High Resolution Screening of Genomic Aberrations in Follicular Lymphoma Using Microarray Based Comparative Genomic Hybridization (MATRIX-CGH).

Follicular Lymphoma (FL), one of the most frequent lymphoma entities in the western world, is characterized by a highly variable clinical course reaching from rapid progression with fatal outcome to cases with long term survival. In a recent study applying chromosomal comparative hybridization (CGH) to FL, in 70% of the cases genomic aberrations were detectable and a loss of genomic material on chromosomal bands 6q25-q27 was the strongest predictor for short overall survival. However, limitations of CGH as a screening method are a restricted genomic resolution to 3–10 Mbp and demanding non-automated evaluation procedures. Thus, high throughput analysis of genomic alterations for risk adapted patient stratification and monitoring within treatment trials should rely on efficient and automated diagnostic techniques. In this study, we used array CGH to a novel generation of DNA Chips containing 2800 genomic DNA probes. Target clones comprised i) contigs mapping to genomic regions of possible pathogenetic relevance in lymphoma (n=610 target clones mapping to e.g. 1p, 2p, 3q, 7q, 9p, 11q, 12q, 13q, 17p, 18q, X); ii) selected oncogenes and tumor suppressor genes (n=686) potentially relevant in hematologic neoplasms; and iii) a large genome-wide cluster of 1502 target DNA clones covering the genome at a distance of app. 2 Mbp (part of the golden path clone set). This chip represents a median genomic resolution of app. 1.5 Mbp.

In total, DNAs from 70 FL samples were analyzed and results were compared to data from chromosomal CGH experiments and clinical data sets. The sensitivity of array CGH was considerably higher compared to chromosomal CGH (aberrations in 95% of cases vs 70% of cases). Most frequent aberrations were gain mapping to chromosome arms 2p (21%), 7p (24%), 7q (30%), 12p (17%), 12q (21%), 18p (21%) and 18q (34%) as well as losses mapping to chromosome arms 1p (19%), 6q (23%), 7p (20%), 11q (26%) and 17p (20%). In addition, several genomic aberrations were identified which have not been described before in FL. Currently, these aberrations are characterized in more detail and results will be correlated with the clinical data set. Moreover, three recurrent sites of genomic polymorphisms in human beings affecting chromosomes 5q, 14q and 15q were identified. In conclusion, these data underline the potential of array CGH for the sensitive detection of genomic imbalances in FL.