Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype - 03/08/11
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, Lilia Ben Slama, PhD a, Felipe Suarez, MD, PhD a, d, Loïc Le Mignot, MSc a, e, Julien Beauté, MD, MSc a, b, Nizar Mahlaoui, MD, MSc a, b, Catherine Dubois d’Enghien, BSc f, Anthony Laugé, BSc f, Janet Hall, PhD g, Jérôme Couturier, MD f, h, Louis Vallée, MD i, Bruno Delobel, MD i, François Rivier, MD, PhD j, Karine Nguyen, MD k, Thierry Billette de Villemeur, MD l, Jean-Louis Stephan, MD a, m, Pierre Bordigoni, MD a, n, Yves Bertrand, MD a, o, Nathalie Aladjidi, MD a, p, Jean-Michel Pedespan, MD q, Caroline Thomas, MD a, r, Isabelle Pellier, MD, MSc a, s, Michel Koenig, MD, PhD t, Olivier Hermine, MD, PhD a, d, Capucine Picard, MD, PhD a, b, w, Despina Moshous, MD, PhD b, Bénédicte Neven, MD, PhD b, Fanny Lanternier, MD u, Stéphane Blanche, MD a, b, Marc Tardieu, MD, PhD v, Marianne Debré, MD a, b, Alain Fischer, MD, PhD a, b, c, w, Dominique Stoppa-Lyonnet, MD, PhD c, f, gCEREDIH Network
Reprint requests: Romain Micol, MD, MPH, PhD, CEREDIH, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 149 rue de Sèvres, 75743, Paris Cedex 15, France.Abstract |
Background |
Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers.
Objective |
We studied A-T progression and investigated whether manifestations were associated with the ATM genotype.
Methods |
We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers.
Results |
Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality. Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations.
Conclusion |
Morbidity and mortality among patients with A-T are associated with ATM genotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies.
Le texte complet de cet article est disponible en PDF.Key words : Cancer, genetics, leukemia, lymphoma, inherited, DNA repair
Abbreviations used : A-T, ATM, CEREDIH, IQR, RTI, IR
Plan
| Supported by Sophie and Yves Ayache, CEREDIH (French National Reference Center for Primary Immunodeficiencies), and INCa (National Cancer Institute of France). |
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| Disclosure of potential conflict of interest: A. Fischer receives research support from CEREDIH. The rest of the authors have declared that they have no conflict of interest. |
Vol 128 - N° 2
P. 382 - août 2011 Retour au numéro
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