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Genomic aberrations in mantle cell lymphoma detected by interphase fluorescence in situ hybridization. Incidence and clinicopathological correlations

¹ Department of Internal Medicine III, University of Ulm
² Department of Physiological Chemistry, University of Ulm
³ Department of Biostatistics, DKFZ, Heidelberg
⁴ Department of Pathology, University of Würzburg
⁵ Department of Pathology, University of Ulm
⁶ Department of Molecular Genetics, DKFZ, Heidelberg, Germany

Correspondence: Stephan Stilgenbauer, M.D., Department of Internal Medicine III, University of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany. E-mail: stephan.stilgenbauer{at}uniklinik-ulm.de

ABSTRACT

Background: The genetic hallmark of mantle cell lymphoma is a t(11;14)(q13;q32). However, additional genomic alterations are likely involved in the pathogenesis of this lymphoma.

Design and Methods: To determine the incidence and clinical relevance of these aberrations, we analyzed 103 wellcharacterized samples of mantle cell lymphoma by fluorescence in situ hybridization for the most common recurrent additional genomic findings.

Results: Screening 16 different regions we detected additional genomic aberrations in 92% of the cases of mantle cell lymphoma. Common gains included 3q26, 8q24, 15q23, 7p15, and common losses 13q14, 11q22–q23, 9p21, 1p22, 17p13, 6q27, and 8p22. Deletions 8p22, 9p21, 13q14, and gain of 7p15 were associated with evidence of clonal heterogeneity. While there was no correlation of additional genomic aberrations and VH-mutation status, gain of 15q23 and deletion 6q27 were associated with lower disease stage (p=0.01 and p=0.04, respectively). Patients with deletion 13q14 had shorter overall survival times (p=0.01), and there was a strong trend towards inferior outcome in patients with deletion 9p21 (p=0.07). In multivariable analysis, loss of 13q14 and an International Prognosis Index score 3 turned out to be significantly associated with inferior clinical outcome (p=0.002 and p<0.001, respectively).

Conclusions: The comprehensive analysis of additional genomic aberrations in mantle cell lymphoma provided further evidence for the prognostic relevance of loss of 13q14, which warrants evaluation within prospective trials. Furthermore, our analysis gave novel insights into the pathogenesis of mantle cell lymphoma with regard to the detection of clonal heterogeneity, possibly indicating clonal evolution in this type of lymphoma.

Key words: mantle cell lymphoma, fluorescence in situ hybridization, genomic aberrations.

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