title: Contralateral upper tract urothelial carcinoma after nephroureterectomy: the predictive role of DNA methylation.
abstract: BACKGROUND
  Aberrant methylation of genes is one of the most common epigenetic modifications involved in the development of urothelial carcinoma. However, it is unknown the predictive role of methylation to contralateral new upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). We retrospectively investigated the predictive role of DNA methylation and other clinicopathological factors in the contralateral upper tract urothelial carcinoma (UTUC) recurrence after radical nephroureterectomy (RNU) in a large single-center cohort of patients.
  
  
  METHODS
  In a retrospective design, methylation of 10 genes was analyzed on tumor specimens belonging to 664 consecutive patients treated by RNU for primary UTUC. Median follow-up was 48 mo (range: 3-144 mo). Gene methylation was accessed by methylation-sensitive polymerase chain reaction, and we calculated the methylation index (MI), a reflection of the extent of methylation. The log-rank test and Cox regression were used to identify the predictor of contralateral UTUC recurrence.
  
  
  RESULTS
  Thirty (4.5%) patients developed a subsequent contralateral UTUC after a median follow-up time of 27.5 (range: 2-139) months. Promoter methylation for at least one gene promoter locus was present in 88.9% of UTUC. Fewer methylation and lower MI (P = 0.001) were seen in the tumors with contralateral UTUC recurrence than the tumors without contralateral recurrence. High MI (P = 0.007) was significantly correlated with poor cancer-specific survival. Multivariate analysis indicated that unmethylated RASSF1A (P = 0.039), lack of bladder recurrence prior to contralateral UTUC (P = 0.009), history of renal transplantation (P < 0.001), and preoperative renal insufficiency (P = 0.002) are independent risk factors for contralateral UTUC recurrence after RNU.
  
  
  CONCLUSIONS
  Our data suggest a potential role of DNA methylation in predicting contralateral UTUC recurrence after RNU. Such information could help identify patients at high risk of new contralateral UTUC recurrence after RNU who need close surveillance during follow up.
authors.affiliation: Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China. zl070501@126.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China. xgy13537221@163.com.
authors.forename: Gengyan
authors.initials: G
authors.lastname: Xiong
authors.affiliation: Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China. fdmailbox@126.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Fang
authors.affiliation: Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China. pineneedle@sina.com.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China. 13051264930@163.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. ciwm@big.ac.cn.
authors.forename: Weimin
authors.initials: W
authors.lastname: Ci
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, Beijing, 100142, China. 664217792@qq.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Urology University of Texas Southwestern Medical Center, 5303 Harry Hines Blvd, Dallas, TX, 75390, USA. singlani@umich.edu.
authors.forename: Nirmish
authors.initials: N
authors.lastname: Singla
authors.affiliation: Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China. wyj7074@sohu.com.
authors.forename: Zhisong
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, No. 8 Xishiku St, Xicheng District, Beijing, 100034, China. zhouliqunmail@sina.com.
authors.forename: Liqun
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009392:Nephrectomy; D011379:Prognosis; D012189:Retrospective Studies; D047368:Tumor Burden; D014571:Urologic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D055815:Young Adult