Incidence, Presentation, and Prognosis of Malignancies in Ataxia-Telangiectasia: A Report From the French National Registry of Primary Immune Deficiencies Felipe Suarez, Nizar Mahlaoui, Danielle Canioni, Chantal Andriamanga, Catherine Dubois d’Enghien, Nicole Brousse, Jean-Philippe Jais, Alain Fischer, Olivier Hermine, and Dominique Stoppa-Lyonnet Felipe Suarez, Nizar Mahlaoui, Danielle Canioni, Nicole Brousse, Jean-Philippe Jais, Alain Fischer, and Olivier Hermine, Hôpital Universitaire Necker–Enfants Malades, Assistance Publique–Hôpitaux de Paris; Felipe Suarez, Nizar Mahlaoui, Chantal Andriamanga, Alain Fischer, and Olivier Hermine, French National Reference Center for Primary Immune Deficiency; Felipe Suarez, Nizar Mahlaoui, Jean- Philippe Jais, Alain Fischer, and Olivier Hermine, Imagine Institute, Institut National de la Recherche Scientifique Unité Mixte de Recherche 1163, Sorbonne Paris Cité, Université Paris Descartes; Felipe Suarez and Olivier Hermine, Centre National de la Recherche Scientifique Equipe de Recher- che Labellisée 8254; Danielle Canioni, Nicole Brousse, and Dominique Stoppa- Lyonnet, Université Paris Descartes; Cathe- rine Dubois d’Enghien and Dominique Stoppa-Lyonnet, Institut Curie; and Alain Fischer, Collège de France, Paris, France. Published online ahead of print at www.jco.org on December 8, 2014. Support information appears at the end of this article. F.S. and N.M. contributed equally to this article. Terms in blue are defined in the glos- sary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Corresponding author: Felipe Suarez, MD, PhD, Department of Hematology, Hôpital Universitaire Necker–Enfants Malades, AP-HP, Paris, France, 149 rue de Sèvres, 75743, Paris Cedex 15, France; e-mail: felipe.suarez@nck.aphp.fr. © 2014 by American Society of Clinical Oncology 0732-183X/15/3302w-202w/$20.00 DOI: 10.1200/JCO.2014.56.5101 A B S T R A C T Purpose Biallelic mutations in ATM cause ataxia-telangiectasia (AT), a rare inherited disease with a high incidence of cancer. Precise estimates of the risk, presentation, and outcomes of cancer in patients with AT need to be addressed in large series. Patients and Methods In this large retrospective cohort, 69 patients with cancers (24.5%) were identified among 279 patients with AT. Centralized review was performed on 60% of the lymphomas. Incidence rates were compared with the French population, and risk factors were analyzed. Results Eight patients developed acute leukemias (including four T-cell acute lymphoblastic leukemias), 12 developed Hodgkin lymphoma (HL), 38 developed non-Hodgkin lymphoma (NHL), three developed T-cell prolymphocytic leukemia (T-PLL), and eight developed carcinoma at a median age of 8.3, 10.6, 9.7, 24.2, and 31.4 years, respectively (P  .001). The majority of NHLs were aggressive B-cell NHL. Epstein-Barr virus was associated with all of the HLs and 50% of the NHLs. Overall survival was shorter in patients with AT who developed cancer compared with those who did not develop cancer (15 v 24 years, respectively; P  .001). Survival was improved in patients who achieved a major response to treatment (3.46 v 0.87 years for major v minor responses, respectively; P = .011). Immunodeficiency was associated with increased risk of cancer. ATM mutation type was associated with a difference in survival in the entire cohort but not with cancer incidence or cancer survival. Conclusion B-cell NHL, HL, and acute lymphoblastic leukemia occur at a high rate and earlier age than carcinomas in AT. T-PLLs are rarer than initially reported. Prognosis is poor, but patients may benefit from treatment with an improved survival. J Clin Oncol 33:202-208. © 2014 by American Society of Clinical Oncology INTRODUCTION Ataxia-telangiectasia (AT), first described more than 70 years ago, 1,2 is a rare autosomal recessive inherited disorder associated with progressive cere- bellar ataxia, oculocutaneous telangiectasia, variable degrees of immune deficiency, and cancer suscepti- bility. 3 AT is caused by biallelic mutations in the ATM gene (Online Mendelian Inheritance in Man No. 607585), located on chromosome 11q22.3-23.1 and coding for a 350-kDa serine-threonine kinase belonging to the phosphoinositidyl 3-kinase–related protein kinase family. 4 ATM is involved in many cellular functions, including cell cycle checkpoint control, apoptosis, DNA damage response (DDR), 5 and more recently, oxidative stress and mitochon- drial metabolism. 6,7 AT is associated with a high incidence of cancer, ranging from 10% to 20%. 8,9 AT patients present with nonmalignant T-cell clones displaying recurrent chromosomal rear- rangements mainly involving chromosomes 7 and 14 10-12 that may evolve to aggressive T-cell prolym- phocytic leukemia (T-PLL). 13 Furthermore, adult T-PLL often shows inactivation of the ATM gene, 14,15 and acquired somatic mutations of ATM are found in several human lymphoproliferative dis- orders including chronic lymphocytic leukemia and mantle-cell lymphomas. These mutations may con- tribute to the genetic instability observed in these tumors. 16,17 In patients with AT, earlier studies pointed to a high incidence of lymphoid malignancies, most notably T-cell acute lymphoblastic leukemias JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 33  NUMBER 2  JANUARY 10 2015 202 © 2014 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on February 13, 2016. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.