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Biochemistry, Genetics and Molecular Biology » "Advances in DNA Repair", book edited by Clark C. Chen, ISBN 978-953-51-2209-8, Published: November 18, 2015 under CC BY 3.0 license. © The Author(s).

Chapter 9

Homologous Recombination Repair Polymorphisms, Cancer Susceptibility and Treatment Outcome

By Katja Goričar and Vita Dolžan
DOI: 10.5772/59729

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Homologous Recombination Repair Polymorphisms, Cancer Susceptibility and Treatment Outcome

Katja Goričar1 and Vita Dolžan1

1. Introduction

DNA repair mechanisms are crucial for the maintenance of genome’s integrity. When DNA damage is not repaired promptly, that may pose a serious threat to genomic stability and can contribute to carcinogenesis. On the other hand, the core molecular mechanism of action in several cancer treatments including chemotherapeutic agents and radiation therapy is induction of DNA damage and the efficacy of DNA repair mechanisms may influence the outcome of cancer treatment. Genetic variability of DNA repair proteins can modify the ability to repair DNA damage and may therefore play an important role in both cancer susceptibility and the outcome of cancer treatment.

DNA damage arises from exposure to endogenous or exogenous factors, including chemotherapeutic agents and radiation therapy [1]. There are several forms of DNA damage and therefore several mechanisms involved in their repair. Complex changes such as double strand breaks (DSBs) can lead to chromosome loss, chromosomal rearrangements or apoptosis and as a result can have a significant impact on cellular processes. DSBs represent one of the most detrimental forms of DNA damage because both strands of DNA are damaged and are thus especially challenging for efficient and accurate DNA repair [2]. One of the important pathways involved in DSB repair is HRR, a complex mechanism consisting of several steps that requires coordinated interplay of various enzymes [3]. This chapter focuses on homologous recombination repair (HRR) and summarizes the current knowledge on how genetic variability in this pathway influences cancer susceptibility and treatment outcome.

2. Homologous recombination repair pathway

HRR is crucial for the repair of DSBs, but is also involved in repair of other types of DNA damage, such as interstrand crosslinks. HRR ensures complete repair of DSBs because the undamaged homologous chromosome serves as a template to repair the damage.

In the first step of HRR, MRN complex is essential for recognition of DSBs. MRN complex consists of three proteins: meiotic recombination 11 homologue (MRE11), DNA repair protein RAD50 (RAD50) and nibrin (NBN). MRN recruits different enzymes to the site of DNA damage and activates them [4]. In the beginning, the broken ends of DSBs are processed to single stranded 3’ ends. DNA repair protein RAD51 homolog 1 (RAD51) then binds to DNA and forms a nucleoprotein filament. With the help of mediator proteins such as X-ray repair cross-complementing group 3 (XRCC3) and XRCC2, RAD51 catalyses the central reaction of HRR: the search for a homologous template and strand transfer between the damaged region and the undamaged homologous chromatid. The 3’ end of the damaged strand invades the homologous chromatid and is elongated by DNA polymerase using the complementary strand of the homologous chromatid as a template, resulting in the formation of Holliday junctions. After resynthesis and ligation of the damaged region, resolvase is needed for the resolution of Holliday junctions. Resolution can lead to either crossover or non-crossover products, but it always results in two intact double-stranded DNA molecules [5].

3. Genetic variability in homologous recombination repair genes

DNA repair mechanisms can be less effective in some individuals, leading to increased cancer susceptibility. Rare mutations in DNA repair genes that result in decreased DNA repair capacity have been linked to different hereditary cancers. DNA repair capacity may also be influenced by genetic polymorphisms that were identified in these genes. In particular, common functional single nucleotide polymorphisms (SNPs) leading to amino acid substitutions as well as SNPs in promoter or miRNA binding sites may influence the activity, stability or expression of DNA repair proteins.

The majority of cancer susceptibility and pharmacogenetic studies related to HRR has focused on genetic variability of NBN, RAD51, XRCC2, and XRCC3. Most commonly investigated SNPs in these genes, their predicted function and their minor allele frequencies (MAFs) in population of European descent are presented in Table 1.

3.2. NBN

MRN complex is involved in DSB recognition in different repair pathways, not only in HRR [14], suggesting that NBN may play a crucial part in DNA repair. NBN consists of three functional regions [6]. The N-terminal region binds to phosphorylated histone H2AX (γ-H2AX) and allows the MRN complex to move close to the sites of DSBs [6]. The central region is involved in signal transduction for damage response, while the C-terminal region is involved in MRE11 binding.

Gene rs number Polymorphism Location Predicted function MAFa
NBN rs1805794p.Glu185GlnExon, nonsynonymousAffects interaction with BRCA1 [6]0.304
rs709816p.Asp399AspExon, synonymousAffects splicing [7]0.357
rs1063054c.*1209A>C3’ UTRAffects miRNA binding [8]0.317
rs2735383c.*541G>C3’ UTRAffects miRNA binding [8-10]0.312
RAD51 rs1801320c.-98G>C5’ UTREnhances promoter activity [11]0.067
rs1801321c.-61G>T5’ UTREnhances promoter activity [11]0.467
XRCC3 rs1799794c.-316A>G5’ UTRAffects transcription factor binding [8]0.184
rs861539p.Thr241MetExon, nonsynonymousMight affect protein structure or function [12]0.433
XRCC2 rs3218536p.Arg188HisExon, nonsynonymousModified sensitivity to DNA damaging agents [13]0.094

Table 1.

Most commonly investigated HRR SNPs and their predicted function.

[i] - aMAF: minor allele frequency in population of European descent included in HapMap project (HapMap-CEU)

Mutations in the NBN gene may lead to autosomal recessive disorder Nijmegen breakage syndrome, presenting with immunodeficiency, increased cancer risk and radiation sensitivity [6]. Rare NBN mutations were associated with chromosomal instability and increased susceptibility to cancer [15] and are presented in Table 2. The most common is a deletion of five nucleotides (675del5), common in Slavic populations [16], that leads to protein truncation [17].

Mutation rs number Predicted function
Asp95Asnrs61753720May affect protein-protein interactions [18], not highly damaging [19]
Ile171Valrs61754966Affects protein structure and protein-protein interactions [20]
Arg215Trprs61753718Impairs histone γ-H2AX binding [4]
Pro266Leurs769420Probably damaging effect [8]
657del5Leads to protein truncation [17]

Table 2.

Most common mutations in the NBN gene.

Besides rare mutations, several common SNPs have been described in both the coding region and the regulatory regions of NBN gene (Table 1). By far the most frequently investigated polymorphism is NBN rs1805794 (p.Glu185Gln) that leads to amino acid change in BRCA1 C-terminal domain [6] and could therefore affect protein-protein interactions with other HRR proteins. Polymorphic rs1805794 C allele was previously associated with decreased DNA damage detected with comet assay in healthy individuals [21]. It was also shown to modify the frequencies of chromatid-type aberrations [22]. NBN rs709816 (p.Asp399Asp) is a synonymous SNP that does not change the amino acid sequence in the central region of NBN. Two other NBN SNPs that may be functionally important, rs2735383 (c.*541G>C) and rs1063054 (c.*1209A>C), are located in the 3’ untranslated region (UTR). Rs1063054 was predicted to affect miRNA binding, but that was not yet validated [4, 8]. On the other hand, studies have already shown that rs2735383 modifies miR-629 and miR-509-5p binding and the polymorphic C allele was associated with lower transcriptional activity [9, 10].

