert, Stefanie, Sutter, Christian, Varon-Mateeva, Raymonda, Wappenschmidt, Barbara, Weber, Bernhard H.F., Arver, Brita, Stenmark-Askmalm, Marie, Loman, Niklas, Rosenquist, Richard, Einbeigi, Zakaria, Nathanson, Katherine L., Rebbeck, Timothy R., Blank, Stephanie V., Cohn, David E., Rodriguez, Gustavo C., Small, Laurie, Friedlander, Michael, Bae-Jump, Victoria L., Fink-Retter, Anneliese, Rappaport, Christine, Gschwantler-Kaulich, Daphne, Pfeiler, Georg, Tea, Muy-Kheng, Lindor, Noralane M., Kaufman, Bella, Paluch, Shani Shimon, Laitman, Yael, Skytte, Anne-Bine, Gerdes, Anne-Marie, Pedersen, Inge Sokilde, Moeller, Sanne Traasdahl, Kruse, Torben A., Jensen, Uffe Birk, Vijai, Joseph, Sarrel, Kara, Robson, Mark, Kauff, Noah, Mulligan, Anna Marie, Glendon, Gord, Ozcelik, Hilmi, Ejlertsen, Bent, Nielsen, Finn C., Jonson, Lars, Andersen, Mette K., Ding, Yuan Chun, Steele, Linda, Foretova, Lenka, Teule, Alex, Lazaro, Conxi, Brunet, Joan, Angel Pujana, Miquel, Mai, Phuong L., Loud, Jennifer T., Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Narod, Steven A., Herzog, Josef, Sand, Sharon R., Tognazzo, Silvia, Agata, Simona, Vaszko, Tibor, Weaver, Joellen, Stavropoulou, Alexandra V., Buys, Saundra S., Romero, Atocha, De la Hoya, Miguel, Aittomäki, Kristiina, Muranen, Taru A., Duran, Mercedes, Chung, Wendy K., Lasa, Adriana, Dorfling, Cecilia M., Miron, Alexander, Benitez, Javier, Senter, Leigha, Huo, Dezheng, Chan, Salina B., Sokolenko, Anna P., Chiquette, Jocelyne, Tihomirova, Laima, Friebel, Tara M., Agnarsson, Bjarni A., Lu, Karen H., Lejbkowicz, Flavio, James, Paul A., Hall, Per, Dunning, Alison M., Tessier, Daniel, Cunningham, Julie, Slager, Susan L., Wang, Chen, Hart, Steven, Stevens, Kristen, Simard, Jacques, Pastinen, Tomi, Pankratz, Vernon S., Offit, Kenneth, Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., KConFab Investigators, SWE-BRCA, Ontario Canc Genetics Network, HEBON, EMBRACE, GEMO Study Collaborators, BCFR, CIMBA, University of Helsinki, Department of Obstetrics and Gynecology, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Medicum, Couch, Fergus J., Wang, Xianshu, McGuffog, Lesley, Lee, Andrew, Olswold, Curtis, Kuchenbaecker, Karoline B., Soucy, Penny, Fredericksen, Zachary, Barrowdale, Daniel, Dennis, Joe, Gaudet, Mia M., Dicks, Ed, Kosel, Matthew, Healey, Sue, Sinilnikova, Olga M., Lee, Adam, Bacot, Francois, Vincent, Daniel, Hogervorst, Frans B.L., Peock, Susan, Stoppa-Lyonnet, Dominique, Jakubowska, Anna, Radice, Paolo, Schmutzler, Rita Katharina, Domchek, Susan M., Piedmonte, Marion, Singer, Christian F., Friedman, Eitan, Thomassen, Mads, Hansen, Thomas V.O., Neuhausen, Susan L., Szabo, Csilla I., Blanco, Ignacio, Greene, Mark H., Karlan, Beth Y., Garber, Judy, Phelan, Catherine M., Weitzel, Jeffrey N., Montagna, Marco, Olah, Edith, Andrulis, Irene L., Godwin, Andrew K., Yannoukakos, Drakoulis, Goldgar, David E., Caldes, Trinidad, Nevanlinna, Heli, Osorio, Ana, Terry, Mary Beth, Daly, Mary B., Van Rensburg, Elizabeth J., Hamann, Ute, Ramus, Susan J., Toland, Amanda Ewart, Caligo, Maria A., Olopade, Olufunmilayo I., Tung, Nadine, Claes, Kathleen, Beattie, Mary S., Southey, Melissa C., Imyanitov, Evgeny N., Tischkowitz, Marc, Janavicius, Ramunas, John, Esther M., Kwong, Ava, Diez, Orland, Balmana, Judith, Barkardottir, Rosa B., Arun, Banu K., Rennert, Gad, Teo, Soo-Hwang, Ganz, Patricia A., Campbell, Ian, Van der Hout, Annemarie H., Van Deurzen, Carolien H.M., Seynaeve, Caroline, Garcia, Encarna B. Gomez, Van Leeuwen, Flora E., Meijers-Heijboer, Hanne