Prognostic significance of promoter CpG island methylation of obesity-related genes in patients with nonmetastatic renal cell carcinoma

Julia Mendoza-Pérez; Jian Gu; Luis A. Herrera; Nizar M. Tannir; Shanyu Zhang; Surena Matin; Jose A. Karam; Christopher G. Wood; Xifeng Wu

doi:10.1002/cncr.30707

Prognostic significance of promoter CpG island methylation of obesity-related genes in patients with nonmetastatic renal cell carcinoma

Julia Mendoza-Pérez, Jian Gu, Luis A. Herrera, Nizar M. Tannir, Shanyu Zhang, Surena Matin, Jose A. Karam, Christopher G. Wood, Xifeng Wu

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

Abstract

BACKGROUND: Greater than 40% of renal cell carcinoma (RCC) cases in the United States are attributed to excessive body weight. Moreover, obesity also may be linked to RCC prognosis. However, the molecular mechanisms underlying these associations are unclear. In the current study, the authors evaluated the role of promoter methylation in obesity-related genes in RCC tumorigenesis and disease recurrence. METHODS: Paired tumors (TU) and normal adjacent (N-Adj) tissues from 240 newly diagnosed and previously untreated white patients with RCC were examined. For the discovery phase, 63 RCC pairs were analyzed. An additional 177 RCC pairs were evaluated for validation. Pyrosequencing was used to determine CpG methylation in 20 candidate obesity-related genes. An independent data set from The Cancer Genome Atlas also was analyzed for functional validation. The association between methylation and disease recurrence was analyzed using multivariate Cox proportional hazards models and Kaplan-Meier survival analysis. RESULTS: Methylation in neuropeptide Y (NPY), leptin (LEP), and leptin receptor (LEPR) was significantly higher in TU compared with N-Adj tissues (P<.0001) in both the discovery and validation groups. High methylation in LEPR was associated with an increased risk of disease recurrence (hazard ratio, 3.15; 95% confidence interval, 1.23-8.07 [P =.02]). Patients with high methylation in LEPR had a shorter recurrence-free survival compared with patients in the low-methylation group (log-rank P = 2.25 × 10⁻³). In addition, high LEPR methylation in TU was associated with more advanced features (P≤.05). Consistent with the findings of the current study, lower LEPR expression in TU compared with N-Adj tissues (P = 1.00 × 10⁻³) was found in data from The Cancer Genome Atlas. CONCLUSIONS: Somatic alterations of promoter methylation in the NPY, LEP, and LEPR genes are involved in RCC tumorigenesis. Furthermore, LEPR methylation appears to be associated with RCC recurrence. Future research to elucidate the biology underlying this association is warranted. Cancer 2017;123:3617-27.

Original language	English (US)
Pages (from-to)	3617-3627
Number of pages	11
Journal	Cancer
Volume	123
Issue number	18
DOIs	https://doi.org/10.1002/cncr.30707
State	Published - Sep 15 2017

Keywords

kidney cancer
leptin receptor (LEPR)
methylation
obesity
recurrence

ASJC Scopus subject areas

Oncology
Cancer Research

MD Anderson CCSG core facilities

Epigenomics Profiling Core Facility

Access to Document

10.1002/cncr.30707

Cite this

@article{8447952da9e64025914d4c4d5efc18b0,

title = "Prognostic significance of promoter CpG island methylation of obesity-related genes in patients with nonmetastatic renal cell carcinoma",

