Abstract 3099: Longitudinal genomic and transcriptomic analysis of mantle cell lymphoma in a targeted combination trial of a selective CDK4/6 inhibitor
Authors: Vijay Priyanka , Blecua Pedro , Di Liberto Maurizio , Chiron David , Huang Xiangao , Elemento Olivier , Martin Peter , Leonard John P. , Mason Christopher E. , Chen-Kiang Selina 
Published: August 2015

We used whole exome (WES) and whole transcriptome sequencing (WTS) to study progression of Mantle Cell Lymphoma (MCL) in the context of a clinical trial of targeted combination therapy of a CDK4 inhibitor PD0332991 (palbociclib) and a proteasome inhibitor bortezomib. Our longitudinal study design coupled with an integrative analysis approach enabled detailed molecular characterization of each subject's disease. This includes multiple time points for three therapy Responders (Rs) and two Non-Responders (NRs); a primary goal was to understand genetic reasons for differential response. To that end, we identified copy number variants (CNVs) and single nucleotide variants (SNVs) specific to NRs that are supported by both WES and WTS data and implicate pathways relevant to mechanisms of drug action.

CNVs were identified using multiple orthogonal methods that use read depth and genome-wide allele frequencies. These revealed a 29Mb chr9 hemizygous deletion unique to NRs. This region includes 15 interferon genes of the type 1 interferon signaling pathway (enrichment: p&lt;10-9), which is involved in B cell differentiation and proliferation, and T cell and natural killer cell activation. Interferon signaling is implicated in bortezomib function and loss of interferon genes may contribute to resistance in non-responders. Additional key genes in deleted regions are JAK2, RPS6, and CDKN2A, a CDK2 inhibitor, loss of which may antagonize palbociclib-induced G1 arrest NRs also shared a 24Mb chr3 duplication resulting in gain of PIK3CA and PIK3CB. Amplification of these genes is common in cancers, including MCL (classical analysis) and DLBCL, and often associated with poor prognosis. But, this is the only longitudinal study of PI3K CNV in a targeted therapy. In context of PD+bortezomib treatment, higher levels of PI3K may affect sensitivity to proteasome inhibition activated autophagy since bortezomib's inhibitory activity involves suppression of the PI3K/AKT/mTOR pathway. PIK3CA is amplified in a responder as well, suggesting additional determinants for clinical response.

Other CNVs differentiating Rs and NRs are a 24Mb chr8 deletion found only in Rs and a 4Mb chr17 deletion found only in NRs, which includes p53 in a subject who also has a p53 mutation, resulting in 100% expression of the mutant allele. The described CNVs result in detectable shifts in expression of a large proportion of affected genes. Coupled with SNV data, where we identified 21 SNVs shared by NRs and absent in Rs, these results offer molecular clues to mechanisms of resistance in NRs, which we are currently pursuing with functional studies.

Overall, we performed a thorough genomic and transcriptomic analysis of a longitudinal investigation of MCL patients during a targeted combination therapy phase I clinical trial and identified potential biomarkers of response spanning CNVs, SNVs, and differentially expressed genes.

Citation Format: Priyanka Vijay, Pedro Blecua, Maurizio Di Liberto, David Chiron, Xiangao Huang, Olivier Elemento, Peter Martin, John P. Leonard, Christopher E. Mason, Selina Chen-Kiang. Longitudinal genomic and transcriptomic analysis of mantle cell lymphoma in a targeted combination trial of a selective CDK4/6 inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3099. doi:10.1158/1538-7445.AM2015-3099