Cyclin D1 Polymorphisms as Predictive and Prognostic Molecular Markers in 90 Mantle Cell Lymphoma Patients Treated with R-HyperCVAD.
Authors: Thompson Michael A. , Kadia Tapan M. , Bekele B. Nebiyou , Wang Michael , Romaguera Jorge E. 
Published: April 2020

Abstract
Background Mantle cell lymphoma (MCL) is an aggressive lymphoma with poor prognosis. Prognostic and predictive molecular markers may aid in identification of patients that may benefit from clinical trials of novel therapies. Cyclin D1 is a highly specific marker of MCL. Alternative splicing in the cyclin D1 gene (CCND1) is modulated by a frequent A/G polymorphism located within the splice donor region of exon 4. CCND1 genotype is associated with the age of onset of HNPCC and with shortened event free survival and greater risk of local relapse in resectable non-small cell lung cancer.
Methods Samples were collected from 90 MCL patients treated with R-HyperCVAD from 1999 to 2002. The DNA was produced from peripheral blood lymphocytes and bone marrow using the Genomic extraction Kit (Promega, Madison, WI). The CCND1 exon 4 (codon 242) polymorphism was evaluated using pyrosequencing in the M. D. Anderson Cancer Center core facility as previously described (Kong et al. Cancer Res60:249–52, 2000). Genotype groups were correlated with clinical characteristics under an IRB approved protocol.
Results The CCND1 genotype frequency for 90 MCL patients was G/G 20%, G/A 54%, A/A 26%. Clinical characteristics were not statistically significantly different between genotype groups. 89 patients were evaluable for response. The ORR at 6 cycles was 100% for all subjects. The CR+CRu rates were G/G 95%, G/A 85%, A/A 96% (p=0.048). The PR rate was higher for patients with genotype G/A (15%) compared to G/G (6%) and A/A (4%). There were no statistically significant differences with respect to failure free survival (FFS) between groups (p=0.361), although there was a trend for a higher FFS in the A/A genotype group. In addition, overall survival (OS) was higher for A/A genotype patients at 61 vs. 49 months for the other genotypes (p=0.01).
Discussion In a previous study of 42 MCL patients the CCND1 genotype frequency was: G/G 31%, G/A 55%, and A/A 14% (Howe and Lynas. Haematologica86:563–9, 2001). They showed that CCND1 polymorphisms did not affect prognosis. However, the chemotherapy regimens were not defined in that study. In our study, a larger number of patients were treated homogeneously with the chemotherapy regimen of R-HyperCVAD. Response rates were high and differed slightly by CCND1 polymorphism. The OS was increased for the A/A genotype with a trend for higher FFS. The discrepancy with prior studies may be related to subject genotype frequencies, treatment regimen, and other factors. The CCND1 polymorphisms may have a different predictive yield with other treatment regimens - eg, bortezomib or mTOR inhibitors. Conclusions Response rates were high in all CCND1 genotype groups, but CR rates were lower in the G/A genotype patients. The OS was increased for the A/A genotype with a trend for higher FFS. Future studies should evaluate the role of CCND1 polymorphisms with other active agents against MCL.