Differential methylation hybridization array of endometrial cancers reveals two novel cancer-specific methylation markers

Israel Zighelboim, Paul J. Goodfellow, Amy P. Schmidt, Ken C. Walls, Mary Ann Mallon, David G. Mutch, Pearlly S. Yan, Hui-ming Huang, Matthew A. Powell

Research output: Contribution to journalArticle

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Abstract

Purpose: To identify novel endometrial cancer-specific methylation markers and to determine their association with clinicopathologic variables and survival outcomes. Experimental Design: Differential methylation hybridization analysis (DMH) was done for 20 endometrioid endometrial cancers using normal endometrial DNA as a reference control. Combined bisulfite restriction analysis (COBRA) was used to verify methylation of sequences identified by DMH. Bisulfite sequencing was undertaken to further define CpG island methylation and to confirm the reliability of the COBRA. The methylation status of newly identified markers and the MLH1 promoter was evaluated by COBRA in a large series of endometrioid (n = 361) and non-endometrioid uterine cancers (n = 23). Results: DMH and COBRA identified two CpG islands methylated in tumors but not in normal DNAs; SESN3 (PY2B4) and TITF1 (SC77F6/154). Bisulfite sequencing showed dense methylation of the CpG islands and confirmed the COBRA assays. SESN3 and TITF1 were methylated in 20% and 70% of endometrioid tumors, respectively. MLH1 methylation was seen in 28% of the tumors. TITF1 and SESN3 methylation was highly associated with MLH1 methylation (P < 0.0001). SESN3 and TITF1 were methylated in endometrioid and non-endometrioid tumors, whereas MLH1 methylation was restricted to endometrioid tumors. Methylation at these markers was not associated with survival outcomes. Conclusions: The 5′ CpG islands for SESN3 and TITF1 are novel cancer-specific methylation markers. Methylation at these loci is strongly associated with aberrant MLH1 methylation in endometrial cancers. SESN3, TITF1 and MLH1 methylation did not predict overall survival or disease-free survival in this large cohort of patients with endometrioid endometrial cancer.

Original languageEnglish (US)
Pages (from-to)2882-2889
Number of pages8
JournalClinical Cancer Research
Volume13
Issue number10
DOIs
StatePublished - May 15 2007
Externally publishedYes

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Endometrial Neoplasms
Methylation
Neoplasms
CpG Islands
Uterine Neoplasms
Survival
DNA
hydrogen sulfite
Disease-Free Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Zighelboim, I., Goodfellow, P. J., Schmidt, A. P., Walls, K. C., Mallon, M. A., Mutch, D. G., ... Powell, M. A. (2007). Differential methylation hybridization array of endometrial cancers reveals two novel cancer-specific methylation markers. Clinical Cancer Research, 13(10), 2882-2889. https://doi.org/10.1158/1078-0432.CCR-06-2367

Differential methylation hybridization array of endometrial cancers reveals two novel cancer-specific methylation markers. / Zighelboim, Israel; Goodfellow, Paul J.; Schmidt, Amy P.; Walls, Ken C.; Mallon, Mary Ann; Mutch, David G.; Yan, Pearlly S.; Huang, Hui-ming; Powell, Matthew A.

In: Clinical Cancer Research, Vol. 13, No. 10, 15.05.2007, p. 2882-2889.

Research output: Contribution to journalArticle

Zighelboim, I, Goodfellow, PJ, Schmidt, AP, Walls, KC, Mallon, MA, Mutch, DG, Yan, PS, Huang, H & Powell, MA 2007, 'Differential methylation hybridization array of endometrial cancers reveals two novel cancer-specific methylation markers', Clinical Cancer Research, vol. 13, no. 10, pp. 2882-2889. https://doi.org/10.1158/1078-0432.CCR-06-2367
Zighelboim, Israel ; Goodfellow, Paul J. ; Schmidt, Amy P. ; Walls, Ken C. ; Mallon, Mary Ann ; Mutch, David G. ; Yan, Pearlly S. ; Huang, Hui-ming ; Powell, Matthew A. / Differential methylation hybridization array of endometrial cancers reveals two novel cancer-specific methylation markers. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 10. pp. 2882-2889.
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abstract = "Purpose: To identify novel endometrial cancer-specific methylation markers and to determine their association with clinicopathologic variables and survival outcomes. Experimental Design: Differential methylation hybridization analysis (DMH) was done for 20 endometrioid endometrial cancers using normal endometrial DNA as a reference control. Combined bisulfite restriction analysis (COBRA) was used to verify methylation of sequences identified by DMH. Bisulfite sequencing was undertaken to further define CpG island methylation and to confirm the reliability of the COBRA. The methylation status of newly identified markers and the MLH1 promoter was evaluated by COBRA in a large series of endometrioid (n = 361) and non-endometrioid uterine cancers (n = 23). Results: DMH and COBRA identified two CpG islands methylated in tumors but not in normal DNAs; SESN3 (PY2B4) and TITF1 (SC77F6/154). Bisulfite sequencing showed dense methylation of the CpG islands and confirmed the COBRA assays. SESN3 and TITF1 were methylated in 20{\%} and 70{\%} of endometrioid tumors, respectively. MLH1 methylation was seen in 28{\%} of the tumors. TITF1 and SESN3 methylation was highly associated with MLH1 methylation (P < 0.0001). SESN3 and TITF1 were methylated in endometrioid and non-endometrioid tumors, whereas MLH1 methylation was restricted to endometrioid tumors. Methylation at these markers was not associated with survival outcomes. Conclusions: The 5′ CpG islands for SESN3 and TITF1 are novel cancer-specific methylation markers. Methylation at these loci is strongly associated with aberrant MLH1 methylation in endometrial cancers. SESN3, TITF1 and MLH1 methylation did not predict overall survival or disease-free survival in this large cohort of patients with endometrioid endometrial cancer.",
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AU - Zighelboim, Israel

