Dataset Information

Prognostic Impact of Circulating Methylated Homeobox A9 DNA in Patients Undergoing Treatment for Recurrent Ovarian Cancer.

ABSTRACT: Methylated Homeobox A9 circulating tumor DNA (meth-HOXA9) has been suggested as a blood-based biomarker in epithelial ovarian cancer (EOC), although its prognostic significance remains unproven. The aim of the present study was to investigate the prognostic impact of meth-HOXA9 in patients with recurrent EOC. DNA was purified from 4 mL plasma and, following bilsulfite conversion, meth-HOXA9 was analyzed using a methylation-specific droplet digital PCR. Detection of meth-HOXA9 was reported as a percentage of total DNA and as a binary variable (detectable and undetectable). Meth-HOXA9 status and its dynamics during palliative treatment were correlated with overall survival (OS) as the primary endpoint. At baseline, meth-HOXA9 was detected in 65.9% (83/126) of the patients. The median OS was 8.9 and 17.9 months in patients with detectable and undetectable meth-HOXA9 at baseline (hazard ratio: 2.04, p = 0.002), which remained significant in the multivariate analysis. Median OS in patients with an increase in meth-HOXA9 after one treatment cycle was 5.3 months compared to 33 months in patients with undetectable meth-HOXA9 (p < 0.001). Meth-HOXA9 was significantly related to poor survival and may serve as a prognostic marker in patients with recurrent EOC. The longitudinal monitoring of meth-HOXA9 is clinically feasible with the perspective of aiding clinical decision making.

SUBMITTER: Faaborg L

PROVIDER: S-EPMC8997085 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Prognostic Impact of Circulating Methylated Homeobox A9 DNA in Patients Undergoing Treatment for Recurrent Ovarian Cancer.

Faaborg Louise L Andersen Rikke Fredslund RF Waldstrøm Marianne M Henriksen Jon Røikjær JR Adimi Parvin P Jakobsen Anders A Steffensen Karina Dahl KD

Cancers 20220330 7

Methylated Homeobox A9 circulating tumor DNA (meth-HOXA9) has been suggested as a blood-based biomarker in epithelial ovarian cancer (EOC), although its prognostic significance remains unproven. The aim of the present study was to investigate the prognostic impact of meth-HOXA9 in patients with recurrent EOC. DNA was purified from 4 mL plasma and, following bilsulfite conversion, meth-HOXA9 was analyzed using a methylation-specific droplet digital PCR. Detection of meth-HOXA9 was reported as a p ...[more]

PMID: 35406538

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Project description:BackgroundThe homeobox A9 gene encodes a transcription factor, and aberrantly methylated homeobox A9 in the circulation has been suggested as a prognostic marker in early stage non-small cell lung cancer (NSCLC). The aim of the present study was to investigate the prognostic impact of methylated homeobox A9 in plasma from patients with advanced NSCLC.MethodsBlood samples were prospectively collected from patients with NSCLC stage III and IV receiving standard first line chemotherapy. Sampling took place before treatment initiation and subsequently before each treatment cycle. Plasma was stored at -80 °C until analysis. DNA was extracted, and following bisulfite conversion methylated homeobox A9 was analyzed by methylation specific droplet digital polymerase chain reaction. Detection of methylated homeobox A9 was assessed as a binary variable. The primary endpoint was overall survival (OS).ResultsA total of 231 patients were included. At baseline methylated homeobox A9 was detected in 78.5% of the patients with a clear correlation to survival. The median OS for patients with and without detectable methylated homeobox A9 was 7.4 and 11.1 months, respectively [hazard ratio (HR) 1.79, 95% confidence interval (CI): 1.35-2.38, P<0.001]. The difference increased after the first cycle of treatment. At this time point the median OS was 6.2 and 15.6 months for patients with and without detectable methylated homeobox A9, respectively (HR 2.07, 95% CI: 1.58-2.73, P<0.001). The independent prognostic impact of detectable methylated homeobox A9 after one treatment cycle assessed by multiple Cox regression including known prognostic factors resulted in a HR of 3.79 (2.19-6.54, P<0.001) compared to undetectable methylated homeobox A9.ConclusionsMeasurable methylated homeobox A9 after the first treatment cycle may serve as a valuable prognostic marker in patients with advanced NSCLC. Routine clinical application with treatment reconsideration calls for further studies, preferably in prospective clinical trials.