3.2. RAD51

RAD51 is a key enzyme of HRR that has both DNA binding and ATPase activities. It interacts with many proteins, for example RAD51 paralogs, BRCA1, BRCA2 and RAD54 [23]. Several SNPs have been described in RAD51 gene, but only few are located in the coding region. On the other hand, there are SNPs in the 5’ UTR that may affect both gene transcription and protein expression, such as RAD51 rs1801320 (c.-98G>C) and rs1801321 (c.-61G>T) that were reported to increase promoter activity [11, 24]. RAD51 rs1801320 polymorphism was also associated with protein over-expression and increased DNA repair [11]. The polymorphic rs1801321 allele facilitates binding of a transcription factor, thus increasing the transcription of the RAD51 gene [24]. This polymorphism was associated with decreased DNA damage detected with comet assay in healthy individuals [21] and lower amount of gamma radiation-induced chromatid breaks [24], suggesting a protective effect.

3.3. XRCC3

XRCC3 is one of XRCC proteins involved in the protection of cell from ionizing radiation and belongs to the RAD51 family [25]. XRCC3 deficiency affects RAD51 foci formation and leads to increased genetic instability and sensitivity to DNA damaging agents [26].

Only a few putatively functional SNPs have been described in the XRCC3 gene. Among them, non-synonymous polymorphism rs861539 (p.Thr241Met) and rs1799794 (c.-316A>G) polymorphism in 5’ UTR were the most frequently studied. XRCC3 rs861539 changes the amino acid residue, which could affect protein structure or function [12]. Polymorphic rs861539 allele was previously associated with decreased DNA damage detected with comet assay in healthy individuals [21] and had a protective effect against chromosomal aberrations [27], but not in all studies [28].

3.4. XRCC2

XRCC2 is also one of the RAD51 paralogs, necessary for successful HRR. It is essential in the early stages of HRR for the formation of RAD51 foci, but it does not require ATP binding [29]. Studies have shown that XRCC2 deficiency leads to defects in RAD51 foci formation, markedly decreased HRR and increased DNA damage, as well as hypersensitivity to radiation [29-31].

Among SNPs that have been described in XRCC2, the only non-synonymous rs3218536 (p.Arg188His) polymorphism attracted the most attention, despite its relatively low MAF and very few individuals carrying two polymorphic alleles. A deletion or a non-conservative substitution in the position 188 markedly increased sensitivity to mitomycin C induced DNA damage, but the common Arg188His substitution only had a small influence on damage sensitivity [32]. As the variant XRCC2 188His allele was associated with increased resistance to cisplatin induced DNA damage, it was suggested that it could be associated with increased DNA repair capacity [13]. The observed differences could be partly due to the use of different DNA damaging agents. It was suggested that lesions caused by different agents could require more precise regulation of protein expression to reach full repair potential [13].

4. Genetic variability in HRR and cancer susceptibility

Due to important role of DSBs in carcinogenesis, several studies have investigated the role of HRR SNPs in cancer susceptibility. To overcome the problem of non-concordant effects observed in some studies, several meta-analyses have been performed. Meta-analyses have the advantage of larger sample sizes and better statistical power. Their results suggested that HRR SNPs may contribute to cancer susceptibility, but their role may not be the same in all cancer types or in all populations, especially as MAFs can differ substantially for some polymorphisms. Another shortcoming of the meta analyses is that gene-gene and gene-environmental interactions could modify the role of SNPs, but the results of meta-analyses are usually not adjusted for confounders. In addition, it is difficult to perform meta-analyses in rare cancers.

4.1. NBN

Genetic variability in NBN was associated with susceptibility to different hematological and solid tumors. Several meta-analyses have been published to date, showing that NBN mutations and polymorphisms may have different effects in different cancer types (Table 3).

Mutation / SNP Reference N of studies N of cases/controls Cancer type Major observation*
Ile171ValBogdanova, 2008 [33]42954/2531BreastNo association
Gao, 2013 [4]104516/9951OverallIncreased risk
53301/3904BreastNo association
2182/720LymphomaIncreased risk
Zhang, 2012 [34]53273/4004BreastNo association
Arg215TrpGao, 2013 [4]96728/9508OverallIncreased risk
657del5Zhang, 2012 [34]97534/14034BreastIncreased risk
Zhang, 2013 [35]1025365BreastIncreased risk
Gao, 2013 [4]2115184/54081OverallIncreased risk
109091/15154BreastIncreased risk
51053/9524LymphomaIncreased risk
23440/2490ProstateIncreased risk
rs1805794Vineis, 2009 [36]4∑4825BladderIncreased risk
Lu, 2009 [37]179734/10325OverallBorderline increased risk
64595/3603BreastNo association
3605/639LungNo association
31446/1452BladderNo association
Stern, 2009 [38]136348/6752BladderModestly increased risk
Wang, 2010 [39]104452/5665BreastDecreased risk
Not credible, some mistakes [40]
Wang, 2013 [41]62348/2401LungIncreased risk
Yao, 2013
146642/7138BreastNo association
He, 2014 [43]4817159/22002
OverallNo association
72837/2973Urinary systemIncreased risk
51682/2213Digestive systemDecreased risk
Zhang, 2014 [44]83542/4210Urinary system cancerIncreased risk, especially in bladder cancer
Gao, 2013 [4]4218901/21430No association in subgroup analysis by cancer type, heterogeneity too big for overall analysis
rs2735383Gao, 2013 [4]137561/8432OverallIncreased risk
42915/3035LungIncreased risk
rs1063054Gao, 2013 [4]92757/5796OverallIncreased risk

Table 3.

Observed influence of NBN genetic variability on cancer risk in meta-analyses.

[i] - *the direction of association for the mutated or polymorphic allele; ∑ - the total number of cases and controls

Rare mutations in the NBN gene have a more deleterious effect on the gene function and therefore have a bigger influence on cancer risk [4]. Even though the results of individual studies differed, several meta-analyses observed similar influence of various NBN mutations on cancer risk (Table 3). NBN 657del5 mutation was associated with increased overall cancer risk, as well as increased risk for breast cancer, prostate cancer, and lymphoma [4, 34, 35]. Interestingly, Ile171Val mutation did not predispose to increased breast cancer risk [4, 33, 34], but it was associated with overall increased risk of cancer and increased lymphoma risk [4]. The results of the meta-analysis showed that Arg215Trp mutation also significantly increased the overall cancer risk, in contrast with Asp95Asn and Pro266Leu mutations that were not associated with increased cancer risk [4].

Most of the meta-analyses investigating the role of NBN polymorphisms in cancer susceptibility were limited to the non-synonymous rs1805794 SNP (Table 3). Most studies have confirmed that polymorphic allele modestly increases bladder cancer risk [36, 38, 43]. The results in other cancer types were more ambiguous as some studies observed an association with increased cancer risk, but several did not (Table 3). Interestingly, in one meta-analysis decreased risk was observed for cancers of digestive system [43]. Decreased risk was also reported in some studies in rare cancer types such as acute myeloid leukemia [45] or osteosarcoma [46]. The observed discrepancies could be due to large heterogeneity between studies. Also NBN genotype distribution differs among populations, as the variant rs1805794 C allele is more common in some populations [21, 47]. Therefore it is not surprising that meta-analyses observed significant influence of NBN SNPs only in specific subgroups: only in Caucasians [37], only in Asians [41], or only among smokers [38]. Further studies should pay special attention to these differences as they could help explain discrepancies among studies. As the effect of a particular SNP may differ among cancer types, analyses should be stratified by cancer type. However, this can present a problem in rare cancer types, as it may be difficult to achieve sufficient power.

