title: Promoter CpG island methylation of RET predicts poor prognosis in stage II colorectal cancer patients.
abstract: Improved prognostic stratification of patients with TNM stage II colorectal cancer (CRC) is desired, since 20-30% of high-risk stage II patients may die within five years of diagnosis. This study was conducted to investigate REarranged during Transfection (RET) gene promoter CpG island methylation as a possible prognostic marker for TNM stage II CRC patients. The utility of RET promoter CpG island methylation in tumors of stage II CRC patients as a prognostic biomarker for CRC related death was studied in three independent series (including 233, 231, and 294 TNM stage II patients, respectively) by using MSP and pyrosequencing. The prognostic value of RET promoter CpG island methylation was analyzed by using Cox regression analysis. In the first series, analyzed by MSP, CRC stage II patients (n = 233) with RET methylated tumors had a significantly worse overall survival as compared to those with unmethylated tumors (HRmultivariable = 2.51, 95%-CI: 1.42-4.43). Despite a significant prognostic effect of RET methylation in stage III patients of a second series, analyzed by MSP, the prognostic effect in stage II patients (n = 231) was not statistically significant (HRmultivariable = 1.16, 95%-CI 0.71-1.92). The third series (n = 294), analyzed by pyrosequencing, confirmed a statistically significant association between RET methylation and poor overall survival in stage II patients (HRmultivariable = 1.91, 95%-CI: 1.04-3.53). Our results show that RET promoter CpG island methylation, analyzed by two different techniques, is associated with a poor prognosis in stage II CRC in two independent series and a poor prognosis in stage III CRC in one series. RET methylation may serve as a useful and robust tool for clinical practice to identify high-risk stage II CRC patients with a poor prognosis. This merits further investigation.
authors.affiliation: Department of Pathology, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Muriel X G
authors.initials: MX
authors.lastname: Draht
authors.affiliation: Department of Pathology, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, The Netherlands; Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Smits
authors.affiliation: Sevice de Pathologie, Centre Hospitalier Universitaire de Dijon, Dijon, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tournier
authors.affiliation: Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Jooste
authors.affiliation: Sevice de Pathologie, Centre Hospitalier Universitaire de Dijon, Dijon, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Chapusot
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Carvalho
authors.affiliation: Department of Pathology, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Arjen H G
authors.initials: AH
authors.lastname: Cleven
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Sarah
authors.initials: S
authors.lastname: Derks
authors.affiliation: Department of Pathology, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Kim A D
authors.initials: KA
authors.lastname: Wouters
authors.affiliation: Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Eric J T
authors.initials: EJ
authors.lastname: Belt
authors.affiliation: Department of Surgery, Kennemer Gasthuis, Haarlem, The Netherlands.
authors.forename: Hein B A C
authors.initials: HB
authors.lastname: Stockmann
authors.affiliation: Department of Pathology, Kennemer Gasthuis, Haarlem, The Netherlands.
authors.forename: Herman
authors.initials: H
authors.lastname: Bril
authors.affiliation: Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Matty P
authors.initials: MP
authors.lastname: Weijenberg
authors.affiliation: Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Piet A
authors.initials: PA
authors.lastname: van den Brandt
authors.affiliation: Department of Pathology, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: de Bruïne
authors.affiliation: Cancer Biology Program, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
authors.affiliation: Sevice de Pathologie, Centre Hospitalier Universitaire de Dijon, Dijon, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Piard
authors.affiliation: Department of Pathology, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Veerle
authors.initials: V
authors.lastname: Melotte
authors.affiliation: Department of Pathology, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: manon.van.engeland@mumc.nl.
authors.forename: Manon
authors.initials: M
authors.lastname: van Engeland
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012007:Rectum / Q000378:metabolism / Q000473:pathology*
keywords: Colon cancer; Colorectal cancer; DNA methylation; Methylation marker; Prognostic biomarker; REarranged during transfection (RET)