Development of a DUSP9 Methylation Screening Assay

Overview

Journal Pathol Oncol Res

Specialty Oncology

Date 2014 May 20

PMID 24838152

Citations 5

Authors

Stefan Jenner

Klaus Herrmann Wiedorn

Dieter Techel

Affiliations

Soon will be listed here.

Abstract

A methylation screening assay for DUSP9 (dual-specificity phosphatase 9) has been developed and applied on 79 FFPE samples from patients with colorectal cancer (CRC) and 22 corresponding tumor free colon samples in this study. Quantitative pyrosequencing was used for the determination of the methylation in the promoter CpG island, including 83 CpG motifs. In this way, the methylation pattern of the 11 tumor samples with the weakest and the strongest methylation could be identified and were compared to their corresponding tumor free colon samples. Forty six percent of the weakly methylated samples showed no significant difference to their tumor free counterparts, whereas in 27% of the cases an increased or reduced methylation was detectable. For the strongly methylated tumor samples only 18% showed no significant difference to their tumor free counterparts, whereas 82% were significantly stronger methylated. In CRC, the aberrant promoter methylation of tumor suppressor genes is one aspect that defines the CpG island methylator phenoptype (CIMP) and is frequently observed in a subpopulation of cases. Patients harboring a CIMP phenotype often show additional clinicopathological characteristics, the so called CIMP features. Interestingly, no CIMP features were found for the weakly methylated samples analyzed in this study but could be seen in 82% of the strongly methylated cases, indicating a possible use for DUSP9 as CIMP marker.

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References

Patterson K, Brummer T, OBrien P, Daly R . Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J. 2009; 418(3):475-89. DOI: 10.1042/bj20082234. View

Hinoue T, Weisenberger D, Pan F, Campan M, Kim M, Young J . Analysis of the association between CIMP and BRAF in colorectal cancer by DNA methylation profiling. PLoS One. 2009; 4(12):e8357. PMC: 2791229. DOI: 10.1371/journal.pone.0008357. View

Keyse S . Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev. 2008; 27(2):253-61. DOI: 10.1007/s10555-008-9123-1. View

Muda M, Boschert U, Smith A, Antonsson B, Gillieron C, Chabert C . Molecular cloning and functional characterization of a novel mitogen-activated protein kinase phosphatase, MKP-4. J Biol Chem. 1997; 272(8):5141-51. DOI: 10.1074/jbc.272.8.5141. View

Baldus S, Schaefer K, Engers R, Hartleb D, Stoecklein N, Gabbert H . Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res. 2010; 16(3):790-9. DOI: 10.1158/1078-0432.CCR-09-2446. View

Ferlay J, Shin H, Bray F, Forman D, Mathers C, Parkin D . Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2011; 127(12):2893-917. DOI: 10.1002/ijc.25516. View

Jeffrey K, Camps M, Rommel C, Mackay C . Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov. 2007; 6(5):391-403. DOI: 10.1038/nrd2289. View

Ogino S, Odze R, Kawasaki T, Brahmandam M, Kirkner G, Laird P . Correlation of pathologic features with CpG island methylator phenotype (CIMP) by quantitative DNA methylation analysis in colorectal carcinoma. Am J Surg Pathol. 2006; 30(9):1175-83. DOI: 10.1097/01.pas.0000213266.84725.d0. View

Jeong D, Yoon T, Jung S, Park B, Park H, Ryu S . Exploring binding sites other than the catalytic core in the crystal structure of the catalytic domain of MKP-4. Acta Crystallogr D Biol Crystallogr. 2011; 67(Pt 1):25-31. DOI: 10.1107/S0907444910042381. View

10.

Ottini L, Falchetti M, Lupi R, Rizzolo P, Agnese V, Colucci G . Patterns of genomic instability in gastric cancer: clinical implications and perspectives. Ann Oncol. 2006; 17 Suppl 7:vii97-102. DOI: 10.1093/annonc/mdl960. View

11.

Liu J, Ni W, Xiao M, Jiang F, Ni R . Decreased expression and prognostic role of mitogen-activated protein kinase phosphatase 4 in hepatocellular carcinoma. J Gastrointest Surg. 2013; 17(4):756-65. DOI: 10.1007/s11605-013-2138-0. View

12.

Weisenberger D, Siegmund K, Campan M, Young J, Long T, Faasse M . CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006; 38(7):787-93. DOI: 10.1038/ng1834. View

13.

Kambara T, Simms L, Whitehall V, Spring K, Wynter C, Walsh M . BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut. 2004; 53(8):1137-44. PMC: 1774130. DOI: 10.1136/gut.2003.037671. View

14.

Bhaduri A, Sowdhamini R . A genome-wide survey of human tyrosine phosphatases. Protein Eng. 2004; 16(12):881-8. DOI: 10.1093/protein/gzg144. View

15.

Toyota M, Ahuja N, Herman J, Baylin S, Issa J . CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A. 1999; 96(15):8681-6. PMC: 17576. DOI: 10.1073/pnas.96.15.8681. View

16.

Kondoh K, Nishida E . Regulation of MAP kinases by MAP kinase phosphatases. Biochim Biophys Acta. 2007; 1773(8):1227-37. DOI: 10.1016/j.bbamcr.2006.12.002. View

17.

Cappell M . The pathophysiology, clinical presentation, and diagnosis of colon cancer and adenomatous polyps. Med Clin North Am. 2004; 89(1):1-42, vii. DOI: 10.1016/j.mcna.2004.08.011. View

18.

Esteller M . Epigenetics in cancer. N Engl J Med. 2008; 358(11):1148-59. DOI: 10.1056/NEJMra072067. View

19.

Feinberg A, Vogelstein B . Hypomethylation of ras oncogenes in primary human cancers. Biochem Biophys Res Commun. 1983; 111(1):47-54. DOI: 10.1016/s0006-291x(83)80115-6. View

20.

Tommasi S, Pinto R, Petriella D, Pilato B, Lacalamita R, Santini D . Oncosuppressor methylation: a possible key role in colon metastatic progression. J Cell Physiol. 2011; 226(7):1934-9. DOI: 10.1002/jcp.22524. View