Tumor Biol. DOI 10.1007/s13277-014-1906-0
RESEARCH ARTICLE
Genetic variation in the major mitotic checkpoint genes and risk of breast cancer: a multigenic study on cancer susceptibility Ping Wang & Yong Wang & Haichao Yan & Qiuping Xie & Liang Zhao & Shaoming Xu & Qunzi Zhao
Received: 27 December 2013 / Accepted: 28 March 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract The mitotic checkpoint system is a mechanism essential for maintaining genomic stability and defects which have been linked to cancer development. We conducted this hospital-based case-control study to investigate whether genetic variants in three major spindle checkpoint genes (BUB3, MAD2L1, and BUB1) had any bearing on an individual risk of breast cancer (BC). A total of 462 incident BC patients and 529 cancer-free controls were enrolled in this study. Results showed that neither variants in BUB3 nor variants in MAD2L1 caused any significant effect on the risk of BC. However, the variant rs12623473 in BUB1 was significantly associated with increased BC risk with the odds ratio (OR) of 1.30 (95 % confidence interval (CI) 1.03–1.64) under the allelic model. The estimated population attributable risk of one copy of the risk allele for developing BC was 10.3 %. The bioinformatics analysis suggested that this variant may regulate the transcriptional ability of BUB1.
Keywords Breast cancer . Case-control study . Mitotic checkpoint gene . Single nucleotide polymorphism
Ping Wang and Yong Wang contributed equally to this work. P. Wang : Y. Wang : H. Yan : Q. Xie : L. Zhao : S. Xu : Q. Zhao Department of Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, 310009 Hangzhou, China Q. Zhao (*) Department of General Surgery, The Affiliated Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China e-mail: [email protected]
Introduction Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer death among women worldwide, comprising 23 % of the total new cancer cases and 14 % of the cancer deaths in 2008 [1]. In China, the incidence of BC has doubled during the past 30 years [2]. Nowadays, BC is ranked as the second most common malignancy among Chinese females, which indicates that this cancer should now be the priority for cancer prevention, early detection, and therapy in China. Chromosomal instability is thought to play an important role in the process leading to cancer [3, 4]. Most BCs show chromosomal instability resulting in aneuploidy [5]. The basis for chromosomal instability has been demonstrated to be the mitotic checkpoint [6]. Abnormal expression levels of the BUB1, MAD2L1, and other genes involved in the mitotic checkpoint have been seen both in BC cell lines and tumor tissues [7, 8]. Genetic variation in these genes may cause interindividual variation in the expression of these genes and, finally, in cancer susceptibility. Therefore, we hypothesized that genetic variants in BUB3, BUB1, and MAD2L which were major spindle checkpoint genes might be associated with the risk of BC. However, through systematic literature search, except one study which focused on the association between these variants and familiar breast cancer risk, only one association study on variants in the mitotic checkpoint genes and breast cancer risk was identified. The study reported that genotypic polymorphisms of the mitotic checkpoint genes were significantly associated with increased breast cancer risk. We conducted this hospital-based case-control study, including five loci that had not been investigated in the previous study, aiming to further understand the relationship between genetic variants in the mitotic checkpoint genes and BC risk.
Tumor Biol.
Methods
SNP selection
Ethics statement
The tag SNPs in the BUB3, MAD2L1, and BUB1 genes were selected from the HapMap project, release 24 (http://www. hapmap.org). To select the tag SNPs, the tagger tool within the Haploview software v4.2 was used, setting a minor allele frequency cutoff of 0.05 in CHB (Han Chinese) population and an r2 threshold of 0.8 [10]. In the present study, we examined six tag SNPs, three major spindle checkpoint genes, and their impact on BC risk (rs11248416, rs11248419, and rs6599657 in BUB3; rs1972014 and rs1546120 in MAD2L1; and rs12623473 in BUB1).
This study was approved by the Institutional Review Board of the Affiliated Union Hospital, together with Tongji Medical College, Huazhong University of Science and Technology; all subjects gave their written informed consent.
