CHFR hypermethylation, a frequent event in acute myeloid leukemia, is independently associated with an adverse outcome

Abstract

The CpG island of the promoter region of the checkpoint with fork-head associated and ring finger gene (CHFR), a mitotic checkpoint gene with tumor-suppressor functions, is hypermethylated in various human cancers. The objective of this study was to evaluate the frequency of aberrant CHFR promoter methylation in acute myeloid leukemia (AML) patients in an attempt to improve prognostication. CHFR promoter methylation levels were analyzed in 358 newly diagnosed AML cases and 30 healthy donors by the use of quantitative methylation-specific polymerase chain reaction. In addition, we analyzed possible association between CHFR hypermethylation and hematological characteristics, chromosome abnormalities, genetic mutations, and survival. Hypermethylation of the CHFR promoter was observed in 24% (85 of 358) AML patients, but not in healthy individuals. CHFR hypermethylation correlated significantly with SRSF2 and DNMT3A mutations. Patients with hypermethylation exhibited lower overall survival and shorter relapse-free survival than nonmethylated cases. In multivariate analysis, CHFR hypermethylation was an independent factor predicting poor overall survival but not relapse-free survival. In conclusion, hypermethylation of the CHFR promoter, frequent in AML, is associated with adverse outcome, and can thus be used for risk stratification.

Upregulation of the checkpoint protein CHFR is associated with tumor suppression in pancreatic cancers

“…However, there has not been a consistent conclusion in this field. In metastatic NSCLC ( 16 ) diminished CHFR expression predicted a better prognosis, but CHFR inactivation in stage II colorectal cancer ( 39 ) and acute myeloid leukemia ( 40 ) were associated with an adverse outcome. In our study, although a significant association between CHFR expression and prognosis of PDAC patients was not observed, further studies with a larger sample size and more clinicopathological data are required to reveal deeper relationship between CHFR and PDAC.…”

<em>RASSF1A</em> hypermethylation is associated with <em>ASXL1</em> mutation and indicates an adverse outcome in non-M3 acute myeloid leukemia

“…To assess the associations of gene mutations occurring in AML patients with the methylation status of the RASSF1A promoter region, DNA sequencing was conducted to detect NPM1 , FLT3-ITD , ASXL1 , IDH1 , DNMT3A , RUNX1 , U2AF1 , TET2 , SRSF2 , NRAS , CEBPA , KIT , and SF3B1 with hyperfrequency-mutation sequences, as previously reported. 9 , 10 , 17 – 22 The primers used for sequencing are shown in Table S3 .…”

Epigenetic Modifications as Biomarkers of Tumor Development, Therapy Response, and Recurrence across the Cancer Care Continuum

“…Cytotoxic chemotherapies like taxanes preferentially affect cancer cells based on their rapid proliferation and cell cycle checkpoint dysfunction. Checkpoint with forkhead and ring finger domains (CHFR) controls cell cycle progression at the G2/M checkpoint and can initiate mitotic arrest; thus downregulation of CHFR encourages uncontrolled cellular division [ 150 , 151 ]. Hypermethylation of CHFR is observed in breast, bladder, colorectal, gastric, nasopharyngeal, lung, esophageal, cervical, hepatocellular, oral squamous, head and neck, and endometrial cancer [ 152 ]; and is a potential marker of taxane sensitivity for many cancer types.…”