Among other NBN SNPs, one meta-analysis included two SNPs in the 3’ UTR, rs2735383 and rs1063054. The results suggested that both SNPs contribute to increased overall cancer risk [4]. However, when the analysis was stratified by cancer type, rs2735383 was only associated with increased lung cancer risk, but no significant association with bladder, nasopharyngeal cancer or leukemia was observed. NBN rs709816 was not associated with modified cancer risk in any of the studies [17].

4.2. RAD51

RAD51 rs1801320 is the most studied polymorphism in this gene despite its relatively low MAF. Several meta-analyses were published on the influence of rs1801320 on breast cancer risk until 2011, but they were mostly inconclusive [48-52]. Several shortcomings in the analyses associated with data and inclusion of these studies were later noted [53], suggesting that many of these studies were unreliable. More recent meta-analyses are presented in Table 4. Some suggested that rs1801320 may increase breast cancer susceptibility [54, 55], but one of the studies suggested a potential role of this polymorphism only in individuals with BRCA2 mutations [56]. BRCA2 directly interacts with RAD51 and influences intracellular transport as well as function of RAD51 [57], thus playing an important role in HRR, so these observations are biologically plausible.

RAD51 rs1801320 SNP was also associated with increased overall cancer risk in the two largest meta-analyses that included more than 40 individual studies [54, 55], however no association was observed in an earlier study [56]. Increased risk for several cancer types, including hematological malignancies, ovarian, colorectal, and endometrial cancer was observed in a recent study [55], but not all were replicated in other studies (Table 4).

Another RAD51 polymorphism, rs1801321 was investigated in only one meta-analysis and even though overall cancer risk was not modified [54], the decreased risk in carriers of polymorphic allele for head and neck cancer confirmed the results of previous studies [24]. Decreased breast cancer risk was also observed in carriers of polymorphic allele [58]. The suggested protective role of rs1801321 is in concordance with the described biological effect of this polymorphism.

Reference N of studies N of cases/controls Cancer type Major observation*
He, 2014 [59]102656/3725Myelodysplastic syndrome and acute leukemiaNo association
3726/604Myelodysplastic syndromeIncreased risk
Wang, 2013 [56]3919068/22630OverallNo association
71605/3121Acute myeloid leukemiaNo association
1411709/11291BreastNo association
62388/4411OvarianNo association
Cheng, 2014 [60]226836/8507OverallNo association
41237/1340Squamous cell carcinoma of the head and neckIncreased risk
4753/720ColorectalNo association
52001/2420OvarianNo association
92845/4027Acute leukemiaNo association
Zhao, 2014 [54]4219142/20363OverallIncreased risk
1711716/9839BreastIncreased risk
Shi, 2014 [61]102648/4369OvarianNo association
Li, 2014 [62]61764/3469Acute myeloid leukemiaNo association
Zhang, 2014 [55]4528956/28372OverallIncreased risk
1919171/17198BreastIncreased risk
72169/3629Hematological malignanciesIncreased risk
43598/3002OvarianIncreased risk
41202/1216Head and neckNo association

Table 4.

Observed influence of RAD51 rs1801320 on cancer risk in meta-analyses.

[i] - *the direction of association for the polymorphic allele

4.3. XRCC3

XRCC3 is by far the most studied HRR gene in cancer susceptibility studies. More than 50 meta-analyses focusing on XRCC3 rs861539 SNP have been published, so only recent studies published in 2014 are presented in Table 5. The polymorphic rs861539 allele was associated mostly with increased breast and bladder cancer risk, but decreased lung or skin cancer risk [63-65]. An interesting observation is almost consistently observed increased cancer risk in carriers of polymorphic allele from Asian populations, while usually no association was observed in Caucasian populations or when different populations were combined.

Reference N of studies N of cases/controls Cancer type Major observation*
Mao, 2014 [66]3623812/25349BreastSlightly increased risk, especially in Asians
Xing, 2014 [67]83215/3106LungNo association
Yuan, 2014 [12]45173/7800OvarianNo association
Feng, 2014 [68]83455/4435GliomaNo association
Li, 2014 [69]51507/3623LarynxNo association
Adel Fahmideh, 2014 [70]53374/3734GliomaNo association
Chen, 2014 [26]154329/7291OverallNo association
82056/3920Non-melanoma skin cancerDecreased risk
51324/2209Basal cell carcinomaDecreased risk
3732/1711Squamous cell carcinomaDecreased risk
Qin, 2014 [71]92209/3269Gastric
No overall, association, increased risk in Asians
Yu, 2014 [72]6723/1399ThyroidNo overall association, increased risk in Caucasians
Yan, 2014 [73]71070/1850LeukemiaNo overall association, increased risk in Asians
Yan, 2014 [74]73635/5473OvarianNo association
Qin, 2014 [75]152339/4162LeukemiaNo overall association, increased risk in acute myeloid leukemia
Wang, 2014 [76]122209/3269GastricNo overall association, decreased risk in Asians
Du, 2014 [77]237777/9868Overall (Chinese mainland population)Increased risk, especially cervical and nasopharyngeal cancer
Wang, 2014 [78]104136/5233GliomaNo overall association, increased risk in Asians
Liu, 2014 [79]134984/7472Brain tumorsNo overall association, increased risk in Asians
Ma, 2014 [80]185667/7609BladderIncreased risk
Peng, 2014 [81]165608/6197BladderIncreased risk

Table 5.

Observed influence of XRCC3 rs861539 on cancer risk in recent meta-analyses.

[i] - *the direction of association for the polymorphic allele

Only a few meta-analyses were performed for XRCC3 rs1799794. This polymorphism in 5’UTR was associated with increased overall and breast cancer risk in earlier studies [64, 82], but the association with breast cancer was not confirmed [83] and a decreased ovarian cancer risk was observed in a more recent meta-analysis [12].

4.4. XRCC2

The majority of cancer susceptibility studies focused solely on the XRCC2 rs3218536 SNP. Different types of cancer were investigated, but most studies were performed in breast and ovarian cancer. Recent meta-analyses summarized in Table 6 tried to overcome the discrepancies observed between individual studies [61, 84-86]. All meta-analyses observed an association of the polymorphic rs3218536 allele with decreased ovarian cancer risk [61, 84, 86]. On the other hand, no association with breast cancer risk was observed in the most recent meta-analyses [61, 84, 86], confirming the results of a previous meta-analysis [85]. Although overall cancer risk was also not significantly affected by XRCC2 rs3218536 [86], it was suggested that different cancer types should be evaluated separately [84]. However, a conclusive role of XRCC2 rs3218536 in other cancer types is still difficult to ascertain, due to the limited number of studies investigating a particular cancer. Nevertheless, polymorphic XRCC2 rs3218536 could be associated with increased risk for cancer of upper aerodigestive tract [84].

