Originally published as JCO Early Release 10.1200/JCO.2008.20.6136 on August 17 2009

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Prognostic Significance of Copy-Number Alterations in Multiple Myeloma

Hervé Avet-Loiseau, Cheng Li, Florence Magrangeas, Wilfried Gouraud, Catherine Charbonnel, Jean-Luc Harousseau, Michel Attal, Gerald Marit, Claire Mathiot, Thierry Facon, Philippe Moreau, Kenneth C. Anderson, Loïc Campion, Nikhil C. Munshi , Stéphane Minvielle

From the L'Institut National de la Santé et de la Recherche Médicale U892, Université de Nantes, Institut Régional du Cancer Nantes-Atlantique; Centre Hospitalier Universitaire de Nantes, Institut Régional du Cancer Nantes-Atlantique, Laboratoire d'Hématologie; Centre Hospitalier Universitaire de Nantes, Institut Régional du Cancer Nantes-Atlantique, Service d'Hématologie Clinique, Nantes; Centre de Lutte contre le Cancer Nantes-Atlantique, Institut Régional du Cancer Nantes-Atlantique, Nantes-Saint Herblain; Centre Hospitalier Universitaire de Toulouse, Service d'Hématologie Clinique, Toulouse; Centre Hospitalier Universitaire de Bordeaux, Service d'Hématologie Clinique, Bordeaux; Institut Curie, Laboratoire d'Hématologie, Paris; Centre Hospitalier Universitaire de Lille, Service d'Hématologie Clinique, Lille, France; Department of Biostatistics, Harvard School of Public Health; Department of Biostatistics and Computational Biology; Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School; and the Boston Veterans Affairs Healthcare System, Department of Medicine, Harvard Medical School, Boston, MA.

Corresponding author: Stéphane Minvielle, PhD, L'Institut National de la Santé et de la Recherche Médicale U892, Université de Nantes, Institut de Biologie, 9 Quai Moncousu, Nantes, 44093 France; e-mail: sminvielle{at}chu-nantes.fr.

Purpose Chromosomal aberrations are a hallmark of multiple myeloma but their global prognostic impact is largely unknown.

Patients and Methods We performed a genome-wide analysis of malignant plasma cells from 192 newly diagnosed patients with myeloma using high-density, single-nucleotide polymorphism (SNP) arrays to identify genetic lesions associated with prognosis.

Results Our analyses revealed deletions and amplifications in 98% of patients. Amplifications in 1q and deletions in 1p, 12p, 14q, 16q, and 22q were the most frequent lesions associated with adverse prognosis, whereas recurrent amplifications of chromosomes 5, 9, 11, 15, and 19 conferred a favorable prognosis. Multivariate analysis retained three independent lesions: amp(1q23.3), amp(5q31.3), and del(12p13.31). When adjusted to the established prognostic variables (ie, t(4;14), del(17p), and serum β₂-microglobulin [Sβ₂M]), del(12p13.31) remained the most powerful independent adverse marker (P < .0001; hazard ratio [HR], 3.17) followed by Sβ₂M (P < .0001; HR, 2.78) and the favorable marker amp(5q31.3) (P = .0005; HR, 0.37). Patients with amp(5q31.3) alone and low Sβ₂M had an excellent prognosis (5-year overall survival, 87%); conversely, patients with del(12p13.31) alone or amp(5q31.3) and del(12p13.31) and high Sβ₂M had a very poor outcome (5-year overall survival, 20%). This prognostic model was validated in an independent validation cohort of 273 patients with myeloma.

Conclusion These findings demonstrate the power and accessibility of molecular karyotyping to predict outcome in myeloma. In addition, integration of expression of genes residing in the lesions of interest revealed putative features of the disease driving short survival.

H.A.L., L.C., N.C.M., and S.M. equally contributed to this article.

Supported in part by grants from the Ligue contre le Cancer (Equipe Labellisée); Grant No. SPORE P50 CA100707-04 (H.A.L., K.C.A., N.C.M.) from the National Cancer Institute; by the Department of Veterans Affairs merit review award; and Grants No. RO1-129295 (N.C.M.), PO1-78378 (K.C.A., N.C.M.), and RO1-50947 (K.C.A.) from the National Institutes of Health.

Written on behalf of the Intergroupe Francophone du Myélome.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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