Gamma-radiation sensitivity and polymorphisms in RAD51L1 modulate glioma risk

Liu, Yanhong; Shete, Sanjay; Wang, Li E.; El‐Zein, Randa; Etzel, Carol J.; Liang, Fu Wen; Armstrong, Georgina; Tsavachidis, Spyros; Gilbert, Mark R.; Aldape, Kenneth; Xing, Jinliang; Wu, Xifeng; Wei, Qingyi; Bondy, Melissa L.

doi:10.1093/carcin/bgq141

Cited by 11 publications

(12 citation statements)

References 38 publications

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“…Of note, a strong correlation between polymorphysms/haplotypes of the RAD51L1 gene and a g-radiation sensitive phenotype in glioma patients has recently been identified, supporting the notion that inability to repair DSBs by HR increases sensitivity to g-radiation and promotes brain tumorigenesis in humans (Liu et al, 2010).…”

Section: Discussionmentioning

confidence: 67%

Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum

et al. 2011

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Heterozygous Patched1 (Ptc1 þ /À ) mice are prone to medulloblastoma (MB), and exposure of newborn mice to ionizing radiation dramatically increases the frequency and shortens the latency of MB. In Ptc1 þ /À mice, MB is characterized by loss of the normal remaining Ptc1 allele, suggesting that genome rearrangements may be key events in MB development. Recent evidence indicates that brain tumors may be linked to defects in DNA-damage repair processes, as various combinations of targeted deletions in genes controlling cell-cycle checkpoints, apoptosis and DNA repair result in MB in mice. Non-homologous end joining (NHEJ) and homologous recombination (HR) contribute to genome stability, and deficiencies in either pathway predispose to genome rearrangements. To test the role of defective HR or NHEJ in tumorigenesis, control and irradiated Ptc1 þ / À mice with two, one or no functional Rad54 or DNA-protein kinase catalytic subunit (DNA-PKcs) alleles were monitored for MB development. We also examined the effect of Rad54 or DNA-PKcs deletion on the processing of endogenous and radiation-induced double-strand breaks (DSBs) in neural precursors of the developing cerebellum, the cells of origin of MB. We found that, although HR and NHEJ collaborate in protecting cells from DNA damage and apoptosis, they have opposite roles in MB tumorigenesis. In fact, although Rad54 deficiency increased both spontaneous and radiation-induced MB development, DNA-PKcs disruption suppressed MB tumorigenesis. Together, our data provide the first evidence that Rad54-mediated HR in vivo is important for suppressing tumorigenesis by maintaining genomic stability.

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Section: Discussionmentioning

confidence: 67%

Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum

et al. 2011

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“…The discrepancy may be attributed to differences in sample size, ethnic populations, and study design, as well as the different roles of HRR genes in diverse cancers. However, the risk implication of RAD51B variants seems to be an exception, which has been robustly replicated in different studies on breast cancer , nasopharyngeal carcinoma , glioma , and cutaneous melanoma , suggesting the significant role of RAD51B variants in cancer risk.…”

Section: Discussionmentioning

confidence: 95%

Genetic variants within microRNA‐binding site of RAD51B are associated with risk of cervical cancer in Chinese women

et al. 2016

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RAD51B plays a central role in homologous recombinational repair (HRR) of DNA double‐strand breaks (DSBs), which is important to prevent genomic instability, a hallmark of cancer. Recent studies suggested that common genetic variants of RAD51B may contribute to cancer susceptibility. In this study, we aimed to investigate whether potentially functional variants within miRNA‐binding sites of RAD51B are associated with risk of cervical cancer. A total of 1486 cervical cancer patients and 1536 cancer‐free controls were enrolled, and two genetic variants, rs963917 (A > G) and rs963918 (T > C), were genotyped in all participants. Using multivariate logistic regression analyses, we found that G allele of rs963917 conferred lower risk of cervical cancer compared to A allele (adjusted OR = 0.89, 95% CI = 0.80–0.99, P = 0.039). Similarly, rs963918 allele C was associated with a decreased risk for cervical cancer compared with allele T (adjusted OR = 0.84, 95% CI = 0.74–0.94, P = 0.004). Haplotype analyses showed that haplotype GC was also correlated with lower risk (OR = 0.83, 95% CI = 0.73–0.95, P = 0.005) compared with the most common haplotype AT. In summary, our study suggested that miRNA‐binding site genetic variants of RAD51B may modify the susceptibility to cervical cancer, which is important to identify individuals with differential risk for this malignancy and to improve the effectiveness of preventive intervention.

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“…Recent evidence suggests that several single nucleotide polymorphisms (SNPs) in the DSB repair pathway genes may be prognostic biomarkers for GBM survival and modulate gamma-radiation-induced mutagen sensitivity in glioma patients [12,13]. Genetic variants in DSB repair pathway genes have been extensively studied in multiple cancers.…”

Section: Introductionmentioning

confidence: 99%

Genetic polymorphisms of DNA double-strand break repair pathway genes and glioma susceptibility

et al. 2013

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BackgroundGenetic variations in DNA double-strand break repair genes can influence the ability of a cell to repair damaged DNA and alter an individual’s susceptibility to cancer. We studied whether polymorphisms in DNA double-strand break repair genes are associated with an increased risk of glioma development.MethodsWe genotyped 10 potentially functional single nucleotide polymorphisms (SNPs) in 7 DNA double-strand break repair pathway genes (XRCC3, BRCA2, RAG1, XRCC5, LIG4, XRCC4 and ATM) in a case–control study including 384 glioma patients and 384 cancer-free controls in a Chinese Han population. Genotypes were determined using the OpenArray platform.ResultsIn the single-locus analysis there was a significant association between gliomas and the LIG4 rs1805388 (Ex2 +54C>T, Thr9Ile) TT genotype (adjusted OR, 3.27; 95% CI, 1.87-5.71), as well as the TC genotype (adjusted OR, 1.62; 95% CI, 1.20-2.18). We also found that the homozygous variant genotype (GG) of XRCC4 rs1805377 (IVS7-1A>G, splice-site) was associated with a significantly increased risk of gliomas (OR, 1.77; 95% CI, 1.12-2.80). Interestingly, we detected a significant additive and multiplicative interaction effect between the LIG4 rs1805388 and XRCC4 rs1805377 polymorphisms with an increasing risk of gliomas. When we stratified our analysis by smoking status, LIG4 rs1805388 was associated with an increased glioma risk among smokers.ConclusionsThese results indicate for the first time that LIG4 rs1805388 and XRCC4 rs1805377, alone or in combination, are associated with a risk of gliomas.

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Gamma-radiation sensitivity and polymorphisms in RAD51L1 modulate glioma risk

Cited by 11 publications

References 38 publications

Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum

Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum

Genetic variants within microRNA‐binding site of RAD51B are associated with risk of cervical cancer in Chinese women

Genetic polymorphisms of DNA double-strand break repair pathway genes and glioma susceptibility

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