Apart from separate evaluation of different cancer types, further studies should investigate the possible interactions that could modify the role of XRCC2 SNPs. Several studies on breast cancer reported an association only in specific subgroups of patients, suggesting that besides genetic variability, also environmental factors and gene-environment interactions could contribute to cancer risk. Such interactions could also help to explain the effect of low penetrance variants on cancer risk.

Reference N of studies N of cases/controls Cancer type Major observation*
Yu, 2010 [85]1618341/19028BreastNo association
He, 2014 [84]1417420/17811BreastNo association
63035/5554OvarianDecreased risk
3499/583Upper aerodigestive tractIncreased risk
Shi, 2014 [61]93279/5934OvarianDecreased risk
Zhang, 2014 [86]3326320/28862OverallNo association
1217230/16485BreastNo association
63035/5554OvarianDecreased risk

Table 6.

Observed influence of XRCC2 rs3218536 on cancer risk in meta-analyses.

[i] - *the direction of association for the polymorphic allele

5. Genetic variability in HRR and cancer treatment outcome

Cancer treatment is often associated with severe adverse effects, however there is considerable interindividual variability regarding the occurrence and severity of adverse effects and regarding treatment efficacy. As cancer treatment is usually based on the use of chemotherapeutic agents and radiation therapy, whose cytotoxic effect results from their ability to induce DNA damage, pharmacogenetic factors such as polymorphisms in DNA repair pathways can contribute to observed differences.

Different agents may cause different forms of DNA damage. DSBs can occur due to the formation of strand crosslinks after treatment with alkylating and platinum-based compounds. Mechanisms involved in DSB repair may also lead to increased sensitivity to topoisomerase inhibitors such as camptothecines, anthracycline, and etoposide. DSB repair may be also important for the repair of radiation-induced DNA damage. Genetic variability of HRR may thus play a role in resistance to chemotherapy, in treatment efficacy and in occurrence of treatment related toxicities.

There are a lot less pharmacogenetic studies investigating the role of genetic variability in HRR in cancer treatment outcome compared to studies on cancer susceptibility. In addition, many studies are small and/or inconclusive and the shortcoming of most of the studies is that DNA repair capacity itself was not measured. Most pharmacogenetic studies focused on XRCC3 polymorphisms and were predominantly investigating their influence on treatment with platinum compounds. XRCC3 rs861539 was associated with shorter survival in ovarian and colorectal cancer [87, 88]. Most studies were however performed in non-small cell lung cancer (NSCLC), where XRCC3 rs861539 was associated with better response rate. Even though this effect was not observed in all the studies, recent meta-analyses confirmed the possible prognostic value of XRCC3 rs861539 in response to cisplatin-based chemotherapy in NSCLC patients (Table 7). Although individual studies observed the association of this SNP with longer overall survival of NSCLC patients [89, 90], that was not confirmed in meta-analyses [91-93]. Several studies also observed an association of XRCC3 rs861539 with decreased toxicity of platinum compounds in malignant mesothelioma, colorectal cancer and other malignancies [94, 95]. XRCC3 rs1799794 was also associated with decreased odds of developing treatment related toxicities in malignant mesothelioma [95]. Some of the discrepancies observed between studies could be explained by different chemotherapy regimens used in different cancer types.

Reference N of studies N of cases Major observation*
Shen, 2013 [92]71186Better response to chemotherapy, no significant influence on overall survival
Qiu, 2013 [91]81289Better response to chemotherapy, no significant influence on overall survival
Zhang, 2013 [93]71514No significant influence on overall survival

Table 7.

Meta-analyses of XRCC3 rs861539 and treatment outcome in non-small cell lung cancer.

[i] - *the direction of association for the polymorphic allele

The role of genetic variability in other HRR genes in cancer treatment outcome is currently not well established. Pharmacogenetic studies of other HRR genes were limited to individual studies in particular cancer types. NBN polymorphisms have been associated with increased treatment-related toxicity of gemcitabine-platinum combination chemotherapy in patients with malignant mesothelioma [95]. On the other hand, NBN rs1805794 was associated with longer progression-free survival in NSCLC patients treated with platinum-based chemotherapy, suggesting it might serve as a favourable prognostic factor [96].

RAD51 rs1801320 and rs1801321 polymorphisms were also associated with altered survival in NSCLC and cervical cancer patients [97-99], but no prognostic role was observed in malignant mesothelioma or sarcoma patients [95, 100].

Similar to other HRR genes, the potential influence of XRCC2 on cancer treatment outcome was not studied as often as cancer risk. The low MAF of XRCC2 rs3218536 could be a part of the reason why there is a lack of studies regarding treatment outcome. XRCC2 rs3218536 was associated with decreased survival in pancreatic cancer and NSCLC patients [99, 101], but the association was significant only in specific subgroups of patients. In pancreatic cancer patients, treated with chemotherapy and radiation, the polymorphic XRCC2 rs3218536 allele was associated with decreased survival only in patients treated with 5-fluorouracil based chemoradiation, but not in patients treated with gemcitabine based chemoradiation [101]. These differences further support observations that the effect of HRR polymorphisms may depend on the type of DNA damage.

Radiation therapy is used for treatment of up to 50% of cancer patients [102]. Adverse events are common and affect patients’ quality of life [103]. They occur mainly locally in irradiated sites and therefore vary between cancer types. Acute toxicities affect rapidly proliferating tissues, but are usually transient and reversible [102]. Erythema and dermatitis are common skin acute adverse events, radiation pneumonitis is a typical complication in lung cancer, while urinary and bowel toxicities occur in prostate cancer.

The new field of radiogenomics aims to identify SNPs associated with radiation toxicity that could be used for personalized radiation therapy of cancer patients, for example patients with low risk for adverse events could receive higher doses of radiation [103]. As DSBs represent the most harmful effect of radiation, several studies have been published regarding HRR SNPs and radiation toxicity.

NBN polymorphisms did not influence toxicity in prostate, breast or lung cancer [99, 104, 105], but NBN rs1805794 was associated with oral mucositis in head and neck cancer patients treated with radiation or chemoradiation [106]. RAD51 rs1801320 was also associated with toxicity in head and neck cancer in one study [107], as well as radiation pneumonitis in lung cancer patients [99]. Other studies did not report any association of RAD51 SNPs and radiation toxicity [104, 108-110]. XRCC2 rs3218536 was not associated with radiation toxicity in any of the studies [99, 104, 111]. Numerous studies investigated the role of XRCC3 poymorphisms in radiation toxicity, but the results are not conclusive. Several studies found no association [99, 105-107, 109, 111-113], but carriers of polymorphic XRCC3 rs1799794 allele had more toxicity after radiation treatment of prostate cancer [104, 114] and XRCC3 rs861539 was associated with increased radiation toxicity in nasopharyngeal cancer [115, 116].

Comparison of radiogenomics studies is difficult, as they were performed in different cancer types treated with different radiation therapy protocols, sometimes in combination with chemotherapy. Additionally, different toxicities were selected as endpoints. Nevertheless, the published data suggest the impact of some of the HRR polymorphisms on the outcomes of radiation therapy, however meta-analyses are needed to validate these observations.

6. Conclusions

The combined evidence from different studies and meta-analyses suggests that SNPs in HRR genes contribute to carcinogenesis and could serve as markers of cancer susceptibility. As HRR proteins often interact in DNA repair, future studies should evaluate if combinations of SNPs in different HRR genes may serve as a better predictor of susceptibility to various cancers.

