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Motofumi Tanaka, Salil Sethi , Donghui Li, Dipen Maru , Gail Bland, James L. Abbruzzese , Cathy Eng. CHFR Methylation as an Epigenetic Marker for Recurrence of Colon Cancer. M. D. Anderson Cancer Center, Houston, Texas. Background.

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chfr methylation as an epigenetic marker for recurrence of colon cancer

Motofumi Tanaka, SalilSethi, DonghuiLi, DipenMaru, Gail Bland, James L. Abbruzzese, Cathy Eng

CHFR Methylation as an Epigenetic Marker for Recurrence of Colon Cancer

M. D. Anderson Cancer Center, Houston, Texas

background
Background
  • Epigenetic inactivation of tumor suppressor genes by promoter hypermethylation has been implicated in carcinogenesis (1,2).
  • Prior studies have indicated the predictive and prognostic utility of these methylated genes in primary colorectal tumors (3,4).
  • However, it is unclear whether the methylation profile of tumor suppressor genes can serve as a potential biomarker for tumor recurrence following curative surgical resection.
background contd
Background(contd.)
  • The recurrence rate of colon cancer after curative surgical resection is reported to be 20%-30% following adjuvant chemotherapy (5).
  • The identification of prognostic indicators for recurrent disease is clearly warranted and may have an impact on the routine colon cancer surveillance.
  • Promoter hypermethylation of the CHFR (checkpoint with forkhead-associated and RING finger domains), ID4 (inhibitor of DNA binding), and RECK (reversion-inducing cysteine rich protein with Kazal motifs) genes have been associated with reduced mRNA and/or protein expression in colorectal cancer.
objective
Objective
  • To identify potential DNA methylation biomarkers to predict recurrence - free survival (RFS) and overall survival (OS) in locally advanced colon cancer patients following curative surgical resection.
methods
Methods

Study Design and Population

  • 72 patients with the AJCC stage II (T3-4N0M0) and III (TXN1-3M0) colon cancer, who had undergone surgical resection at M.D. Anderson from 1999-2007, were included.
  • A retrospective chart review was conducted to collect demographic and clinical information.
  • A waiver of informed consent was provided.
  • Patients with a family history of HNPCC were excluded.
methods contd
Methods(contd.)

DNA methylation

  • DNA samples were extracted from the fresh frozen colon cancer tumor tissues and were subjected to a treatment with withbisulfite.
  • Pyrosequencing method (Biotage Co.) was used to quantitatively detect methylation status.
  • Methylation status was evaluated in promoter regions within 300 base pairs from the transcription start site (TSS) of CHFR, ID4, and RECK genes, and also in the MINT1 loci. Mean methylated rate of multiple CpG sites was used for analysis.
  • We defined <15%, 15%-30%, and >30% in methylated rate as methylation-negative, -low, and -high, respectively.
methods contd1
Methods(contd.)

Statistical Analysis

  • Survival outcomes were determined by Kaplan-Meier plot, log-rank test for univariate analysis and Cox’s proportional hazard model for multivariate analysis.
  • The correlation between clinicopathological features and methylation status was analyzed by χ2 test.
results
Results
  • The median follow-up period was 56.6 months.
  • 17 (23.6%) patients developed recurrence during the follow up, and 9 (12.5%) patients have died.
  • Methylation rates of CHFR, MINT1, ID4, and RECK genes were 61.1%, 31.9%, 48.6%, and 8.3%, respectively.
  • The CHFR methylation-high (43%) group was found to have a lower RFS (P=.009) and OS (P=.018%) when compared with the CHFR methylation-negative (39%) and -low (18%) group (Fig 1).
  • Methylation status of MINT1, ID4, and RECK 23 was not associated with RFS and OS.
  • CHFR methylation-high group was more frequently found to have a N2 disease (P=.042) with a higher propensity to affect the right-side (P=.004).
  • Multivariate analysis indicated that T4disease and the CHFR methylation-high were significant predictors for tumor recurrence.
patient demographics
Patient Demographics

* Log rank test

kaplan meier survival and chfr methylation
Kaplan-Meier survival and CHFR methylation

CHFR < 30%

CHFR > 30%

P = 0.009

kaplan meier survival and chfr methylation1
Kaplan-Meier survival and CHFR methylation

CHFR < 30%

CHFR > 30%

P = 0.023

multivariate analysis of recurrence free survival
Multivariate analysis of Recurrence-free survival

*HR adjusted for age, sex, tumor site, and adjuvant chemotherapy

discussion
Discussion
  • CHFR is a check-point protein in the cell cycle that delays the entry into metaphase in response to mitotic stress (6).
  • Hypermethylation of CHFR is closely associated with a loss of gene expression and a mitotic check-point dysfunction, which in turn sensitizes the affected cells to microtubule inhibitors (7).
  • Decreased CHFR expression was reported to be associated with malignant progression i.e. accelerated growth rate, higher mitotic index, enhanced invasiveness, and increased motility, when studied in vitro, (8).
discussion cont d
Discussion(cont’d.)
  • Our analysis indicates that the epigenetic inactivation of CHFR is associated with lymph node metastasis which is a poor prognostic indicator of recurrence and survival.
  • Increased methylation of the CHFR promoter is a potential epigenetic marker for colon cancer recurrence and overall survival.
  • Further analysis with a greater sample size will be conductedfor validation. If validated, CHFR methylation may have an impact on the current recommendations for colon cancer surveillance.
references
References
  • Grady WM, et al. Gastroenterology. 2008; 135: 1079-99.
  • Feinberg AP, et al. Nature Rev Cancer 2004; 4: 143-53.
  • Shen L, et al. Clin Cancer Res. 2007; 13: 6093-8.
  • Umetani N, et al. Clin Cancer Res 2004; 10: 7475-83
  • André T, et al. N Engl J Med 2004; 350: 2343–51
  • Scolnick DM, et al. Nature 2000; 406: 430-35
  • Satoh A, et al. Cancer Res 2003; 63: 8606–13
  • Privette LM, et al. Cancer Res 2007; 67; 6064-74