E.J., Gille, Johannes J.P., Ausems, Margreet G.E.M., Blok, Marinus J., Ligtenberg, Marjolijn J.L., Rookus, Matti A., Devilee, Peter, Verhoef, Senno, Van Os, Theo A.M., Wijnen, Juul T., Frost, Debra, Ellis, Steve, Fineberg, Elena, Platte, Radka, Evans, D. Gareth, Izatt, Louise, Eeles, Rosalind A., Adlard, Julian, Eccles, Diana M., Cook, Jackie, Brewer, Carole, Douglas, Fiona, Hodgson, Shirley, Morrison, Patrick J., Side, Lucy E., Donaldson, Alan, Houghton, Catherine, Rogers, Mark T., Dorkins, Huw, Eason, Jacqueline, Gregory, Helen, McCann, Emma, Murray, Alex, Calender, Alain, Hardouin, Agnes, Berthet, Pascaline, Delnatte, Capucine, Nogues, Catherine, Lasset, Christine, Houdayer, Claude, Leroux, Dominique, Rouleau, Etienne, Prieur, Fabienne, Damiola, Francesca, Sobol, Hagay, Coupier, Isabelle, Venat-Bouvet, Laurence, Castera, Laurent, Gauthier-Villars, Marion, Leone, Melanie, Pujol, Pascal, Mazoyer, Sylvie, Bignon, Yves-Jean, Zlowocka-Perlowska, Elzbieta, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska, Katarzyna, Huzarski, Tomasz, Spurdle, Amanda B., Viel, Alessandra, Peissel, Bernard, Bonanni, Bernardo, Melloni, Giulia, Ottini, Laura, Papi, Laura, Varesco, Liliana, Tibiletti, Maria Grazia, Peterlongo, Paolo, Volorio, Sara, Manoukian, Siranoush, Pensotti, Valeria, Arnold, Norbert, Engel, Christoph, Deissler, Helmut, Gadzicki, Dorothea, Gehrig, Andrea, Kast, Karin, Rhiem, Kerstin, Meindl, Alfons, Niederacher, Dieter, Ditsch, Nina, Plendl, Hansjoerg, Preisler-Adams, Sabine, Engert, Stefanie, Sutter, Christian, Varon-Mateeva, Raymonda, Wappenschmidt, Barbara, Weber, Bernhard H.F., Arver, Brita, Stenmark-Askmalm, Marie, Loman, Niklas, Rosenquist, Richard, Einbeigi, Zakaria, Nathanson, Katherine L., Rebbeck, Timothy R., Blank, Stephanie V., Cohn, David E., Rodriguez, Gustavo C., Small, Laurie, Friedlander, Michael, Bae-Jump, Victoria L., Fink-Retter, Anneliese, Rappaport, Christine, Gschwantler-Kaulich, Daphne, Pfeiler, Georg, Tea, Muy-Kheng, Lindor, Noralane M., Kaufman, Bella, Paluch, Shani Shimon, Laitman, Yael, Skytte, Anne-Bine, Gerdes, Anne-Marie, Pedersen, Inge Sokilde, Moeller, Sanne Traasdahl, Kruse, Torben A., Jensen, Uffe Birk, Vijai, Joseph, Sarrel, Kara, Robson, Mark, Kauff, Noah, Mulligan, Anna Marie, Glendon, Gord, Ozcelik, Hilmi, Ejlertsen, Bent, Nielsen, Finn C., Jonson, Lars, Andersen, Mette K., Ding, Yuan Chun, Steele, Linda, Foretova, Lenka, Teule, Alex, Lazaro, Conxi, Brunet, Joan, Angel Pujana, Miquel, Mai, Phuong L., Loud, Jennifer T., Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Narod, Steven A., Herzog, Josef, Sand, Sharon R., Tognazzo, Silvia, Agata, Simona, Vaszko, Tibor, Weaver, Joellen, Stavropoulou, Alexandra V., Buys, Saundra S., Romero, Atocha, De la Hoya, Miguel, Aittomäki, Kristiina, Muranen, Taru A., Duran, Mercedes, Chung, Wendy K., Lasa, Adriana, Dorfling, Cecilia M., Miron, Alexander, Benitez, Javier, Senter, Leigha, Huo, Dezheng, Chan, Salina B., Sokolenko, Anna P., Chiquette, Jocelyne, Tihomirova, Laima, Friebel, Tara M., Agnarsson, Bjarni A., Lu, Karen H., Lejbkowicz, Flavio, James, Paul A., Hall, Per, Dunning, Alison M., Tessier, Daniel, Cunningham, Julie, Slager, Susan L., Wang, Chen, Hart, Steven, Stevens, Kristen, Simard, Jacques, Pastinen, Tomi, Pankratz, Vernon S., Offit, Kenneth, Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., KConFab Investigators, SWE-BRCA, Ontario Canc Genetics Network, HEBON, EMBRACE, GEMO Study Collaborators, BCFR, and CIMBA

Published
2013

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