Cancer treatments are often characterized by a narrow therapeutic index and a balance between the desired therapeutic effect and the acceptable treatment-related toxicity has to be achieved. In the future, the improved understanding of the role of HRR genetic variability in the response to treatment of a particular cancer with a particular chemotherapeutic regimen could contribute to identification of predictive or prognostic biomarkers that could help to stratify patients based on their risk for adverse events and guide treatment selection. Thus, treatment from which a particular patient would benefit the most could be selected.

In conclusion, genetic variability in HRR may modify DNA repair capacity and may therefore play an important role in both cancer susceptibility and the outcome of cancer treatment. A better understanding of the role of SNPs in HRR genes in different cancers and cancer treatments is however needed before they could be employed as markers of cancer susceptibility or treatment outcome in personalized medicine.


1 - Wood RD, Mitchell M, Sgouros J, Lindahl T. Human DNA repair genes. Science 2001;291(5507): 1284-1289.
2 - Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA. DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 2008;8(3): 193-204.
3 - McHugh PJ, Spanswick VJ, Hartley JA. Repair of DNA interstrand crosslinks: molecular mechanisms and clinical relevance. Lancet Oncol 2001;2(8): 483-490.
4 - Gao P, Ma N, Li M, Tian QB, Liu DW. Functional variants in NBS1 and cancer risk: evidence from a meta-analysis of 60 publications with 111 individual studies. Mutagenesis 2013;28(6): 683-697.
5 - Li X, Heyer WD. Homologous recombination in DNA repair and DNA damage tolerance. Cell Res 2008;18(1): 99-113.
6 - Kobayashi J, Antoccia A, Tauchi H, Matsuura S, Komatsu K. NBS1 and its functional role in the DNA damage response. DNA Repair (Amst) 2004;3(8-9): 855-861.
7 - Yuan HY, Chiou JJ, Tseng WH, Liu CH, Liu CK, Lin YJ, et al. FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization. Nucleic Acids Res 2006;34(Web Server issue): W635-641.
8 - Xu Z, Taylor JA. SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies. Nucleic Acids Res 2009;37(Web Server issue): W600-605.
9 - Yang L, Li Y, Cheng M, Huang D, Zheng J, Liu B, et al. A functional polymorphism at microRNA-629-binding site in the 3'-untranslated region of NBS1 gene confers an increased risk of lung cancer in Southern and Eastern Chinese population. Carcinogenesis 2012;33(2): 338-347.
10 - Zheng J, Zhang C, Jiang L, You Y, Liu Y, Lu J, et al. Functional NBS1 polymorphism is associated with occurrence and advanced disease status of nasopharyngeal carcinoma. Mol Carcinog 2011;50(9): 689-696.
11 - Hasselbach L, Haase S, Fischer D, Kolberg HC, Sturzbecher HW. Characterisation of the promoter region of the human DNA-repair gene Rad51. Eur J Gynaecol Oncol 2005;26(6): 589-598.
12 - Yuan C, Liu X, Yan S, Wang C, Kong B. Analyzing association of the XRCC3 gene polymorphism with ovarian cancer risk. Biomed Res Int 2014;2014: 648137.
13 - Danoy P, Sonoda E, Lathrop M, Takeda S, Matsuda F. A naturally occurring genetic variant of human XRCC2 (R188H) confers increased resistance to cisplatin-induced DNA damage. Biochem Biophys Res Commun 2007;352(3): 763-768.
14 - van den Bosch M, Bree RT, Lowndes NF. The MRN complex: coordinating and mediating the response to broken chromosomes. EMBO Rep 2003;4(9): 844-849.
15 - Nijmegen breakage syndrome. The International Nijmegen Breakage Syndrome Study Group. Arch Dis Child 2000;82(5): 400-406.
16 - Varon R, Seemanova E, Chrzanowska K, Hnateyko O, Piekutowska-Abramczuk D, Krajewska-Walasek M, et al. Clinical ascertainment of Nijmegen breakage syndrome (NBS) and prevalence of the major mutation, 657del5, in three Slav populations. Eur J Hum Genet 2000;8(11): 900-902.
17 - Berardinelli F, di Masi A, Antoccia A. NBN Gene Polymorphisms and Cancer Susceptibility: A Systemic Review. Curr Genomics 2013;14(7): 425-440.
18 - Varon R, Reis A, Henze G, von Einsiedel HG, Sperling K, Seeger K. Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL). Cancer Res 2001;61(9): 3570-3572.
19 - Cerosaletti KM, Morrison VA, Sabath DE, Willerford DM, Concannon P. Mutations and molecular variants of the NBS1 gene in non-Hodgkin lymphoma. Genes Chromosomes Cancer 2002;35(3): 282-286.
20 - Zhang Y, Zhou J, Lim CU. The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control. Cell Res 2006;16(1): 45-54.
21 - Goricar K, Erculj N, Zadel M, Dolzan V. Genetic polymorphisms in homologous recombination repair genes in healthy Slovenian population and their influence on DNA damage. Radiol Oncol 2012;46(1): 46-53.
22 - Musak L, Soucek P, Vodickova L, Naccarati A, Halasova E, Polakova V, et al. Chromosomal aberrations in tire plant workers and interaction with polymorphisms of biotransformation and DNA repair genes. Mutat Res 2008;641(1-2): 36-42.
23 - Thacker J. The RAD51 gene family, genetic instability and cancer. Cancer Lett 2005;219(2): 125-135.
24 - Lu J, Wang LE, Xiong P, Sturgis EM, Spitz MR, Wei Q. 172G>T variant in the 5' untranslated region of DNA repair gene RAD51 reduces risk of squamous cell carcinoma of the head and neck and interacts with a P53 codon 72 variant. Carcinogenesis 2007;28(5): 988-994.
25 - Thacker J, Zdzienicka MZ. The XRCC genes: expanding roles in DNA double-strand break repair. DNA Repair (Amst) 2004;3(8-9): 1081-1090.
26 - Chen X, Wang Z, Yan Y, Li P, Yang Z, Qin L, et al. XRCC3 C18067T polymorphism contributes a decreased risk to both basal cell carcinoma and squamous cell carcinoma: evidence from a meta-analysis. PLoS One 2014;9(1): e84195.
27 - Kundu M, Ghosh P, Mitra S, Das JK, Sau TJ, Banerjee S, et al. Precancerous and non-cancer disease endpoints of chronic arsenic exposure: the level of chromosomal damage and XRCC3 T241M polymorphism. Mutat Res 2011;706(1-2): 7-12.
28 - Vodicka P, Kumar R, Stetina R, Sanyal S, Soucek P, Haufroid V, et al. Genetic polymorphisms in DNA repair genes and possible links with DNA repair rates, chromosomal aberrations and single-strand breaks in DNA. Carcinogenesis 2004;25(5): 757-763.
