Most commonly investigated HRR SNPs and their predicted function.
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 . 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 . 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 . 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 . 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 .
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
MRN complex is involved in DSB recognition in different repair pathways, not only in HRR , suggesting that NBN may play a crucial part in DNA repair. NBN consists of three functional regions . The N-terminal region binds to phosphorylated histone H2AX (γ-H2AX) and allows the MRN complex to move close to the sites of DSBs . The central region is involved in signal transduction for damage response, while the C-terminal region is involved in MRE11 binding.
|rs1805794||p.Glu185Gln||Exon, nonsynonymous||Affects interaction with BRCA1 ||0.304|
|rs709816||p.Asp399Asp||Exon, synonymous||Affects splicing ||0.357|
|rs1063054||c.*1209A>C||3’ UTR||Affects miRNA binding ||0.317|
|rs2735383||c.*541G>C||3’ UTR||Affects miRNA binding [8-10]||0.312|
|rs1801320||c.-98G>C||5’ UTR||Enhances promoter activity ||0.067|
|rs1801321||c.-61G>T||5’ UTR||Enhances promoter activity ||0.467|
|rs1799794||c.-316A>G||5’ UTR||Affects transcription factor binding ||0.184|
|rs861539||p.Thr241Met||Exon, nonsynonymous||Might affect protein structure or function ||0.433|
|rs3218536||p.Arg188His||Exon, nonsynonymous||Modified sensitivity to DNA damaging agents ||0.094|
Mutations in the
|Asp95Asn||rs61753720||May affect protein-protein interactions , not highly damaging |
|Ile171Val||rs61754966||Affects protein structure and protein-protein interactions |
|Arg215Trp||rs61753718||Impairs histone γ-H2AX binding |
|Pro266Leu||rs769420||Probably damaging effect |
|657del5||Leads to protein truncation |
Besides rare mutations, several common SNPs have been described in both the coding region and the regulatory regions of
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 . Several SNPs have been described in
XRCC3 is one of XRCC proteins involved in the protection of cell from ionizing radiation and belongs to the RAD51 family . XRCC3 deficiency affects RAD51 foci formation and leads to increased genetic instability and sensitivity to DNA damaging agents .
Only a few putatively functional SNPs have been described in the
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 . 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
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.
Genetic variability in
|Ile171Val||Bogdanova, 2008 ||4||2954/2531||Breast||No association|
|Gao, 2013 ||10||4516/9951||Overall||Increased risk|
|Zhang, 2012 ||5||3273/4004||Breast||No association|
|Arg215Trp||Gao, 2013 ||9||6728/9508||Overall||Increased risk|
|657del5||Zhang, 2012 ||9||7534/14034||Breast||Increased risk|
|Zhang, 2013 ||10||25365||Breast||Increased risk|
|Gao, 2013 ||21||15184/54081||Overall||Increased risk|
|rs1805794||Vineis, 2009 ||4||∑4825||Bladder||Increased risk|
|Lu, 2009 ||17||9734/10325||Overall||Borderline increased risk|
|Stern, 2009 ||13||6348/6752||Bladder||Modestly increased risk|
|Wang, 2010 ||10||4452/5665||Breast||Decreased risk|
Not credible, some mistakes 
|Wang, 2013 ||6||2348/2401||Lung||Increased risk|
|He, 2014 ||48||17159/22002||Overall||No association|
|7||2837/2973||Urinary system||Increased risk|
|5||1682/2213||Digestive system||Decreased risk|
|Zhang, 2014 ||8||3542/4210||Urinary system cancer||Increased risk, especially in bladder cancer|
|Gao, 2013 ||42||18901/21430||No association in subgroup analysis by cancer type, heterogeneity too big for overall analysis|
|rs2735383||Gao, 2013 ||13||7561/8432||Overall||Increased risk|
