Ghesquieres Hervé, Slager Susan L, Jardin Fabrice, Veron Amelie S, Asmann Yan W, Maurer Matthew J, Fest Thierry, Habermann Thomas M, Bene Marie C, Novak Anne J, Mareschal Sylvain, Haioun Corinne, Lamy Thierry, Ansell Stephen M, Tilly Herve, Witzig Thomas E, Weiner George J, Feldman Andrew L, Dogan Ahmet, Cunningham Julie M, Olswold Curtis L, Molina Thierry Jo, Link Brian K, Milpied Noel, Cox David G, Salles Gilles A, Cerhan James R
Hervé Ghesquieres, Universite Claude Bernard Lyon 1, Centre Leon Berard; Amelie S. Veron and David G. Cox, L'Institut National de la Santé et de la Recherche Médicale (INSERM) U1052, Cancer Research Center of Lyon, Centre Leon Berard, Lyon; Hervé Ghesquieres and Gilles A. Salles, Faculté de Médecine Lyon-Sud; Gilles A. Salles, Universite Claude Bernard Lyon 1, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite; Fabrice Jardin, Sylvain Mareschal, and Herve Tilly, INSERM U918, Centre Henri Becquerel, Rouen; Thierry Fest, INSERM U917, Université de Rennes 1, Hopital Pontchaillou; Thierry Lamy, Université de Rennes 1, Hopital Pontchaillou, Rennes; Marie C. Bene, Centre Hospitalier Universitaire Nantes, Nantes; Corinne Haioun, Hospital Henri Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP) and University Paris Est, Créteil; Thierry Jo Molina, Universite Paris Descartes, AP-HP, Hôpital Necker, Paris; Noel Milpied, University Hospital and University of Bordeaux, Bordeaux, France; Hervé Ghesquieres, Susan L. Slager, Matthew J. Maurer, Thomas M. Habermann, Anne J. Novak, Stephen M. Ansell, Thomas E. Witzig, Andrew L. Feldman, Ahmet Dogan, Julie M. Cunningham, Curtis L. Olswold, and James R. Cerhan, Mayo Clinic, Rochester, MN; Yan W. Asmann, Mayo Clinic, Jacksonville, FL; and George J. Weiner and Brian K. Link, University of Iowa, Iowa City, IA.
J Clin Oncol. 2015 Nov 20;33(33):3930-7. doi: 10.1200/JCO.2014.60.2573. Epub 2015 Oct 12.
We performed a multistage genome-wide association study to identify inherited genetic variants that predict outcome in diffuse large B-cell lymphoma patients treated with immunochemotherapy.
We conducted a meta-analysis of two genome-wide association study data sets, one from the LNH2003B trial (N = 540), a prospective clinical trial from the Lymphoma Study Association, and the other from the Molecular Epidemiology Resource study (N = 312), a prospective observational study from the University of Iowa-Mayo Clinic Lymphoma Specialized Program of Research Excellence. Top single nucleotide polymorphisms were then genotyped in independent cohorts of patients from the Specialized Program of Research Excellence (N = 391) and the Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang (GOELAMS) -075 randomized trial (N = 294). We calculated the hazard ratios (HRs) and 95% CIs for event-free survival (EFS) and overall survival (OS) using a log-additive genetic model with adjustment for age, sex, and age-adjusted International Prognostic Index.
In a meta-analysis of the four studies, the top loci for EFS were marked by rs7712513 at 5q23.2 (near SNX2 and SNCAIP; HR, 1.39; 95% CI, 1.23 to 1.57; P = 2.08 × 10(-7)), and rs7765004 at 6q21 (near MARCKS and HDAC2; HR, 1.38; 95% CI, 1.22 to 1.57; P = 7.09 × 10(-7)), although they did not reach conventional genome-wide significance (P = 5 × 10(-8)). Both rs7712513 (HR, 1.49; 95% CI, 1.29 to 1.72; P = 3.53 × 10(-8)) and rs7765004 (HR, 1.47; 95% CI, 1.27 to 1.71; P = 5.36 × 10(-7)) were also associated with OS. In exploratory analyses, a two-single nucleotide polymorphism risk score was highly predictive of EFS (P = 1.78 × 10(-12)) and was independent of treatment, IPI, and cell-of-origin classification.
Our study provides encouraging evidence for associations between loci at 5q23.2 and 6q21 with EFS and OS in patients with diffuse large B-cell lymphoma treated with immunochemotherapy, suggesting novel biology and the potential contribution of host genetics to the prognosis of this aggressive malignancy.
我们进行了一项多阶段全基因组关联研究，以确定可预测接受免疫化疗的弥漫性大B细胞淋巴瘤患者预后的遗传变异。
我们对两个全基因组关联研究数据集进行了荟萃分析，一个来自淋巴瘤研究协会的前瞻性临床试验LNH2003B试验（N = 540），另一个来自爱荷华大学 - 梅奥诊所淋巴瘤卓越研究专项计划的前瞻性观察性研究分子流行病学资源研究（N = 312）。然后，在来自卓越研究专项计划（N = 391）的独立患者队列和西部 - 东部急性白血病和血液病组（GOELAMS）-075随机试验（N = 294）中对顶级单核苷酸多态性进行基因分型。我们使用对数加性遗传模型计算无事件生存期（EFS）和总生存期（OS）的风险比（HRs）和95%置信区间（CIs），并对年龄、性别和年龄调整后的国际预后指数进行调整。
在四项研究的荟萃分析中，EFS的顶级位点由5q23.2处的rs7712513（靠近SNX2和SNCAIP；HR，1.39；95% CI，1.23至1.57；P = 2.08×10⁻⁷）和6q21处的rs7765004（靠近MARCKS和HDAC2；HR，1.38；95% CI）标记，1.22至1.57；P = 7.09×10⁻⁷），尽管它们未达到传统的全基因组显著性水平（P = 5×10⁻⁸）。rs7712513（HR，1.49；95% CI，1.29至1.72；P = 3.53×10⁻⁸）和rs7765004（HR，1.47；95% CI，1.27至1.71；P = 5.36×10⁻⁷）也与OS相关。在探索性分析中，一个双单核苷酸多态性风险评分对EFS具有高度预测性（P = 1.78×10⁻¹²），并且独立于治疗、IPI和起源细胞分类。
我们的研究为5q23.2和6q21位点与接受免疫化疗的弥漫性大B细胞淋巴瘤患者的EFS和OS之间的关联提供了令人鼓舞的证据，提示了新的生物学机制以及宿主遗传学对这种侵袭性恶性肿瘤预后的潜在贡献。