29 - O'Regan P, Wilson C, Townsend S, Thacker J. XRCC2 is a nuclear RAD51-like protein required for damage-dependent RAD51 focus formation without the need for ATP binding. J Biol Chem 2001;276(25): 22148-22153.
30 - Johnson RD, Liu N, Jasin M. Mammalian XRCC2 promotes the repair of DNA double-strand breaks by homologous recombination. Nature 1999;401(6751): 397-399.
31 - Griffin CS, Simpson PJ, Wilson CR, Thacker J. Mammalian recombination-repair genes XRCC2 and XRCC3 promote correct chromosome segregation. Nat Cell Biol 2000;2(10): 757-761.
32 - Rafii S, O'Regan P, Xinarianos G, Azmy I, Stephenson T, Reed M, et al. A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer. Hum Mol Genet 2002;11(12): 1433-1438.
33 - Bogdanova N, Schurmann P, Waltes R, Feshchenko S, Zalutsky IV, Bremer M, et al. NBS1 variant I171V and breast cancer risk. Breast Cancer Res Treat 2008;112(1): 75-79.
34 - Zhang ZH, Yang LS, Huang F, Hao JH, Su PY, Sun YH. Current evidence on the relationship between two polymorphisms in the NBS1 gene and breast cancer risk: a meta-analysis. Asian Pac J Cancer Prev 2012;13(11): 5375-5379.
35 - Zhang G, Zeng Y, Liu Z, Wei W. Significant association between Nijmegen breakage syndrome 1 657del5 polymorphism and breast cancer risk. Tumour Biol 2013;34(5): 2753-2757.
36 - Vineis P, Manuguerra M, Kavvoura FK, Guarrera S, Allione A, Rosa F, et al. A field synopsis on low-penetrance variants in DNA repair genes and cancer susceptibility. J Natl Cancer Inst 2009;101(1): 24-36.
37 - Lu M, Lu J, Yang X, Yang M, Tan H, Yun B, et al. Association between the NBS1 E185Q polymorphism and cancer risk: a meta-analysis. BMC Cancer 2009;9: 124.
38 - Stern MC, Lin J, Figueroa JD, Kelsey KT, Kiltie AE, Yuan JM, et al. Polymorphisms in DNA repair genes, smoking, and bladder cancer risk: findings from the international consortium of bladder cancer. Cancer Res 2009;69(17): 6857-6864.
39 - Wang Z, Cui D, Lu W. NBS1 8360G > C polymorphism is associated with breast cancer risk: a meta-analysis. Breast Cancer Res Treat 2010;123(2): 557-561.
40 - Wang F, Zhao S, Qin H. NBS1 8360G > C polymorphism is associated with breast cancer risk was not credible: appraisal of a recent meta-analysis. Breast Cancer Res Treat 2011;128(1): 291-292.
41 - Wang L, Cheng J, Gao J, Wang J, Liu X, Xiong L. Association between the NBS1 Glu185Gln polymorphism and lung cancer risk: a systemic review and meta-analysis. Mol Biol Rep 2013;40(3): 2711-2715.
42 - Yao F, Fang Y, Chen B, Jin F, Wang S. Association between the NBS1 Glu185Gln polymorphism and breast cancer risk: a meta-analysis. Tumour Biol 2013;34(2): 1255-1262.
43 - He YZ, Chi XS, Zhang YC, Deng XB, Wang JR, Lv WY, et al. NBS1 Glu185Gln polymorphism and cancer risk: update on current evidence. Tumour Biol 2014;35(1): 675-687.
44 - Zhang Y, Huang YS, Lin WQ, Zhang SD, Li QW, Hu YZ, et al. NBS1 Glu185Gln polymorphism and susceptibility to urinary system cancer: a meta-analysis. Tumour Biol 2014.
45 - Li N, Xu Y, Zheng J, Jiang L, You Y, Wu H, et al. NBS1 rs1805794G>C polymorphism is associated with decreased risk of acute myeloid leukemia in a Chinese population. Mol Biol Rep 2013;40(5): 3749-3756.
46 - Goricar K, Kovac V, Jazbec J, Lamovec J, Dolzan V. Homologous recombination repair polymorphisms and the risk for osteosarcoma. J Med Biochem 2014 Mar 6.
47 - Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 2001;29(1): 308-311.
48 - Gao LB, Pan XM, Li LJ, Liang WB, Zhu Y, Zhang LS, et al. RAD51 135G/C polymorphism and breast cancer risk: a meta-analysis from 21 studies. Breast Cancer Res Treat 2011;125(3): 827-835.
49 - Zhou GW, Hu J, Peng XD, Li Q. RAD51 135G>C polymorphism and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 2011;125(2): 529-535.
50 - Yu KD, Yang C, Fan L, Chen AX, Shao ZM. RAD51 135G>C does not modify breast cancer risk in non-BRCA1/2 mutation carriers: evidence from a meta-analysis of 12 studies. Breast Cancer Res Treat 2011;126(2): 365-371.
51 - Sun H, Bai J, Chen F, Jin Y, Yu Y, Jin L, et al. RAD51 G135C polymorphism is associated with breast cancer susceptibility: a meta-analysis involving 22,399 subjects. Breast Cancer Res Treat 2011;125(1): 157-161.
52 - Wang Z, Dong H, Fu Y, Ding H. RAD51 135G>C polymorphism contributes to breast cancer susceptibility: a meta-analysis involving 26,444 subjects. Breast Cancer Res Treat 2010;124(3): 765-769.
53 - He XF, Su J, Zhang Y, Ding DP, Wang W, Liu Y. Need for clarification of data in the recent meta-analysis about RAD51 135G>C polymorphism and breast cancer risk. Breast Cancer Res Treat 2011;129(2): 649-651; author reply 652-643.
54 - Zhao M, Chen P, Dong Y, Zhu X, Zhang X. Relationship between Rad51 G135C and G172T variants and the susceptibility to cancer: a meta-analysis involving 54 case-control studies. PLoS One 2014;9(1): e87259.
55 - Zhang BB, Wang DG, Xuan C, Sun GL, Deng KF. Genetic 135G/C polymorphism of RAD51 gene and risk of cancer: a meta-analysis of 28,956 cases and 28,372 controls. Fam Cancer 2014.
56 - Wang W, Li JL, He XF, Li AP, Cai YL, Xu N, et al. Association between the RAD51 135 G>C polymorphism and risk of cancer: a meta-analysis of 19,068 cases and 22,630 controls. PLoS One 2013;8(9): e75153.
57 - Venkitaraman AR. Functions of BRCA1 and BRCA2 in the biological response to DNA damage. J Cell Sci 2001;114(Pt 20): 3591-3598.
58 - Kuschel B, Auranen A, McBride S, Novik KL, Antoniou A, Lipscombe JM, et al. Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum Mol Genet 2002;11(12): 1399-1407.
59 - He YZ, Hu X, Chi XS, Zhang YC, Deng XB, Wei MT, et al. Association between RAD51 gene polymorphism (-135G/C) and susceptibility of myelodysplastic syndrome and acute leukemia: evidence based on a meta-analysis. Tumour Biol 2014;35(1): 615-621.
60 - Cheng D, Shi H, Zhang K, Yi L, Zhen G. RAD51 Gene 135G/C polymorphism and the risk of four types of common cancers: a meta-analysis. Diagn Pathol 2014;9: 18.
