title: Association of germline variation in CCNE1 and CDK2 with breast cancer risk, progression and survival among Chinese Han women.
abstract: BACKGROUND
  Somatic alterations of cyclin-dependent kinase 2 (CDK2)-cyclin E complex have been shown to contribute to breast cancer (BC) development and progression. This study aimed to explore the effects of single nucleotide polymorphisms (SNPs) in CDK2 and CCNE1 (a gene encoding G1/S specific cyclin E1 protein, formerly called cyclin E) on BC risk, progression and survival in a Chinese Han population.
  
  
  RESULTS
  We herein genotyped 6 haplotype-tagging SNPs (htSNPs) of CCNE1 and 2 htSNPs of CDK2 in 1207 BC cases and 1207 age-matched controls among Chinese Han women, and then reconstructed haplotype blocks according to our genotyping data and linkage disequilibrium status of these htSNPs. For CCNE1, the minor allele homozygotes of three htSNPs were associated with BC risk (rs3218035: adjusted odds ratio [aOR] = 3.35, 95% confidence interval [CI] = 1.69-6.67; rs3218038: aOR = 1.81, 95% CI = 1.22-2.70; rs3218042: aOR = 2.64, 95% CI = 1.31-5.34), and these three loci showed a dose-dependent manner in increasing BC risk (P(trend) = 0.0001). Moreover, the 5-SNP haplotype CCGTC, which carried none of minor alleles of the 3 at-risk SNPs, was associated with a favorable event-free survival (hazard ratio [HR] = 0.53, 95% CI = 0.32-0.90). Stratified analysis suggested that the minor-allele homozygote carriers of rs3218038 had a worse event-free survival among patients with aggressive tumours (in tumour size>2 cm group: HR = 2.06, 95% CI = 1.06-3.99; in positive lymph node metastasis group: HR = 2.41, 95% CI = 1.15-5.03; in stage II-IV group: HR = 2.03, 95% CI = 1.09-3.79). For CDK2, no significant association was found.
  
  
  CONCLUSIONS
  This study indicates that genetic variants in CCNE1 may contribute to BC risk and survival in Chinese Han population. They may become molecular markers for individual evaluation of BC susceptibility and prognosis. Nevertheless, further validation studies are needed.
authors.affiliation: Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People' Republic of China.
authors.forename: Ji-Yuan
authors.initials: JY
authors.lastname: Han
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Yun-Tao
authors.initials: YT
authors.lastname: Xie
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Zheng
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ruan
authors.forename: Ai-Ping
authors.initials: AP
authors.lastname: Song
authors.forename: Xin-Xia
authors.initials: XX
authors.lastname: Tian
authors.forename: Wei-Gang
authors.initials: WG
authors.lastname: Fang
mesh_terms: D044466:Asian People / Q000235:genetics*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002681:China; D019927:Cyclin E / Q000235:genetics*; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics*; D018450:Disease Progression; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005854:Germ Cells / Q000378:metabolism*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D015810:Linkage Disequilibrium / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D015513:Oncogene Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016016:Proportional Hazards Models; D012307:Risk Factors
chemical_list: C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2