Clock-Cancer Connection in Non-Hodgkin's Lymphoma: A Genetic Association Study and Pathway Analysis of the Circadian Gene Cryptochrome 2

Circadian genes have the potential to influence a variety of cancer-related biological pathways, including immunoregulation, which may influence susceptibility to non-Hodgkin's lymphoma (NHL). However, few studies have examined the role of circadian genes in lymphomagenesis. The current study examined Cryptochrome 2 (CRY2), a core circadian gene and transcriptional repressor, as a potential circadian biomarker for NHL. We first performed genetic association analyses of tagging single nucleotide polymorphisms (SNP) in CRY2 and NHL risk using DNA samples from a population-based case-control study (n = 455 cases and 527 controls). Three SNPs were found to be significantly associated with risk of NHL when combining all subtypes [dbSNP IDs, odds ratios (ORs), and 95% confidence intervals: rs11038689, OR, 2.34 (1.28-4.27), P = 0.006; rs7123390, OR, 2.40 (1.39-4.13), P = 0.002; and rs1401417, OR, 2.97 (1.57-5.63, P = 0.001)]. Each of these associatiions remained significant when restricting the analysis to B-cell cases and when further restricting to follicular lymphomas. An analysis of CRY2 diplotypes confirmed these significant findings. To further determine the functional effect of CRY2, we silenced the gene in vitro and performed a. whole genome expression microarray. A pathway-based analysis showed that genes significantly altered by CRY2 knockdown formed networks associated with immune response: and hematologic system development. In addition, these genes were predicted to have significant effects on several disease processes, including cancer (B-H P = 3.75E(-9)) and hematologic disease (B-H P = 8.01E(-8)). In conclusion, both genetic association and functional analyses suggest that the circadian gene CRY2 may play an important role in NHL development. [Cancer Res 2009;69(8):3605-13]