AUTHOR=Cui Jian , Luo Jiangtao , Kim Yeong C. , Snyder Carrie , Becirovic Dina , Downs Bradley , Lynch Henry , Wang San Ming 

TITLE=Differences of Variable Number Tandem Repeats in XRCC5 Promoter Are Associated with Increased or Decreased Risk of Breast Cancer in BRCA Gene Mutation Carriers

JOURNAL=Frontiers in Oncology

VOLUME=6

YEAR=2016

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2016.00092

DOI=10.3389/fonc.2016.00092

ISSN=2234-943X

ABSTRACT=<p>Ku80 is a subunit of the Ku heterodimer that binds to DNA double-strand break ends as part of the non-homologous end joining (NHEJ) pathway. Ku80 is also involved in homologous recombination (HR) <italic>via</italic> its interaction with <italic>BRCA1</italic>. Ku80 is encoded by the <italic>XRCC5</italic> gene that contains a variable number tandem repeat (VNTR) insertion in its promoter region. Different VNTR genotypes can alter <italic>XRCC5</italic> expression and affect Ku80 production, thereby affecting NHEJ and HR pathways. VNTR polymorphism is associated with multiple types of sporadic cancer. In this study, we investigated its potential association with familial breast cancer at the germline level. Using PCR, PAGE, Sanger sequencing, and statistical analyses, we compared VNTR genotypes in the <italic>XRCC5</italic> promoter between healthy individuals and three types of familial breast cancer cases: mutated <italic>BRCA1</italic> (<italic>BRCA1</italic><sup>+</sup>), mutated <italic>BRCA2</italic> (<italic>BRCA2</italic><sup>+</sup>), and wild-type <italic>BRCA1</italic>/<italic>BRCA2</italic> (<italic>BRCAx</italic>). We observed significant differences of VNTR genotypes between control and <italic>BRCA1</italic><sup>+</sup> group (<italic>P</italic> &lt; 0.0001) and <italic>BRCA2</italic><sup>+</sup> group (<italic>P</italic> = 0.0042) but not <italic>BRCAx</italic> group (<italic>P</italic> = 0.2185), and the differences were significant between control and cancer-affected <italic>BRCA1</italic><sup>+</sup> cases (<italic>P</italic> &lt; 0.0001) and <italic>BRCA2</italic><sup>+</sup> cases (<italic>P</italic> = 0.0092) but not cancer-affected <italic>BRCAx</italic> cases (<italic>P</italic> = 0.4251). Further analysis indicated that 2R/2R (OR = 1.94, 95%CI = 1.26–2.95, <italic>P</italic> = 0.0096) and 2R/1R (OR = 1.58, 95%CI = 1.11–2.26, <italic>P</italic> = 0.0388) were associated with increased risk but 1R/1R (OR = 0.55, 95%CI = 0.35–0.84, <italic>P</italic> = 0.0196) and 1R/0R (OR = 0, 95%CI = 0–0.29, <italic>P</italic> = 0.0012) were associated with decreased risk in cancer-affected <italic>BRCA1</italic><sup>+</sup> group; 2R/1R (OR = 1.94, 95%CI = 1.14–3.32, <italic>P</italic> = 0.0242) was associated with increased risk in cancer-affected <italic>BRCA2</italic><sup>+</sup> group. No correlation was observed for the altered risk between cancer-affected or -unaffected carriers and between different age of cancer diagnosis in cancer-affected carriers. The frequently observed VNTR association with in <italic>BRCA1</italic><sup>+</sup> and <italic>BRCA2</italic><sup>+</sup> breast cancer group indicates that VNTR polymorphism in the <italic>XRCC5</italic> promoter is associated with altered risk of breast cancer in <italic>BRCA1</italic><sup>+</sup> and <italic>BRCA2</italic><sup>+</sup> carriers.</p>