abstract = "BACKGROUND: Greater than 40% of renal cell carcinoma (RCC) cases in the United States are attributed to excessive body weight. Moreover, obesity also may be linked to RCC prognosis. However, the molecular mechanisms underlying these associations are unclear. In the current study, the authors evaluated the role of promoter methylation in obesity-related genes in RCC tumorigenesis and disease recurrence. METHODS: Paired tumors (TU) and normal adjacent (N-Adj) tissues from 240 newly diagnosed and previously untreated white patients with RCC were examined. For the discovery phase, 63 RCC pairs were analyzed. An additional 177 RCC pairs were evaluated for validation. Pyrosequencing was used to determine CpG methylation in 20 candidate obesity-related genes. An independent data set from The Cancer Genome Atlas also was analyzed for functional validation. The association between methylation and disease recurrence was analyzed using multivariate Cox proportional hazards models and Kaplan-Meier survival analysis. RESULTS: Methylation in neuropeptide Y (NPY), leptin (LEP), and leptin receptor (LEPR) was significantly higher in TU compared with N-Adj tissues (P<.0001) in both the discovery and validation groups. High methylation in LEPR was associated with an increased risk of disease recurrence (hazard ratio, 3.15; 95% confidence interval, 1.23-8.07 [P =.02]). Patients with high methylation in LEPR had a shorter recurrence-free survival compared with patients in the low-methylation group (log-rank P = 2.25 × 10−3). In addition, high LEPR methylation in TU was associated with more advanced features (P≤.05). Consistent with the findings of the current study, lower LEPR expression in TU compared with N-Adj tissues (P = 1.00 × 10−3) was found in data from The Cancer Genome Atlas. CONCLUSIONS: Somatic alterations of promoter methylation in the NPY, LEP, and LEPR genes are involved in RCC tumorigenesis. Furthermore, LEPR methylation appears to be associated with RCC recurrence. Future research to elucidate the biology underlying this association is warranted. Cancer 2017;123:3617-27.",

keywords = "kidney cancer, leptin receptor (LEPR), methylation, obesity, recurrence",

author = "Julia Mendoza-P{\'e}rez and Jian Gu and Herrera, {Luis A.} and Tannir, {Nizar M.} and Shanyu Zhang and Surena Matin and Karam, {Jose A.} and Wood, {Christopher G.} and Xifeng Wu",

note = "Funding Information: Supported in part by the National Institutes of Health (grant R01 CA170298) as well as the Center for Translational and Public Health Genomics and the Duncan Family Institute for Cancer Prevention and Risk Assessment at The University of Texas MD Anderson Cancer Center. Funding Information: Nizar M. Tannir has received grants, personal fees, and nonfinancial support from Bristol-Myers Squibb, Exelixis, and Novartis; personal fees and nonfinancial support from Nektar, Pfizer, Argos, and Calithera; and grants from Epizyme and Miranti for work performed outside of the current study. Jose A. Karam has acted as a paid consultant and advisory board member for Pfizer, Novartis, and EMD Serono for work performed outside of the current study. Publisher Copyright: {\textcopyright} 2017 American Cancer Society",

year = "2017",

month = sep,

day = "15",

doi = "10.1002/cncr.30707",

language = "English (US)",

volume = "123",

pages = "3617--3627",

journal = "Cancer",

issn = "0008-543X",

publisher = "John Wiley and Sons Inc.",

number = "18",

}

TY - JOUR

T1 - Prognostic significance of promoter CpG island methylation of obesity-related genes in patients with nonmetastatic renal cell carcinoma

AU - Mendoza-Pérez, Julia

AU - Gu, Jian

AU - Herrera, Luis A.

AU - Tannir, Nizar M.

AU - Zhang, Shanyu

AU - Matin, Surena

AU - Karam, Jose A.

AU - Wood, Christopher G.

AU - Wu, Xifeng

N1 - Funding Information: Supported in part by the National Institutes of Health (grant R01 CA170298) as well as the Center for Translational and Public Health Genomics and the Duncan Family Institute for Cancer Prevention and Risk Assessment at The University of Texas MD Anderson Cancer Center. Funding Information: Nizar M. Tannir has received grants, personal fees, and nonfinancial support from Bristol-Myers Squibb, Exelixis, and Novartis; personal fees and nonfinancial support from Nektar, Pfizer, Argos, and Calithera; and grants from Epizyme and Miranti for work performed outside of the current study. Jose A. Karam has acted as a paid consultant and advisory board member for Pfizer, Novartis, and EMD Serono for work performed outside of the current study. Publisher Copyright: © 2017 American Cancer Society

PY - 2017/9/15

Y1 - 2017/9/15

N2 - BACKGROUND: Greater than 40% of renal cell carcinoma (RCC) cases in the United States are attributed to excessive body weight. Moreover, obesity also may be linked to RCC prognosis. However, the molecular mechanisms underlying these associations are unclear. In the current study, the authors evaluated the role of promoter methylation in obesity-related genes in RCC tumorigenesis and disease recurrence. METHODS: Paired tumors (TU) and normal adjacent (N-Adj) tissues from 240 newly diagnosed and previously untreated white patients with RCC were examined. For the discovery phase, 63 RCC pairs were analyzed. An additional 177 RCC pairs were evaluated for validation. Pyrosequencing was used to determine CpG methylation in 20 candidate obesity-related genes. An independent data set from The Cancer Genome Atlas also was analyzed for functional validation. The association between methylation and disease recurrence was analyzed using multivariate Cox proportional hazards models and Kaplan-Meier survival analysis. RESULTS: Methylation in neuropeptide Y (NPY), leptin (LEP), and leptin receptor (LEPR) was significantly higher in TU compared with N-Adj tissues (P<.0001) in both the discovery and validation groups. High methylation in LEPR was associated with an increased risk of disease recurrence (hazard ratio, 3.15; 95% confidence interval, 1.23-8.07 [P =.02]). Patients with high methylation in LEPR had a shorter recurrence-free survival compared with patients in the low-methylation group (log-rank P = 2.25 × 10−3). In addition, high LEPR methylation in TU was associated with more advanced features (P≤.05). Consistent with the findings of the current study, lower LEPR expression in TU compared with N-Adj tissues (P = 1.00 × 10−3) was found in data from The Cancer Genome Atlas. CONCLUSIONS: Somatic alterations of promoter methylation in the NPY, LEP, and LEPR genes are involved in RCC tumorigenesis. Furthermore, LEPR methylation appears to be associated with RCC recurrence. Future research to elucidate the biology underlying this association is warranted. Cancer 2017;123:3617-27.

AB - BACKGROUND: Greater than 40% of renal cell carcinoma (RCC) cases in the United States are attributed to excessive body weight. Moreover, obesity also may be linked to RCC prognosis. However, the molecular mechanisms underlying these associations are unclear. In the current study, the authors evaluated the role of promoter methylation in obesity-related genes in RCC tumorigenesis and disease recurrence. METHODS: Paired tumors (TU) and normal adjacent (N-Adj) tissues from 240 newly diagnosed and previously untreated white patients with RCC were examined. For the discovery phase, 63 RCC pairs were analyzed. An additional 177 RCC pairs were evaluated for validation. Pyrosequencing was used to determine CpG methylation in 20 candidate obesity-related genes. An independent data set from The Cancer Genome Atlas also was analyzed for functional validation. The association between methylation and disease recurrence was analyzed using multivariate Cox proportional hazards models and Kaplan-Meier survival analysis. RESULTS: Methylation in neuropeptide Y (NPY), leptin (LEP), and leptin receptor (LEPR) was significantly higher in TU compared with N-Adj tissues (P<.0001) in both the discovery and validation groups. High methylation in LEPR was associated with an increased risk of disease recurrence (hazard ratio, 3.15; 95% confidence interval, 1.23-8.07 [P =.02]). Patients with high methylation in LEPR had a shorter recurrence-free survival compared with patients in the low-methylation group (log-rank P = 2.25 × 10−3). In addition, high LEPR methylation in TU was associated with more advanced features (P≤.05). Consistent with the findings of the current study, lower LEPR expression in TU compared with N-Adj tissues (P = 1.00 × 10−3) was found in data from The Cancer Genome Atlas. CONCLUSIONS: Somatic alterations of promoter methylation in the NPY, LEP, and LEPR genes are involved in RCC tumorigenesis. Furthermore, LEPR methylation appears to be associated with RCC recurrence. Future research to elucidate the biology underlying this association is warranted. Cancer 2017;123:3617-27.

KW - kidney cancer

KW - leptin receptor (LEPR)

KW - methylation

KW - obesity

KW - recurrence

UR - http://www.scopus.com/inward/record.url?scp=85026667118&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026667118&partnerID=8YFLogxK

U2 - 10.1002/cncr.30707

DO - 10.1002/cncr.30707

M3 - Article

C2 - 28543182

AN - SCOPUS:85026667118

SN - 0008-543X

VL - 123

SP - 3617

EP - 3627

JO - Cancer

JF - Cancer

IS - 18

ER -

Prognostic significance of promoter CpG island methylation of obesity-related genes in patients with nonmetastatic renal cell carcinoma

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

Other files and links

Fingerprint

Cite this