Exome Sequencing of the t(4;14) and t(11;14) Translocation Specific Subgroups of MM

摘要: Abstract 1817 The two most frequent etiological translocations in multiple myeloma (MM) are t(4;14), which deregulates FGFR3 and MMSET has a poor outcome t(11;14) directly cyclin D1 an indolent course. is present at 10–15% both MGUS MM but the t(4;14) only 3–4% of compared to 11% MM. Consequently it thought that patients with have less stable disease progresses more quickly than other subtypes. In order address hypothesis cases prone acquire mutations so progress, we number mutational spectrum these variants. DNA was extracted from CD138-selected bone marrow cells 10 12 newly presenting 50 ng genomic used capture exome using SureSelect Human All Exon 50Mb target enrichment set (Agilent). We previously validated this approach shown parity approaches larger starting amounts DNA. Libraries were prepared tumor non-tumor same patient sequenced 76 bp paired end reads on GAIIx (Illumina). Samples median depth 61x, 99% >1x 85% >20x exomic coverage. Following base calling quality control metrics raw fastq aligned reference human genome. Genome Analysis Tool Kit call indels single nucleotide variants (SNVs), BreakDancer detect structural These variant calls recalibrated soft filters applied remove potential false-positives dbSNP, HapMap thousand genomes project as truth sets. Variants occurred normal samples filtered out tumor-specific annotated Annovar. As well identification commonly affected genes, functional annotation analysis identify pathways. group 22 level showed mutation comprised 32,000 SNVs 1,800 per patient, 1,600 500 sample only. Structural copy inferred data also identified previous results technologies. 250 indels, not dbSNP constitute tumor-acquired mutations. able validate some had analyzed platforms (98% concordance). Ti/Tv ratio consistent any specific exposure or mechanism. distribution biased toward insertions rather deletions, predominantly being multiples three produce in-frame mutants. total sequencing 60 exomes available pathway confirmed deregulation pathways mutated myeloma, addition novel deregulated genes note increase t(4;14). Each average non-synonymous range 29 101, clear outliers. There bias excess within did reach statistical significance. Importantly, overlap between individual limited few consistently across whole. contrast, different entities shows marked similarities, involvement mediating cell adhesion t(4;14)s. Although greater mutations, 111 versus 237, respectively. This observation implies group, suggesting they under selective pressure group. work show higher frequency numbers Overall, etiologically distinct groups having similar driving progression, focus gene. Disclosures: No relevant conflicts interest declare.