Rearrangements affecting the chromosomal band 1q21-22 are the third most frequent in B-cell NHL and are associated with a significantly poor outcome. In addition, 1q21-22 rearrangements are also frequent in all lineages of cancer. Therefore, identification of genes deregulated in these rearrangements is important to biology and clinical management of cancer per se. At the beginning of the current funding period, no gene perturbed at this site in any cancer was identified. During past four years, four distinct breakpoints have been cloned from 1q21-22 from IG gene-associated translocations in B-cell NHL, three by us (MUC1, FCGR, MUM2/MUM3) and one (BCL9) by another group. In each case, a deregulated gene was identified. The goal of our program is to identify all the breakpoint clusters and the relevant deregulated genes at this chromosomal site and investigate their biological and clinical significance. We propose five Specific Aims. 1. Construct a YAC/BAC contig of the 1q21-22 region and, utilizing two color FISH, map the breakpoint clusters in individual tumors with 1q21-22 rearrangements within BAC reagents to identify breakpoints and frequency of breaks. 2. Isolate rearranging genes from 1q21-22 in cases with IG gene-associated translocations following cloning strategies established by us and others. 3. Isolate rearranging genes from 1q21-22 in cases without IG gene-associated translocations by mapping the breakpoints in BACs and identifying deregulated genes adjacent to the breakpoints following established genomic cloning strategies. 4. Investigate the functional significance of FCGR2B gene deregulation in translocations involving the 1q21-22 region 5. Investigate the clinical significance of recurring molecular breakpoints in 1q21-22 region identified by FISH and expression of MUC1 and FCGR2B genes in NHL by correlation analysis. Our analysis of 1q21-22 rearrangements in B-cell NHL can be expected to identify novel genes with potential significance to cell function and lymphomagenesis as well as known genes with novel functions associated with lymphomagenesis and clinical behavior. They will also enable the identification of individual genes that associate with specific patterns of clinical behavior. In addition, the mapping of NHL breakpoints will provide a platform for addressing breakpoints in this region found in other cancer types.
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