61 - Shi S, Qin L, Tian M, Xie M, Li X, Qi C, et al. The effect of RAD51 135 G>C and XRCC2 G>A (rs3218536) polymorphisms on ovarian cancer risk among Caucasians: a meta-analysis. Tumour Biol 2014;35(6): 5797-5804.
62 - Li C, Liu Y, Hu Z, Zhou Y. Genetic polymorphisms of RAD51 and XRCC3 and acute myeloid leukemia risk: a meta-analysis. Leuk Lymphoma 2014;55(6): 1309-1319.
63 - He XF, Wei W, Li JL, Shen XL, Ding DP, Wang SL, et al. Association between the XRCC3 T241M polymorphism and risk of cancer: evidence from 157 case-control studies. Gene 2013;523(1): 10-19.
64 - Han S, Zhang HT, Wang Z, Xie Y, Tang R, Mao Y, et al. DNA repair gene XRCC3 polymorphisms and cancer risk: a meta-analysis of 48 case-control studies. Eur J Hum Genet 2006;14(10): 1136-1144.
65 - Huang G, Cai S, Wang W, Zhang Q, Liu A. Association between XRCC1 and XRCC3 polymorphisms with lung cancer risk: a meta-analysis from case-control studies. PLoS One 2013;8(8): e68457.
66 - Mao CF, Qian WY, Wu JZ, Sun DW, Tang JH. Association between the XRCC3 Thr241Met Polymorphism and Breast Cancer Risk: an Updated Meta-analysis of 36 Case-control Studies. Asian Pac J Cancer Prev 2014;15(16): 6613-6618.
67 - Xing ZS, Zhu G, Yang YL, Feng GQ, Ding GC. Meta analysis of XRCC3 Thr241Met polymorphism and lung cancer susceptibility of populations in East Asia. Asian Pac J Trop Med 2014;7(6): 483-487.
68 - Feng Y, Zeng M, Xu Q. Association between XRCC3 T241M polymorphism and glioma risk: a meta-analysis. Tumour Biol 2014;35(6): 5589-5592.
69 - Li D, You HH, Jia YJ, Guo JD, Du HL. Association of C722T polymorphism in XRCC3 gene with larynx cancer: a meta-analysis. Tumour Biol 2014;35(6): 5427-5430.
70 - Adel Fahmideh M, Schwartzbaum J, Frumento P, Feychting M. Association between DNA repair gene polymorphisms and risk of glioma: a systematic review and meta-analysis. Neuro Oncol 2014;16(6): 807-814.
71 - Qin XP, Zhou Y, Chen Y, Li NN, Wu XT. XRCC3 Thr241Met polymorphism and gastric cancer susceptibility: a meta-analysis. Clin Res Hepatol Gastroenterol 2014;38(2): 226-234.
72 - Yu XL, Liu H, Wang B, Fu ZJ, Yuan Y, Yan SL, et al. Significant associations between X-ray repair cross-complementing group 3 genetic polymorphisms and thyroid cancer risk. Tumour Biol 2014;35(3): 2009-2015.
73 - Yan Y, Liang H, Li T, Guo S, Li M, Qin X, et al. Association of XRCC3 Thr241Met polymorphism and leukemia risk: evidence from a meta-analysis. Leuk Lymphoma 2014;55(9): 2130-2134.
74 - Yan Y, Liang H, Li R, Xie L, Li M, Li S, et al. XRCC3 Thr241Met polymorphism and ovarian cancer risk: a meta-analysis. Tumour Biol 2014;35(3): 2711-2715.
75 - Qin L, Chen X, Li P, Yang Z, Mo W. Comprehensive assessment of the association between DNA repair gene XRCC3 Thr241Met polymorphism and leukemia risk. Tumour Biol 2014;35(3): 2521-2528.
76 - Wang Z, Chen X, Liu B, Li S, Liu M, Xue H. Quantitative assessment of the associations between DNA repair gene XRCC3 Thr241Met polymorphism and gastric cancer. Tumour Biol 2014;35(2): 1589-1598.
77 - Du L, Xiong T, He Q, Wang Y, Shen J, Peng Y, et al. The Thr241Met polymorphism in the XRCC3 gene is associated with increased risk of cancer in Chinese mainland populations. Tumour Biol 2014;35(2): 1371-1376.
78 - Wang R, Li M, Gao WW, Gu Y, Guo Y, Wang G, et al. Quantitative assessment of the association between XRCC3 C18607T polymorphism and glioma risk. Tumour Biol 2014;35(2): 1101-1105.
79 - Liu J, Zhou Z, Lai T, Yin J. Association between XRCC3 Thr241Met polymorphism and risk of brain tumors: a meta-analysis. Tumour Biol 2014;35(2): 1083-1087.
80 - Ma Q, Zhao Y, Wang S, Zhang X, Zhang J, Du M, et al. Genetic polymorphisms of XRCC3 Thr241Met (C18067T, rs861539) and bladder cancer risk: a meta-analysis of 18 research studies. Tumour Biol 2014;35(2): 1473-1480.
81 - Peng Q, Mo C, Tang W, Chen Z, Li R, Zhai L, et al. DNA repair gene XRCC3 polymorphisms and bladder cancer risk: a meta-analysis. Tumour Biol 2014;35(3): 1933-1944.
82 - Qiu LX, Mao C, Yao L, Yu KD, Zhan P, Chen B, et al. XRCC3 5'-UTR and IVS5-14 polymorphisms and breast cancer susceptibility: a meta-analysis. Breast Cancer Res Treat 2010;122(2): 489-493.
83 - He XF, Wei W, Su J, Yang ZX, Liu Y, Zhang Y, et al. Association between the XRCC3 polymorphisms and breast cancer risk: meta-analysis based on case-control studies. Mol Biol Rep 2012;39(5): 5125-5134.
84 - He Y, Zhang Y, Jin C, Deng X, Wei M, Wu Q, et al. Impact of XRCC2 Arg188His polymorphism on cancer susceptibility: a meta-analysis. PLoS One 2014;9(3): e91202.
85 - Yu KD, Chen AX, Qiu LX, Fan L, Yang C, Shao ZM. XRCC2 Arg188His polymorphism is not directly associated with breast cancer risk: evidence from 37,369 subjects. Breast Cancer Res Treat 2010;123(1): 219-225.
86 - Zhang Y, Wang H, Peng Y, Liu Y, Xiong T, Xue P, et al. The Arg188His polymorphism in the XRCC2 gene and the risk of cancer. Tumour Biol 2014;35(4): 3541-3549.
87 - Cheng CX, Xue M, Li K, Li WS. Predictive value of XRCC1 and XRCC3 gene polymorphisms for risk of ovarian cancer death after chemotherapy. Asian Pac J Cancer Prev 2012;13(6): 2541-2545.
88 - Liu Y, Chen H, Chen L, Hu C. Prediction of genetic polymorphisms of DNA repair genes XRCC1 and XRCC3 in the survival of colorectal cancer receiving chemotherapy in the Chinese population. Hepatogastroenterology 2012;59(116): 977-980.
89 - de las Penas R, Sanchez-Ronco M, Alberola V, Taron M, Camps C, Garcia-Carbonero R, et al. Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients. Ann Oncol 2006;17(4): 668-675.
90 - Chen X, Sun H, Ren S, Kim Curran V, Zhang L, Zhou S, et al. Association of XRCC3 and XPD751 SNP with efficacy of platinum-based chemotherapy in advanced NSCLC patients. Clin Transl Oncol 2012;14(3): 207-213.
91 - Qiu M, Xu L, Yang X, Ding X, Hu J, Jiang F, et al. XRCC3 Thr241Met is associated with response to platinum-based chemotherapy but not survival in advanced non-small cell lung cancer. PLoS One 2013;8(10): e77005.
