Background: Multiple myeloma (MM) is a plasma cells malignancy charac- terized by a complex and heterogeneous genomic landscape. Using whole- exome and targeted sequencing, two main active mutational processes have been identified in MM provide initial insight into both initial pathogenic mechanisms and the processes affecting disease progression. However, lim- ited numbers of mutations identified using WES does not allow interrogation of question whether different parts of the genome are targeted by different mutational processes. Aims: Here we interrogate various genomic regions and mutation types such as non-coding regions and protein coding regions with missense mutations, to understand activated processes that cause DNA alteration in MM. Methods: We have processed 39 purified CD138+ MM cells samples with Whole Genome Sequencing; ten samples also have RNA and ATAC sequenc- ing. Public WES data from 999 samples were collected from dbGaP and CoMMpass study. Mutational processes were analyzed using non-negative matrix factorization and multiple linear regression model. Results: We identified an average >5000 SNVs per patient sample with a total of over 200K SNVs from WGS and additional >170K SNVs from pub- lic WES data. Overall C>T mutations constituted 30% of all detected muta- tions across the genome, including a small fraction of C>T mutations within CpG islands. Majority of the mutations were observed in the intergenic (IGR), introns and non-coding RNAs regions (lincRNAs and ncRNA). Tran- scribed strand of the genome showed enrichment in C>A and C>T muta- tions. With non-negative matrix factorization we were able to identify 8 mutational processes in MM genome six of which were not described before. Although APOBEC/AID processes were the majority for the non coding genome, DNA repair related processes were highly active in the coding genome. We have integrated WGS, ATACseq and RNAseq data from same patients and identified that DNA damage activity increased in the expressed genes and sub clonal populations. We have confirmed our results using pub- licly available WES data from 999 samples. Summary and Conclusions: C>A and C>T enrichment on the transcribed strand has been connected to high transcriptional activities and different mechanisms such as single versus double-strand DNA repair functions. Tar- geting of non-coding regions by APOBEC/AID could be part of ongoing somatic hypermutation in MM. However, missense mutations may be driven by DNA double-strand break-repair by homologous recombination and DNA mismatch repair processes. Increased intensity for DNA repair signa- tures in subclonal missense mutations may indicate that these processes may occur late during the MM progression. Future studies that can compare paired samples from early stage to relapsed and refractory myeloma can help us understand if DNA repair processes become dominant during the MM development.
|Titolo:||DNA repair processes target transcribed region in multiple myeloma|
|Settore Scientifico Disciplinare:||Settore MED/15 - Malattie del Sangue|
|Data di pubblicazione:||2018|
|Appare nelle tipologie:||01 - Articolo su periodico|