Project description:BackgroundMethylated DNA in fluids may be a suitable biomarker for cancer patients. XAF1 has been shown to be frequently down-regulated in human gastric cancer (GC). Here, we investigated if XAF1 methylation in GC could be a useful biomarker.MethodsReal-time RT-PCR was used to detect XAF1 mRNA expression; immunohistochemistry and western blot were used to examine XAF1 protein expression in GC tissues (n = 202) and their corresponding para-cancerous histological normal tissues (PCHNTs). Real-time methylation specific-PCR was used to investigate XAF1 promoter methylation in the same panel of GC tissues, their PCHNTs and sera.ResultsWe confirmed frequent XAF1 down-regulation in both mRNA and protein levels in GC tissues as compared to normal controls and PCHNTs. XAF1 hypermethylation was evidenced in 83.2% (168/202) of GC tissues and 27.2% (55/202) of PCHNTs, while no methylation was detected in the 88 normal controls. The methylation level in GC tissues was significantly higher than that in PCHNTs (p<0.05). The hypermethylation of XAF1 significantly correlated with the down-regulation of XAF1 in GC tissues in both mRNA and protein levels (p<0.001 each). Moreover, we detected high frequency of XAF1 methylation (69.8%, 141 out of 202) in the sera DNAs from the same patients, while the sera DNAs from 88 non-tumor controls were negative for XAF1 methylation. The XAF1 methylation in both GC tissues and in the sera could be a good biomarker for diagnosis of GC (AUC = 0.85 for tissue and AUC = 0.91 for sera) and significantly correlated with poorer prognosis (p<0.001). In addition, after-surgery negative-to-positive transition of XAF1 methylation in sera strongly associated with tumor recurrence.Conclusions1) Dysfunction of XAF1 is frequent and is regulated through XAF1 promoter hypermethylation; 2) Detection of circulating methylated XAF1 DNAs in the serum may be a useful biomarker in diagnosis, evaluating patient's outcome (prognosis and recurrence) for GC patients.

Project description:BackgroundColorectal cancer (CRC) has a high rate of recurrence, in particular for advanced disease, but prognosis based on staging and pathology at surgery can have limited efficacy. The presence of circulating tumor DNA (ctDNA) at diagnosis could be used to improve the prediction for disease recurrence.ObjectivesTo assess the impact of detecting methylated BCAT1/IKZF1 ctDNA at diagnosis in combination with demographic, lifestyle, clinical factors and tumor pathology, to assess predictive value for recurrence.DesignA retrospective cohort study.MethodsThe cohort included 180 patients (36 with recurrent CRC), who had undergone complete treatment and surveillance for a minimum of 3 years. Participant clinical details and ctDNA methylated BCAT1/IKZF1 results were compared between those with and without recurrence, and cox regression analysis assessed each factor on disease-free survival.ResultsClinical factors independently associated with reduced disease-free survival included nodal involvement (HR = 3.83, 95% CI 1.56-9.43, P = .003), M1 stage (HR = 4.41, 95% CI 1.18-16.45, P = .027), a resection margin less than 2 mm (HR = 4.60, 95% CI 1.19-17.76, P = .027), perineural involvement (HR = 2.50, 95% CI 1.01-6.17, P = .047) and distal tumors (HR = 3.13, 95% CI 1.07-9.18, P = .037). Methylated BCAT1/IKZF1 was detected in 51.7% (93/180) of pre-treatment plasma samples. When a positive ctDNA finding was considered in combination with these clinical prognostic factors, there was improved predictive power of recurrence for patients with perineural involvement (HR = 4.44, 95% CI 1.92-10.26, P < .001), and it marginally improved the predictive factor for M1 stage (HR = 7.59, 95% CI 2.30-25.07, P = .001) and distal tumors (HR = 5.04, 95% CI 1.88-13.49, P = .001).ConclusionsNodal invasion, metastatic disease, distal tumor site, low resection margins and perineural invasion were associated with disease recurrence. Pre-treatment methylated ctDNA measurement can improve the predictive value for recurrence in a subset of patients, particularly those with perineural involvement.RegistrationAustralian and New Zealand Clinical Trials Registry #12611000318987.

Dataset Information

Prognostic Impact of Circulating Methylated Homeobox A9 DNA in Patients Undergoing Treatment for Recurrent Ovarian Cancer.

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Prognostic Impact of Circulating Methylated Homeobox A9 DNA in Patients Undergoing Treatment for Recurrent Ovarian Cancer.

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