92 - Shen XY, Lu FZ, Wu Y, Zhao LT, Lin ZF. XRCC3 Thr241Met polymorphism and clinical outcomes of NSCLC patients receiving platinum-based chemotherapy: a systematic review and meta-analysis. PLoS One 2013;8(8): e69553.
93 - Zhang W, Yan B, Jiang L. Predictive effect of XRCC3 Thr241Met polymorphism on platinum-based chemotherapy in lung cancer patients: meta-analysis. Tumour Biol 2013;34(6): 3989-3993.
94 - Cecchin E, D'Andrea M, Lonardi S, Zanusso C, Pella N, Errante D, et al. A prospective validation pharmacogenomic study in the adjuvant setting of colorectal cancer patients treated with the 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) regimen. Pharmacogenomics J 2013;13(5): 403-409.
95 - Erculj N, Kovac V, Hmeljak J, Franko A, Dodic-Fikfak M, Dolzan V. DNA repair polymorphisms and treatment outcomes of patients with malignant mesothelioma treated with gemcitabine-platinum combination chemotherapy. J Thorac Oncol 2012;7(10): 1609-1617.
96 - Xu JL, Hu LM, Huang MD, Zhao W, Yin YM, Hu ZB, et al. Genetic variants of NBS1 predict clinical outcome of platinum-based chemotherapy in advanced non-small cell lung cancer in Chinese. Asian Pac J Cancer Prev 2012;13(3): 851-856.
97 - Nogueira A, Catarino R, Coelho A, Araujo A, Gomes M, Medeiros R. Influence of DNA repair RAD51 gene variants in overall survival of non-small cell lung cancer patients treated with first line chemotherapy. Cancer Chemother Pharmacol 2010;66(3): 501-506.
98 - Nogueira A, Catarino R, Faustino I, Nogueira-Silva C, Figueiredo T, Lombo L, et al. Role of the RAD51 G172T polymorphism in the clinical outcome of cervical cancer patients under concomitant chemoradiotherapy. Gene 2012;504(2): 279-283.
99 - Yin M, Liao Z, Huang YJ, Liu Z, Yuan X, Gomez D, et al. Polymorphisms of homologous recombination genes and clinical outcomes of non-small cell lung cancer patients treated with definitive radiotherapy. PLoS One 2011;6(5): e20055.
100 - Szkandera J, Absenger G, Liegl-Atzwanger B, Pichler M, Stotz M, Gerger S, et al. Common gene variants in RAD51, XRCC2 and XPD are not associated with clinical outcome in soft-tissue sarcoma patients. Cancer Epidemiol 2013;37(6): 1003-1009.
101 - Li D, Liu H, Jiao L, Chang DZ, Beinart G, Wolff RA, et al. Significant effect of homologous recombination DNA repair gene polymorphisms on pancreatic cancer survival. Cancer Res 2006;66(6): 3323-3330.
102 - West CM, Barnett GC. Genetics and genomics of radiotherapy toxicity: towards prediction. Genome Med 2011;3(8): 52.
103 - Kerns SL, Ostrer H, Rosenstein BS. Radiogenomics: using genetics to identify cancer patients at risk for development of adverse effects following radiotherapy. Cancer Discov 2014;4(2): 155-165.
104 - Damaraju S, Murray D, Dufour J, Carandang D, Myrehaug S, Fallone G, et al. Association of DNA repair and steroid metabolism gene polymorphisms with clinical late toxicity in patients treated with conformal radiotherapy for prostate cancer. Clin Cancer Res 2006;12(8): 2545-2554.
105 - Popanda O, Tan XL, Ambrosone CB, Kropp S, Helmbold I, von Fournier D, et al. Genetic polymorphisms in the DNA double-strand break repair genes XRCC3, XRCC2, and NBS1 are not associated with acute side effects of radiotherapy in breast cancer patients. Cancer Epidemiol Biomarkers Prev 2006;15(5): 1048-1050.
106 - Venkatesh GH, Manjunath VB, Mumbrekar KD, Negi H, Fernandes DJ, Sharan K, et al. Polymorphisms in radio-responsive genes and its association with acute toxicity among head and neck cancer patients. PLoS One 2014;9(3): e89079.
107 - Pratesi N, Mangoni M, Mancini I, Paiar F, Simi L, Livi L, et al. Association between single nucleotide polymorphisms in the XRCC1 and RAD51 genes and clinical radiosensitivity in head and neck cancer. Radiother Oncol 2011;99(3): 356-361.
108 - Falvo E, Strigari L, Citro G, Giordano C, Arcangeli S, Soriani A, et al. Dose and polymorphic genes xrcc1, xrcc3, gst play a role in the risk of articledeveloping erythema in breast cancer patients following single shot partial breast irradiation after conservative surgery. BMC Cancer 2011;11: 291.
109 - Falvo E, Strigari L, Citro G, Giordano C, Boboc G, Fabretti F, et al. SNPs in DNA repair or oxidative stress genes and late subcutaneous fibrosis in patients following single shot partial breast irradiation. J Exp Clin Cancer Res 2012;31: 7.
110 - Werbrouck J, De Ruyck K, Duprez F, Veldeman L, Claes K, Van Eijkeren M, et al. Acute normal tissue reactions in head-and-neck cancer patients treated with IMRT: influence of dose and association with genetic polymorphisms in DNA DSB repair genes. Int J Radiat Oncol Biol Phys 2009;73(4): 1187-1195.
111 - Chang-Claude J, Ambrosone CB, Lilla C, Kropp S, Helmbold I, von Fournier D, et al. Genetic polymorphisms in DNA repair and damage response genes and late normal tissue complications of radiotherapy for breast cancer. Br J Cancer 2009;100(10): 1680-1686.
112 - Alsbeih G, Al-Harbi N, Al-Hadyan K, El-Sebaie M, Al-Rajhi N. Association between normal tissue complications after radiotherapy and polymorphic variations in TGFB1 and XRCC1 genes. Radiat Res 2010;173(4): 505-511.
113 - Alsbeih G, El-Sebaie M, Al-Harbi N, Al-Hadyan K, Shoukri M, Al-Rajhi N. SNPs in genes implicated in radiation response are associated with radiotoxicity and evoke roles as predictive and prognostic biomarkers. Radiat Oncol 2013;8: 125.
114 - Fachal L, Gomez-Caamano A, Peleteiro P, Carballo A, Calvo-Crespo P, Sanchez-Garcia M, et al. Association of a XRCC3 polymorphism and rectum mean dose with the risk of acute radio-induced gastrointestinal toxicity in prostate cancer patients. Radiother Oncol 2012;105(3): 321-328.
115 - Cheuk IW, Yip SP, Kwong DL, Wu VW. Association of and gene haplotypes with the development of radiation-induced fibrosis in patients with nasopharyngeal carcinoma. Mol Clin Oncol 2014;2(4): 553-558.
116 - Zou Y, Song T, Yu W, Zhao R, Wang Y, Xie R, et al. XRCC3 polymorphisms are associated with the risk of developing radiation-induced late xerostomia in nasopharyngeal carcinoma patients treated with intensity modulation radiated therapy. Jpn J Clin Oncol 2014;44(3): 241-248.