AU - Goodfellow, Paul J.

AU - Schmidt, Amy P.

AU - Walls, Ken C.

AU - Mallon, Mary Ann

AU - Mutch, David G.

AU - Yan, Pearlly S.

AU - Huang, Hui-ming

AU - Powell, Matthew A.

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N2 - Purpose: To identify novel endometrial cancer-specific methylation markers and to determine their association with clinicopathologic variables and survival outcomes. Experimental Design: Differential methylation hybridization analysis (DMH) was done for 20 endometrioid endometrial cancers using normal endometrial DNA as a reference control. Combined bisulfite restriction analysis (COBRA) was used to verify methylation of sequences identified by DMH. Bisulfite sequencing was undertaken to further define CpG island methylation and to confirm the reliability of the COBRA. The methylation status of newly identified markers and the MLH1 promoter was evaluated by COBRA in a large series of endometrioid (n = 361) and non-endometrioid uterine cancers (n = 23). Results: DMH and COBRA identified two CpG islands methylated in tumors but not in normal DNAs; SESN3 (PY2B4) and TITF1 (SC77F6/154). Bisulfite sequencing showed dense methylation of the CpG islands and confirmed the COBRA assays. SESN3 and TITF1 were methylated in 20% and 70% of endometrioid tumors, respectively. MLH1 methylation was seen in 28% of the tumors. TITF1 and SESN3 methylation was highly associated with MLH1 methylation (P < 0.0001). SESN3 and TITF1 were methylated in endometrioid and non-endometrioid tumors, whereas MLH1 methylation was restricted to endometrioid tumors. Methylation at these markers was not associated with survival outcomes. Conclusions: The 5′ CpG islands for SESN3 and TITF1 are novel cancer-specific methylation markers. Methylation at these loci is strongly associated with aberrant MLH1 methylation in endometrial cancers. SESN3, TITF1 and MLH1 methylation did not predict overall survival or disease-free survival in this large cohort of patients with endometrioid endometrial cancer.

AB - Purpose: To identify novel endometrial cancer-specific methylation markers and to determine their association with clinicopathologic variables and survival outcomes. Experimental Design: Differential methylation hybridization analysis (DMH) was done for 20 endometrioid endometrial cancers using normal endometrial DNA as a reference control. Combined bisulfite restriction analysis (COBRA) was used to verify methylation of sequences identified by DMH. Bisulfite sequencing was undertaken to further define CpG island methylation and to confirm the reliability of the COBRA. The methylation status of newly identified markers and the MLH1 promoter was evaluated by COBRA in a large series of endometrioid (n = 361) and non-endometrioid uterine cancers (n = 23). Results: DMH and COBRA identified two CpG islands methylated in tumors but not in normal DNAs; SESN3 (PY2B4) and TITF1 (SC77F6/154). Bisulfite sequencing showed dense methylation of the CpG islands and confirmed the COBRA assays. SESN3 and TITF1 were methylated in 20% and 70% of endometrioid tumors, respectively. MLH1 methylation was seen in 28% of the tumors. TITF1 and SESN3 methylation was highly associated with MLH1 methylation (P < 0.0001). SESN3 and TITF1 were methylated in endometrioid and non-endometrioid tumors, whereas MLH1 methylation was restricted to endometrioid tumors. Methylation at these markers was not associated with survival outcomes. Conclusions: The 5′ CpG islands for SESN3 and TITF1 are novel cancer-specific methylation markers. Methylation at these loci is strongly associated with aberrant MLH1 methylation in endometrial cancers. SESN3, TITF1 and MLH1 methylation did not predict overall survival or disease-free survival in this large cohort of patients with endometrioid endometrial cancer.

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