TY - JOUR
T1 - A variant at a potentially functional microRNA-binding site in BRIP1 was associated with risk of squamous cell carcinoma of the head and neck
AU - Liu, Hongliang
AU - Gao, Fengqin
AU - Dahlstrom, Kristina R.
AU - Li, Guojun
AU - Sturgis, Erich M.
AU - Zevallos, Jose P.
AU - Wei, Qingyi
AU - Liu, Zhensheng
N1 - Funding Information:
This study was supported by the National Institutes of Health grant R01 ES111740-11 (to Q. W.), and a start-up fund (to Q. Wei) from Duke Cancer Institute. QW was also supported from the Duke University Medical Center and the Duke Cancer Institute as part of the P30 Cancer Center Support Grant (NIH CA014236).
Publisher Copyright:
© 2015, International Society of Oncology and BioMarkers (ISOBM).
PY - 2016/6/1
Y1 - 2016/6/1
N2 - DNA double-strand breaks (DSBs) are one of the most serious forms of DNA damage to the cell, causing genomic instability and ultimately carcinogenesis. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) at the micro RNA (miRNA)-binding sites of DSB repair genes may influence cancer risk by dysregulating target gene expression. To test our hypothesis, we firstly performed functional prediction for common SNPs in DSB genes and found 12 potentially functional SNPs located at the miRNA-binding sites. We then investigated their associations with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1087 patients and 1090 cancer-free controls in a non-Hispanic white population. As a result, SNP rs7213430 in BRIP1 was found to be significantly associated with cancer risk (Ptrend = 0.021). Compared with the AA homozygotes, the G allele carriers had an increased risk of SCCHN (adjusted OR 1.16, 95 % CI 1.02–1.31). Marginal significance was found for another SNP rs15869 in BRCA2 (P = 0.053). Further, functional analyses showed that SNP rs7213430 is within the miR-101 seed-binding region, and the variant G allele could lead to significantly lower luciferase activity and BRIP1 mRNA expression, compared to the A allele with the presence of miR-101. Our results suggested that SNP rs7213430 in the 3′-UTR of BRIP1 might contribute to SCCHN susceptibility by affecting the binding activity of miR-101 and resulting in a decreased BRIP1 expression. Additional larger population and functional studies are warranted to confirm our findings.
AB - DNA double-strand breaks (DSBs) are one of the most serious forms of DNA damage to the cell, causing genomic instability and ultimately carcinogenesis. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) at the micro RNA (miRNA)-binding sites of DSB repair genes may influence cancer risk by dysregulating target gene expression. To test our hypothesis, we firstly performed functional prediction for common SNPs in DSB genes and found 12 potentially functional SNPs located at the miRNA-binding sites. We then investigated their associations with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1087 patients and 1090 cancer-free controls in a non-Hispanic white population. As a result, SNP rs7213430 in BRIP1 was found to be significantly associated with cancer risk (Ptrend = 0.021). Compared with the AA homozygotes, the G allele carriers had an increased risk of SCCHN (adjusted OR 1.16, 95 % CI 1.02–1.31). Marginal significance was found for another SNP rs15869 in BRCA2 (P = 0.053). Further, functional analyses showed that SNP rs7213430 is within the miR-101 seed-binding region, and the variant G allele could lead to significantly lower luciferase activity and BRIP1 mRNA expression, compared to the A allele with the presence of miR-101. Our results suggested that SNP rs7213430 in the 3′-UTR of BRIP1 might contribute to SCCHN susceptibility by affecting the binding activity of miR-101 and resulting in a decreased BRIP1 expression. Additional larger population and functional studies are warranted to confirm our findings.
KW - DNA double strands break
KW - Genetic susceptibility
KW - Head and neck cancer
KW - MicroRNA
KW - Polymorphism
UR - http://www.scopus.com/inward/record.url?scp=84951999318&partnerID=8YFLogxK
U2 - 10.1007/s13277-015-4682-6
DO - 10.1007/s13277-015-4682-6
M3 - Article
C2 - 26711789
AN - SCOPUS:84951999318
SN - 1010-4283
VL - 37
SP - 8057
EP - 8066
JO - Tumor Biology
JF - Tumor Biology
IS - 6
ER -