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Prepublished online as a Blood First Edition Paper on February 6, 2003; DOI 10.1182/blood-2002-10-3017.
Submitted October 29, 2002
Accepted January 23, 2003
CLINICAL AND BIOLOGIC IMPLICATIONS OF RECURRENT GENOMIC ABERRATIONS IN MYELOMA
Rafael Fonseca*, Emily Blood, Montserrat Rue, David Harrington, Martin M Oken, Robert A Kyle, Gordon W Dewald, Brian Van Ness, Scott A Van Wier, Kimberly J Henderson, Richard J Bailey, and Philip R Greipp
Division of Hematology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
Eastern Cooperative Oncology Group Statistical Center, Dana Farber Cancer Institute, Boston, MA, USA
Virginia Piper Cancer Institute, Minneapolis, MN, USA
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA
* Corresponding author; email: fonseca.rafael{at}mayo.edu.
Non-random recurrent chromosomal abnormalities are ubiquitous in multiple myeloma (MM) and include among others translocations of the immunoglobulin (Ig) heavy chain locus (IgH). IgH translocations in MM result in the upregulation of oncogenes, and include more commonly t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16)(q32;q23). Based on the recurrent nature of these translocations and their finding since the early stages of the plasma cell (PC) disorders we hypothesized that they would confer biologic and clinical variability. In addition, deletions of 13q14 and 17p13 have also been associated with a shortened survival. We used cytoplasmic-Ig enhanced interphase fluorescent in-situ hybridization to detect deletions (13q14 and 17p13.1), and translocations involving IgH in 351 patients treated with conventional chemotherapy entered into the Eastern Cooperative Oncology Group clinical trial E9486/9487. Translocations were frequently unbalanced with loss of one of the derivative chromosomes. The presence of t(4;14)(p16;q32) (n=42; 26 versus 45 months, P<0.001), t(14;16)(q32;q23) (n=15; 16 versus 41 months, P=0.003), -17p13 (n=37; 23 versus 44 months, P=0.005), and -13q14 (n=176; 35 versus 51 months, P=0.028) were associated with shorter survival. A stratification of patients into three distinct categories allowed for prognostication; poor prognosis group (t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13), intermediate prognosis (-13q14), and good prognosis group (all others), with median survivals of 24.7, 42.3, and 50.5 months respectively (P<0.001). This molecular cytogenetic classification identifies patients into poor, intermediate and good risk categories. More importantly it provides further compelling evidence that MM is composed of subgroups of patients categorized according to their underlying genomic aberrations.
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