Abstract
B-cell non-Hodgkin’s lymphoma (B-NHL) is a constellation of mature B-cell neoplasms characterized by distinct pathological and molecular genetic features, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), MATL-type lymphoma (MALT-L). These B-NHLs undergo a wide variety of genetic alterations, including gains and losses of genetic materials, as well as abnormalities in allelic composition, and these alterations may collectively comprise unique genomic profiles specific to different subtypes of B-NHL, which are tightly linked to the pathogenesis of each B-NHL subtype. Recently, we have developed a robust method (CNAG/AsCNAR) to detect allelic imbalances and other copy number changes in cancer genomes using SNP-genotyping microarrays (Nannya et al. Cancer Res, 2005 and Yamamoto et al. Am J Hum Genet, 2007). Without depending on the availability of constitutive genomic DNA, it enables sensitive detection of allelic imbalances including loss of heterozygosity (LOH) as well as copy number (CN) alterations in the face of 70–80% of normal cell components. In the current study, we performed SNP-chip/CNAG/AsCNAR analysis of 171 B-NHL specimens, including 65 cases of DLBCL, 61 cases of FL, and 45 cases of MALT-L in order to comparatively investigate the unique genomic profiles of different B-NHL subtypes. A large number of gains and losses of chromosomal/genomic segments as well as allelic imbalances were identified. While individual genomic profiles are substantially variable among different cases, they collectively showed a characteristic genomic profile in each B-NHL subtypes; +1q, +2p and +18 are common to DLBCL and FL, while +3 and +11q were more frequently found in DLBCL and +11p was more characteristic to FL. MALT-L also showed +3 and +18, but rarely had +1q and +2p. CN neutral LOH due to mitotic recombination (uniparental disomy; UPD) events are frequently found in DLBCL (70%) and FL (54%), but less common in MALT-L. UPD most commonly involves 1p, 1q, 6p, 9p and 12q. In total, 29 loci of high-grade amplification were identified. Among these recurring amplifications were observed at 1q and 2p, which involves FCGR2B, and cRel genes, respectively. These amplifications were detected in both DLBCL and FL, but rare in MALT-L. Total 14 loci of homozygous deletion were also detected and differentially distributed among different B-NHL subtypes. In conclusion, SNP-chip with CNAG/AsCNAR analysis revealed characteristic genomic signatures of distinctive B-NHL subtypes, implicating their unique pathogenesis.
Clock-Cancer Connection in Non–Hodgkin's Lymphoma: A Genetic Association Study and Pathway Analysis of the Circadian Gene Cryptochrome 2