Identification and validation of SRY-box containing gene family member SOX30 methylation as a prognostic and predictive biomarker in myeloid malignancies

Abstract

BackgroundMethylation-associated SOX family genes have been proved to be involved in multiple essential processes during carcinogenesis and act as potential biomarkers for cancer diagnosis, staging, prediction of prognosis, and monitoring of response to therapy. Herein, we revealed SOX30 methylation and its clinical implication in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).ResultsIn the discovery stage, we identified that SOX30 methylation, a frequent event in AML, was negatively associated with SOX30 expression and correlated with overall survival (OS) and leukemia-free survival (LFS) in cytogenetically normal AML among SOX family members from The Cancer Genome Atlas (TCGA) datasets. In the validation stage, we verified that SOX30 methylation level was significantly higher in AML even in MDS-derived AML compared to controls, whereas SOX30 hypermethylation was not a frequent event in MDS. SOX30 methylation was inversely correlated with SOX30 expression in AML patients. Survival analysis showed that SOX30 hypermethylation was negatively associated with complete remission (CR), OS, and LFS in AML, where it only affected LFS in MDS. Notably, among MDS/AML paired patients, SOX30 methylation level was significantly increased in AML stage than in MDS stage. In addition, SOX30 methylation was found to be significantly decreased in AML achieved CR when compared to diagnosis time and markedly increased in relapsed AML when compared to the CR population.ConclusionsOur findings revealed that SOX30 methylation was associated with disease progression in MDS and acted as an independent prognostic and predictive biomarker in AML.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0523-y) contains supplementary material, which is available to authorized users.

<p>Increased <em>MCL-1</em> expression predicts poor prognosis and disease recurrence in acute myeloid leukemia</p>

“…Total RNA was isolated using Trizol reagent (Invitrogen, Carlsbad, CA, USA). Reverse transcription was performed as reported previously 17,18…”

MicroRNA-335/ID4 dysregulation predicts clinical outcome and facilitates leukemogenesis by activating PI3K/Akt signaling pathway in acute myeloid leukemia

“…The characteristics of AML patients were summarized in Table 1. Treatment regimens for AML patients were induction chemotherapy and subsequent consolidation chemotherapy as reported [34, 35].…”

Genome-Wide Methylation Sequencing Identifies Progression-Related Epigenetic Drivers in Myelodysplastic Syndromes

“…In addition to genetic alterations, epigenetic modi cations especially in DNA methylation have been shown involved in cancer progression including MDS [24][25][26]. Previous studies almost focused on the single gene change during MDS progression, such as CDKN2B, SOCS1, NR4A2, ABAT, ID4, GPX3, SOX30, and etc [9][10][11][27][28][29][30]. However, little studies showed the whole-genome DNA methylation alterations during MDS progression.…”

“…The frequently mutant genes TET2 and IDH1/2 in MDS-derived secondary AML (sAML) are methylation-related genes suggesting that aberrant epigenetic programming may play a crucial role in MDS progression [8]. Previously, we have also identi ed that single genes including GPX3, ID4, and SOX30 methylation were associated with disease progression in MDS [9][10][11]. To gain new insights into the epigenetic mechanism underlying disease evolution in MDS, we conducted reduced representation bisul te sequencing (RRBS) of bone marrow (BM) samples from four paired MDS/sAML patients and intended to discover methylation-associated epigenetic drivers in MDS progression.…”