|rs1063054||Gao, 2013 ||9||2757/5796||Overall||Increased risk|
Rare mutations in the
Most of the meta-analyses investigating the role of
|He, 2014 ||10||2656/3725||Myelodysplastic syndrome and acute leukemia||No association|
|3||726/604||Myelodysplastic syndrome||Increased risk|
|Wang, 2013 ||39||19068/22630||Overall||No association|
|7||1605/3121||Acute myeloid leukemia||No association|
|Cheng, 2014 ||22||6836/8507||Overall||No association|
|4||1237/1340||Squamous cell carcinoma of the head and neck||Increased risk|
|9||2845/4027||Acute leukemia||No association|
|Zhao, 2014 ||42||19142/20363||Overall||Increased risk|
|Shi, 2014 ||10||2648/4369||Ovarian||No association|
|Li, 2014 ||6||1764/3469||Acute myeloid leukemia||No association|
|Zhang, 2014 ||45||28956/28372||Overall||Increased risk|
|7||2169/3629||Hematological malignancies||Increased risk|
|4||1202/1216||Head and neck||No association|
|Mao, 2014 ||36||23812/25349||Breast||Slightly increased risk, especially in Asians|
|Xing, 2014 ||8||3215/3106||Lung||No association|
|Yuan, 2014 ||4||5173/7800||Ovarian||No association|
|Feng, 2014 ||8||3455/4435||Glioma||No association|
|Li, 2014 ||5||1507/3623||Larynx||No association|
|Adel Fahmideh, 2014 ||5||3374/3734||Glioma||No association|
|Chen, 2014 ||15||4329/7291||Overall||No association|
|8||2056/3920||Non-melanoma skin cancer||Decreased risk|
|5||1324/2209||Basal cell carcinoma||Decreased risk|
|3||732/1711||Squamous cell carcinoma||Decreased risk|
|Qin, 2014 ||9||2209/3269||Gastric||No overall, association, increased risk in Asians|
|Yu, 2014 ||6||723/1399||Thyroid||No overall association, increased risk in Caucasians|
|Yan, 2014 ||7||1070/1850||Leukemia||No overall association, increased risk in Asians|
|Yan, 2014 ||7||3635/5473||Ovarian||No association|
|Qin, 2014 ||15||2339/4162||Leukemia||No overall association, increased risk in acute myeloid leukemia|
|Wang, 2014 ||12||2209/3269||Gastric||No overall association, decreased risk in Asians|
|Du, 2014 ||23||7777/9868||Overall (Chinese mainland population)||Increased risk, especially cervical and nasopharyngeal cancer|
|Wang, 2014 ||10||4136/5233||Glioma||No overall association, increased risk in Asians|
|Liu, 2014 ||13||4984/7472||Brain tumors||No overall association, increased risk in Asians|
|Ma, 2014 ||18||5667/7609||Bladder||Increased risk|
|Peng, 2014 ||16||5608/6197||Bladder||Increased risk|
Only a few meta-analyses were performed for
The majority of cancer susceptibility studies focused solely on the
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.
|Yu, 2010 ||16||18341/19028||Breast||No association|
|He, 2014 ||14||17420/17811||Breast||No association|
|3||499/583||Upper aerodigestive tract||Increased risk|
|Shi, 2014 ||9||3279/5934||Ovarian||Decreased risk|
|Zhang, 2014 ||33||26320/28862||Overall||No association|
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
|Shen, 2013 ||7||1186||Better response to chemotherapy, no significant influence on overall survival|
|Qiu, 2013 ||8||1289||Better response to chemotherapy, no significant influence on overall survival|
|Zhang, 2013 ||7||1514||No significant influence on overall survival|
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.
Similar to other HRR genes, the potential influence of
Radiation therapy is used for treatment of up to 50% of cancer patients . Adverse events are common and affect patients’ quality of life . 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 . 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 . As DSBs represent the most harmful effect of radiation, several studies have been published regarding HRR SNPs and radiation toxicity.
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.
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.
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