Subjects This hospital-based case-control study included 462 consecutive BC patients and 529 cancer-free controls between June 2009 and December 2011 from the Affiliated Union Hospital, Wuhan, China. All subjects were genetically unrelated Han Chinese females from Hubei and surrounding areas. The cases were consecutively diagnosed and histopathologically confirmed with primary BC with no restriction in regards of age or histological type. The controls were healthy individuals randomly selected from women attending the health examination clinic of the same hospital during the same period. The inclusion criteria for cases were (1) without any radiotherapy or chemotherapy before the patient’s blood was drawn and (2) without a family history of BC. The inclusion criteria for controls were (1) genetically unrelated to BC patients; (2) without a history of cancer or breast disease; (3) without any evidence of breast cancer, suspicious precancerous lesions of the breast, or other cancers upon physical examination along with sonography or mammography; and (4) frequencymatched to the cases for age (±5 years). At recruitment, a 2-ml peripheral venous blood sample and questionnaire data were collected from each subject. The criteria for determining menopause include any of the following, according to the National Comprehensive Cancer Network (NCCN) guidelines for BC: (1) prior bilateral oophorectomy; (2) age ≥60 years; (3) age
RESEARCH ARTICLE
Genetic variation in the major mitotic checkpoint genes and risk of breast cancer: a multigenic study on cancer susceptibility Ping Wang & Yong Wang & Haichao Yan & Qiuping Xie & Liang Zhao & Shaoming Xu & Qunzi Zhao
Received: 27 December 2013 / Accepted: 28 March 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract The mitotic checkpoint system is a mechanism essential for maintaining genomic stability and defects which have been linked to cancer development. We conducted this hospital-based case-control study to investigate whether genetic variants in three major spindle checkpoint genes (BUB3, MAD2L1, and BUB1) had any bearing on an individual risk of breast cancer (BC). A total of 462 incident BC patients and 529 cancer-free controls were enrolled in this study. Results showed that neither variants in BUB3 nor variants in MAD2L1 caused any significant effect on the risk of BC. However, the variant rs12623473 in BUB1 was significantly associated with increased BC risk with the odds ratio (OR) of 1.30 (95 % confidence interval (CI) 1.03–1.64) under the allelic model. The estimated population attributable risk of one copy of the risk allele for developing BC was 10.3 %. The bioinformatics analysis suggested that this variant may regulate the transcriptional ability of BUB1.
Keywords Breast cancer . Case-control study . Mitotic checkpoint gene . Single nucleotide polymorphism
Ping Wang and Yong Wang contributed equally to this work. P. Wang : Y. Wang : H. Yan : Q. Xie : L. Zhao : S. Xu : Q. Zhao Department of Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, 310009 Hangzhou, China Q. Zhao (*) Department of General Surgery, The Affiliated Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China e-mail: [email protected]
Introduction Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer death among women worldwide, comprising 23 % of the total new cancer cases and 14 % of the cancer deaths in 2008 [1]. In China, the incidence of BC has doubled during the past 30 years [2]. Nowadays, BC is ranked as the second most common malignancy among Chinese females, which indicates that this cancer should now be the priority for cancer prevention, early detection, and therapy in China. Chromosomal instability is thought to play an important role in the process leading to cancer [3, 4]. Most BCs show chromosomal instability resulting in aneuploidy [5]. The basis for chromosomal instability has been demonstrated to be the mitotic checkpoint [6]. Abnormal expression levels of the BUB1, MAD2L1, and other genes involved in the mitotic checkpoint have been seen both in BC cell lines and tumor tissues [7, 8]. Genetic variation in these genes may cause interindividual variation in the expression of these genes and, finally, in cancer susceptibility. Therefore, we hypothesized that genetic variants in BUB3, BUB1, and MAD2L which were major spindle checkpoint genes might be associated with the risk of BC. However, through systematic literature search, except one study which focused on the association between these variants and familiar breast cancer risk, only one association study on variants in the mitotic checkpoint genes and breast cancer risk was identified. The study reported that genotypic polymorphisms of the mitotic checkpoint genes were significantly associated with increased breast cancer risk. We conducted this hospital-based case-control study, including five loci that had not been investigated in the previous study, aiming to further understand the relationship between genetic variants in the mitotic checkpoint genes and BC risk.
Tumor Biol.
Methods
SNP selection
Ethics statement
The tag SNPs in the BUB3, MAD2L1, and BUB1 genes were selected from the HapMap project, release 24 (http://www. hapmap.org). To select the tag SNPs, the tagger tool within the Haploview software v4.2 was used, setting a minor allele frequency cutoff of 0.05 in CHB (Han Chinese) population and an r2 threshold of 0.8 [10]. In the present study, we examined six tag SNPs, three major spindle checkpoint genes, and their impact on BC risk (rs11248416, rs11248419, and rs6599657 in BUB3; rs1972014 and rs1546120 in MAD2L1; and rs12623473 in BUB1).
This study was approved by the Institutional Review Board of the Affiliated Union Hospital, together with Tongji Medical College, Huazhong University of Science and Technology; all subjects gave their written informed consent.
Subjects This hospital-based case-control study included 462 consecutive BC patients and 529 cancer-free controls between June 2009 and December 2011 from the Affiliated Union Hospital, Wuhan, China. All subjects were genetically unrelated Han Chinese females from Hubei and surrounding areas. The cases were consecutively diagnosed and histopathologically confirmed with primary BC with no restriction in regards of age or histological type. The controls were healthy individuals randomly selected from women attending the health examination clinic of the same hospital during the same period. The inclusion criteria for cases were (1) without any radiotherapy or chemotherapy before the patient’s blood was drawn and (2) without a family history of BC. The inclusion criteria for controls were (1) genetically unrelated to BC patients; (2) without a history of cancer or breast disease; (3) without any evidence of breast cancer, suspicious precancerous lesions of the breast, or other cancers upon physical examination along with sonography or mammography; and (4) frequencymatched to the cases for age (±5 years). At recruitment, a 2-ml peripheral venous blood sample and questionnaire data were collected from each subject. The criteria for determining menopause include any of the following, according to the National Comprehensive Cancer Network (NCCN) guidelines for BC: (1) prior bilateral oophorectomy; (2) age ≥60 years; (3) age
