TY - JOUR
T1 - Methylation of subtelomeric repeat D4Z4 in peripheral blood leukocytes is associated with biochemical recurrence in localized prostate cancer patients
AU - Han, Yuyan
AU - Xu, Junfeng
AU - Kim, Jeri
AU - Wu, Xifeng
AU - Gu, Jian
N1 - Funding Information:
We thank the DNA Methylation Analysis Core of MD Anderson Cancer Center for performing the pyrosequening and Dr. Marcos Estecio for helpful discussion. Conflict of Interest Statement: None declared.
Funding Information:
This study was financially supported by an individual researcher award (RP140556) from the Cancer Prevention and Research Institute of Texas (CPRIT) and a National Cancer Institute Specialized Program of Research Excellence (SPORE) grant (CA140388).
Publisher Copyright:
© The Author 2017. Published by Oxford University Press.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Global DNA methylation may affect chromosome structure and genomic stability and is involved in carcinogenesis. In this study, we aimed to investigate whether methylation of pericentromeric repeat NBL2 and subtelomeric repeat D4Z4 in peripheral blood was associated with the aggressiveness of prostate cancer (PCa). We measured the methylation status of different CpG sites of NBL2 and D4Z4 in 795 PCa patients and compared their methylation levels among patients with different Gleason Score at diagnosis. We then analyzed the association of the NBL2 and D4Z4 methylation with the risk of biochemical recurrence (BCR) in patients receiving radical prostatectomy or radiotherapy using a multivariate Cox proportional hazards model. In addition, we used the Kaplan-Meier survival function and log-rank tests to assess BCRfree survival associated with D4Z4 methylation. There was no significant difference in methylation level of NBL2 and D4Z4 between clinically defined aggressive and non-aggressive PCa at diagnosis. However, the methylation of D4Z4 was associated with BCR, while the methylation of NBL2 was not. In tertile analysis, patients in the highest tertile of D4Z4 methylation had an increased risk of BCR (HR = 2.17, 95% CI 1.36-3.48) compared to patients in the lower tertiles after adjustment of age, body mass index, smoking status, pack year, D'Amico risk groups and treatments. Among the four CpG sites in this region, the association was mostly attributable to the methylation of the second CpG site of D4Z4. These data suggest that higher methylation in D4Z4 was associated with worse prognosis of localized PCa patients.
AB - Global DNA methylation may affect chromosome structure and genomic stability and is involved in carcinogenesis. In this study, we aimed to investigate whether methylation of pericentromeric repeat NBL2 and subtelomeric repeat D4Z4 in peripheral blood was associated with the aggressiveness of prostate cancer (PCa). We measured the methylation status of different CpG sites of NBL2 and D4Z4 in 795 PCa patients and compared their methylation levels among patients with different Gleason Score at diagnosis. We then analyzed the association of the NBL2 and D4Z4 methylation with the risk of biochemical recurrence (BCR) in patients receiving radical prostatectomy or radiotherapy using a multivariate Cox proportional hazards model. In addition, we used the Kaplan-Meier survival function and log-rank tests to assess BCRfree survival associated with D4Z4 methylation. There was no significant difference in methylation level of NBL2 and D4Z4 between clinically defined aggressive and non-aggressive PCa at diagnosis. However, the methylation of D4Z4 was associated with BCR, while the methylation of NBL2 was not. In tertile analysis, patients in the highest tertile of D4Z4 methylation had an increased risk of BCR (HR = 2.17, 95% CI 1.36-3.48) compared to patients in the lower tertiles after adjustment of age, body mass index, smoking status, pack year, D'Amico risk groups and treatments. Among the four CpG sites in this region, the association was mostly attributable to the methylation of the second CpG site of D4Z4. These data suggest that higher methylation in D4Z4 was associated with worse prognosis of localized PCa patients.
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U2 - 10.1093/carcin/bgx064
DO - 10.1093/carcin/bgx064
M3 - Article
C2 - 28854562
AN - SCOPUS:85028434434
SN - 0143-3334
VL - 38
SP - 821
EP - 826
JO - Carcinogenesis
JF - Carcinogenesis
IS - 8
ER -