Novel Chromatin Modifying Gene Alterations and Significant Survival Association of ATM and P53 in Mantle Cell Lymphoma

• Published in: Blood 2014-12, Vol.124 (21), p.3033-3033
• Main Authors: Wang, Kai, Nahas, Michelle K., Yelensky, Roman, Otto, Geoff A., Lipson, Doron, He, Jie, Ross, Jeff, Stephens, Phil J, Chow, Kar Fai, Zielonka, Tania, Bhattacharyya, Pritish K, Protomastro, Ewelina A, Feldman, Tatyana, Mato, Anthony R., Skarbnik, Alan P, Bejot, Coleen, Gadaleta, Gabriella, Pecora, Andrew L, Miller, Vincent A., Goy, Andre
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V124.21.3033.3033

Background: The survival of mantle cell lymphoma (MCL) has improved (median OS now >5 years) due to the use of dose-intensive strategies in younger patients (pts) achieving a deeper and earlier response (including molecular CR) and the application of novel therapies in the relapsed/refractory setting, where patients are typically chemoresistant. However, given the median age at onset in the mid to late 60’s, and the remaining variability in outcomes, additional strategies are needed. A number of prognostic factors have been reported in MCL including MIPI, Ki67 and blastoid variants among others, the latter being frequently associated with del 17p or p53 mutations and a particularly poor outcome. Recent studies have begun to describe the genomic landscape of MCL by whole-genome, whole-exome and targeted sequencing. However, comprehensive evaluation of genomic alterations relevant for MCL pathogenesis and that could be potentially informative for patient’s prognosis and patient’s stratification remains to be elucidated. Methods: We studied 33 FFPE or cryopreserved blood MCL specimens by performing integrated DNA and RNA sequencing (N=18) or DNA sequencing alone (N=15). All samples were obtained at diagnosis before patients received Rituximab-HyperCVAD as frontline therapy. In this MCL cohort, treated at our institution, the median age was 59 y (range 35-75), all were stage IV, median Ki-67 was 30 % (range 5-80%), MIPI was low risk (27%), intermediate risk (30%), high risk (42%), and there were 4 blastoid variants (2 with del 17p by FISH or cytogenetics). Genomic DNA and total RNA were extracted and captured using custom bait-sets targeting all exons of 405 cancer-related genes by DNA-Seq, and 265 frequently rearranged genes by RNA-Seq (FoundationOne Heme). Captured libraries were sequenced to high depth in a CLIA-certified, CAP-accredited, NYS-approved clinical laboratory, with an average depth of 400X for DNA and >8M unique pairs for RNA. Results: In total, we identified 125 genomic alterations with an average of 3.8 per sample, including 45 base substitutions/indels, 33 truncations, 1 gene amplification, 6 gene deletions, and 40 rearrangements (Figure 1). IGH/CCND1 t(11,14) translocation was detected in 32/33 samples, and CCND1 over-expression was found in all translocation positive cases by RNA-seq, when available. Consistent with published reports, ATM and TP53 were among the most frequently altered genes, found in 45% and 18% of the samples, respectivel