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. 2019 May;13(5):1110-1120.
doi: 10.1002/1878-0261.12470. Epub 2019 Mar 1.

A common SNP in the UNG gene decreases ovarian cancer risk in BRCA2 mutation carriers

Juan Miguel Baquero  1 , Carlos Benítez-Buelga  2 , Victoria Fernández  1 , Miguel Urioste  3   4 , Jose Luis García-Giménez  3   5 , Rosario Perona  3   6 ; CIMBA Consortium  7 ; Javier Benítez  1   3   8 , Ana Osorio  1   3
Affiliations

A common SNP in the UNG gene decreases ovarian cancer risk in BRCA2 mutation carriers

Juan Miguel Baquero et al. Mol Oncol. 2019 May.

Abstract

Single nucleotide polymorphisms (SNPs) in DNA glycosylase genes involved in the base excision repair (BER) pathway can modify breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We previously found that SNP rs34259 in the uracil-DNA glycosylase gene (UNG) might decrease ovarian cancer risk in BRCA2 mutation carriers. In the present study, we validated this finding in a larger series of familial breast and ovarian cancer patients to gain insights into how this UNG variant exerts its protective effect. We found that rs34259 is associated with significant UNG downregulation and with lower levels of DNA damage at telomeres. In addition, we found that this SNP is associated with significantly lower oxidative stress susceptibility and lower uracil accumulation at telomeres in BRCA2 mutation carriers. Our findings help to explain the association of this variant with a lower cancer risk in BRCA2 mutation carriers and highlight the importance of genetic changes in BER pathway genes as modifiers of cancer susceptibility for BRCA1 and BRCA2 mutation carriers.

Keywords: BRCA2; DNA damage; cancer risk modifier; oxidative stress susceptibility; telomere damage; uracil-DNA glycosylase.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
UNG mRNA and protein levels. (A) UNG mRNA levels in the various FBOC groups according to the presence or absence of the SNP [noncarriers (GG)/carriers (GC/CC)]. (B) UNG1 protein levels in controls (n = 10) and BRCA2 mutation carriers (n = 20) according to the presence or absence of the SNP [noncarriers (GG)/carriers (GC/CC)]. Actin levels were used to normalize for protein loading. (C) Quantification of UNG1 protein levels of the western blot shown in (B). Bars show the mean and the standard error of the mean (SEM). Numbers in brackets indicate sample size. (D) Correlation analysis between UNG1 mRNA and protein levels in the patients shown in (B). Unpaired t‐tests were performed for statistical significance in (A) and (C), Spearman's test was used to test the significance of the correlation in panel (D).
Figure 2
Figure 2
Telomere DNA damage in the various FBOC groups according to the presence or absence of the UNG SNP. (A) DNA oxidation at telomeres. (B) Detection of uracil at telomeres in FBOC patients. Bars show the mean and the SEM. Numbers in brackets indicate sample size. Mann–Whitney U‐test was used in (A), unpaired t‐test was used in (B).
Figure 3
Figure 3
Immunodetection of protein‐bound carbonyl groups in plasma samples from the FBOC series. Carbonylation levels in the different groups stratified according to the presence or absence of SNP rs34259 in UNG [noncarriers (GG)/carriers (GC/CC)]. Bars show the mean and the SEM. Numbers in brackets indicate sample size. Unpaired t‐tests were performed for statistical significance. A.U., arbitrary units.
Figure 4
Figure 4
Telomere length and percentage of short telomeres. (A) Distribution of telomere length (kb) values adjusted for age in the FBOC series according to the presence or absence of the UNG SNP [noncarriers (GG)/carriers (GC/CC)]. (B) Comparative analysis of FBOC groups regarding the percentage of short (< 3 kb) telomeres. Bars show the mean and the SEM. Numbers in brackets indicate sample size. Unpaired t‐tests were performed for statistical significance.
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References

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