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Recurrent chromosomal abnormalities are frequently observed in hematological malignancies but are rare in solid tumors. However, signature translocations have been characterized in Ewing’s Sarcoma (e.g., EWSR1/FLI1 in more than 90% of tumors). In addition, distinct translocations have been discovered in liposarcoma, Askin’s tumor and extraskeletal myxoid chondrosarcoma. Primarily two related genes, FUS and RBP56 (which share protein sequence homology with EWSR1) are also involved in signature translocations of these rare sarcomas. We have characterized the pattern of genetic variation in FUS and RBP56 to identify sequence similarities that could play a role in the translocation events. Most breakpoints in FUS occurred in a region of 3.2 kb spanning exon 6 and intron 7. The mean conservation score was 0.712 using the phastCons17way algorithm. In contrast, in the 1.2 kb region where most of the breakpoints occur in RBP56, the mean conservation score was only 0.046. Re-sequence of 3.5 kb of FUS across the breakpoint region in the SNP500Cancer population (32 Caucasians, 24 African Americans, 23 admixed/Hispanic and 23 Pacific Rim individuals) identified 19 SNPs. Nucleotide diversity, pi, was 2.3x10-4 and population mutation frequency, theta, was 6.7x10-4. An analysis of the Perlegen data on the UCSC genome browser (23 individuals of African American Descent, 24 individuals of European Descent and 24 individuals of Chinese Descent) using Tajima’s D in FUS and RBP56 did not reveal an excess of common variation nor evidence for recent selection.

Using HapMap phase II data for FUS and RPB56, we determined that the pattern of linkage disequilibrium (LD) is similar in Caucasians and East Asians, namely, in each case, the gene resides within one large haplotype block. In the Yoruba population, an analysis of FUS and RBP56 reveals that there are two haplotype blocks, which could be a vestige of more rapidly disintegrating LD or a possible recombination hot spot (in the case of FUS). Further analyses of the data set do not point towards recent selection but the limited haplotype heterozygosity for both FUS and RBP56 is striking. Further studies are warranted to investigate the population genetics of FUS and RBP56 in order to investigate the molecular bases for translocation events in rare sarcomas.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA