Single-Nucleotide Polymorphisms in LEP and LEPR Associated With Breast Cancer Risk: Results From a Multicenter Case-Control Study in Chinese Females

Liang Li; Xingchen Meng; Liyuan Liu; Yujuan Xiang; Fei Wang; Lixiang Yu; Fei Zhou; Chao Zheng; Wenzhong Zhou; Shude Cui; Fuguo Tian; Zhimin Fan; Cuizhi Geng; Xuchen Cao; Zhenlin Yang; Xiang Wang; Hong Liang; Shu Wang; Hongchuan Jiang; Xuening Duan; Haibo Wang; Guolou Li; Qitang Wang; Jianguo Zhang; Feng Jin; Jinhai Tang; Liang Li; Shiguang Zhu; Wenshu Zuo; Chunmiao Ye; Gengshen Yin; Zhongbing Ma; Shuya Huang; Zhigang Yu

doi:10.3389/fonc.2022.809570

Single-Nucleotide Polymorphisms in LEP and LEPR Associated With Breast Cancer Risk: Results From a Multicenter Case-Control Study in Chinese Females

Front Oncol. 2022 Feb 10:12:809570. doi: 10.3389/fonc.2022.809570. eCollection 2022.

Authors

Liang Li^{1

2

3

4}, Xingchen Meng^{1

2}, Liyuan Liu^{1

3

4}, Yujuan Xiang^{1

3

4}, Fei Wang^{1

3

4}, Lixiang Yu^{1

3

4}, Fei Zhou^{1

3

4}, Chao Zheng^{1

3

4}, Wenzhong Zhou^{1

3

4}, Shude Cui⁵, Fuguo Tian⁶, Zhimin Fan⁷, Cuizhi Geng⁸, Xuchen Cao⁹, Zhenlin Yang¹⁰, Xiang Wang¹¹, Hong Liang¹², Shu Wang¹³, Hongchuan Jiang¹⁴, Xuening Duan¹⁵, Haibo Wang¹⁶, Guolou Li¹⁷, Qitang Wang¹⁸, Jianguo Zhang¹⁹, Feng Jin²⁰, Jinhai Tang²¹, Liang Li²², Shiguang Zhu²³, Wenshu Zuo²⁴, Chunmiao Ye^{1

2}, Gengshen Yin^{1

2}, Zhongbing Ma^{1

3

4}, Shuya Huang^{1

3

4}, Zhigang Yu^{1

3

4}

Affiliations

¹ Department of Breast Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
² School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.
³ Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, China.
⁴ Shandong Provincial Engineering Laboratory of Translational Research on Prevention and Treatment of Breast Disease, Jinan, China.
⁵ Department of Breast Surgery, Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China.
⁶ Department of Breast Surgery, Shanxi Cancer Hospital, Taiyuan, China.
⁷ Department of Breast Surgery, The First Hospital of Jilin University, Changchun, China.
⁸ Department of Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
⁹ Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
¹⁰ Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Binzhou Medical University, Binzhou, China.
¹¹ Department of Breast Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China.
¹² Department of General Surgery, Linyi People's Hospital, Linyi, China.
¹³ Department of Breast Disease Center, Peking University People's Hospital, Beijing, China.
¹⁴ Department of General Surgery, Beijing Chaoyang Hospital, Beijing, China.
¹⁵ Department of Breast Disease Center, Peking University First Hospital, Beijing, China.
¹⁶ Department of Breast Center, Qingdao University Affiliated Hospital, Qingdao, China.
¹⁷ Department of Breast and Thyroid Surgery, Weifang Traditional Chinese Hospital, Weifang, China.
¹⁸ Department of Breast Surgery, The Second Affiliated Hospital of Qingdao Medical College, Qingdao Central Hospital, Qingdao, China.
¹⁹ Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
²⁰ Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China.
²¹ Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, China.
²² Department of Breast and Thyroid Surgery, Zibo Central Hospital, Zibo, China.
²³ Department of Breast Surgery, Yantai Yuhuangding Hospital, Yantai, China.
²⁴ Department of Breast Cancer Center, Shandong Cancer Hospital, Jinan, China.

Abstract

Background: Leptin (LEP) plays a physiological role through its specific receptor (LEPR) and is involved in the occurrence and development of breast cancer. Our current study aimed at determining the influence of single-nucleotide polymorphisms (SNPs) in the genes coding for LEP and LEPR on breast cancer risk.

Methods: In the present study, 963 breast cancer cases and 953 controls were enrolled. Five SNPs of LEP and two of LEPR were chosen to evaluate the correlation of selected SNPs with breast cancer susceptibility among women in northern and eastern China. Analyses were further stratified by body mass index (BMI), waist-hip rate (WHR), estrogen receptor, and progesterone receptor status. The expression patterns of risk variant-associated genes were detected by expression quantitative trait locus (eQTL) analysis with eQTLGen and The Cancer Genome Atlas database.

Results: There were significant differences between breast cancer cases and control groups in the menopausal status and family history of breast cancer. Two SNPs (rs1137101 and rs4655555) of the LEPR gene decreased overall breast cancer risk, and other five SNPs showed no significant association with breast cancer risk. rs1137101 (GA vs. GG; adjusted OR = 0.719, 95% CI = 0.578-0.894, p = 0.003) and rs4655555 (TT vs. AA; adjusted OR = 0.574, 95% CI = 0.377-0.873, p = 0.009) significantly decreased breast cancer risk after Bonferroni correction for multiple testing. In subgroup analyses, the GA and GA + AA genotypes of LEPR rs1137101 associated with decreased breast cancer risk in the subgroup of BMI ≤ 24 kg/m² or WHR ≥ 0.85 after Bonferroni correction. Furthermore, we found that the expressions of rs4655555-associated gene LEPR and leptin receptor overlapping transcript (LEPROT) were upregulated in breast cancer tumor tissues compared with adjacent normal tissues, and a higher expression of LEPR in tumor tissues was correlated with poor prognosis of breast cancer patients using The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) data.

Conclusion: Our study demonstrated that the polymorphisms rs1137101 and rs4655555 located in the LEPR gene decreased breast cancer risk in Chinese females, which might be a research-worthy bio-diagnostic marker and applied for early prediction and risk assessment of breast cancer.

Keywords: LEPR; breast cancer risk; case–control study; leptin; single-nucleotide polymorphisms.

Copyright © 2022 Li, Meng, Liu, Xiang, Wang, Yu, Zhou, Zheng, Zhou, Cui, Tian, Fan, Geng, Cao, Yang, Wang, Liang, Wang, Jiang, Duan, Wang, Li, Wang, Zhang, Jin, Tang, Li, Zhu, Zuo, Ye, Yin, Ma, Huang and Yu.