Abstract Introduction: Linking markers together into large phase-blocks, and examining the interaction of different sequencing modalities, allows complex genomic and epigenomic states to be integrated to generate true multiomic haplotypes at the chromosomal level. Methods: Fourteen multiple myeloma patient-derived xenografts were used to generate multiomic data including short- (Illumina) and long-read (PacBio) whole genome sequencing (WGS) to identify single nucleotide variations (SNVs), copy number (CN) abnormalities, structural variation (SV), and DNA methylation, as well as expression, chromatin states (Cut14) and additional SV events linked to the t(11;14) including a t(3;14), t(11;17), and t(3;17) which created a cyclical pattern. We found that 70-83.5% of reads support specific combinations of haplotype interactions, and that all four SV events were linked and involved the same haplotypes on each chromosome. The pattern of interactions combined with breakpoint analysis in this case indicated a four-way complex reciprocal translocation between chromosomes 3,11,14 and 17. Integration of epigenetic data in this complex SV showed DNA hyper-methylation 17 kb upstream of CCND1 next to the t(11;14) breakpoint as well as increased H3K27ac marks on the same haplotype, indicating spreading of the activating broad domain from the IGH super-enhancer on chromosome 14. Equally, the hypomethylated DNA marks at the IGH promoter are spread to chromosome 3, via the t(3;14), resulting in over-expression of the proto-oncogene SKIL. The same is true for the t(3;17), which shows hypomethylation on both sides of the breakpoint, compared to the non-translocated allele. Conclusion: We have generated the first chromosome scale haplotype-resolved genomes in multiple myeloma and integrated them with epigenetic states to identify interactions across chromosomes and resolve complex SVs as well as their epigenomic consequences to understand the intricate nature of how the genome is organized. Citation Format: Nathan J. Becker, Enze Liu, J. Zachary Sanborn, Attaya Suvannasankha, Kelvin Lee, Dickran Kazandjian, Benjamin Diamond, Abhishek Pandey, Rafat Abonour, Ola Landgren, Elizabeth M. Munding, Aneta Mikulasova, Brian A. Walker. Chromosome-level phasing to resolve haplotypes using multiomic data in multiple myeloma reveals complex distal interactions between chromosomes that impacts epigenetic states and gene expression abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5940.
Becker et al. (Fri,) studied this question.