Title : Genetic and epigenetic alterations of SOX7 in multiple myeloma and allied neoplasms
Abstract:
Multiple myeloma (MM) is one of the most frequent hematological malignancies. Its incidence and mortality rate is globally increasing. Most MM patients experience relapse, which leads to poor prognosis. The genes associated with MM development or relapse have not been totally elucidated yet. The recurrently deleted 8p23.1 locus in MM includes tumor suppressor gene candidates. As a transcription factor, SOX7 was shown to be downregulated through genetic or epigenetic alterations in different cancer types. However, the aberrations of SOX7 were not evaluated in multiple myeloma or allied plasma cell neoplasms such as smoldering MM (SMM) or plasma cell leukemia (PCL). In this study, we reanalyzed the publicly available datasets to evaluate SOX7 copy number, promoter methylation, and transcript expression levels in MM or related neoplasms. Furthermore, we performed qPCR and qRT-PCR analyses with the in-house MM cohort to cross-validate SOX7 copy number and transcript level estimates. We observed frequent SOX7 deletions in newly diagnosed and relapsed MM cases. The SOX7 promoter was hypermethylated in most MM cell lines as well as many MM and PCL patient tumor samples. Consistent with these aberrations, SOX7 was transcriptionally silent in MM cell lines and underexpressed in MM and high-risk SMM cases. When we analyzed patient-matched MM cases, we observed moderate levels of positive correlation between SOX7 copy numbers in tumor tissues obtained at diagnosis and relapse. In these patient-matched samples, SOX7 deletion and promoter methylation levels had a tendency to be mutually exclusive. As a noteworthy observation, SOX7 promoter methylation levels were significantly higher in relapsed cases compared to the diagnostic ones. Given that small SOX7 mutations were very rare, deletion and promoter hypermethylation may be the main mechanisms for SOX7 underexpression in MM and allied neoplasms. These genetic and epigenetic aberrations may be pathologically and clinically signficant in these plasma cell neoplasms.
