Single Nucleotide Polymorphisms of DNA Repair Genes as Predictors of Radioresponse

doi:10.1016/j.semradonc.2010.05.003

Seminars in Radiation Oncology

Volume 20, Issue 4, October 2010, Pages 232-240

https://doi.org/10.1016/j.semradonc.2010.05.003 Get rights and content

Radiation therapy is a key modality in the treatment of cancer. Substantial progress has been made in unraveling the molecular events which underpin the responses of malignant and surrounding normal tissues to ionizing radiation. An understanding of the genes involved in processes such as DNA double-strand break repair, DNA damage response, cell-cycle control, apoptosis, cellular antioxidant defenses, and cytokine production, has evolved toward examination of how genetic variants, most often, single nucleotide polymorphisms (SNPs), may influence interindividual radioresponse. Experimental approaches, such as candidate SNP-association studies, genome-wide association studies, and massively parallel sequencing are being proposed to address these questions. We present a focused review of the evidence supporting an association between SNPs in DNA repair genes and radioresponse in normal tissues and tumors. Although preliminary results indicate possible associations, there are methodological weaknesses in many of the studies, and independent validation of SNPs as biomarkers of radioresponse in much larger cohorts will likely require research cooperation through international consortia.

Section snippets

Normal Tissue Complications of RT for Cancer

Acute/early effects on normal epithelial tissues (<90 days after RT start) are usually (but not always) transient and related to an interruption of epithelial-cell generation, consequent thinning or denudation of epithelia, and healing. Late effects are more persistent and troublesome and when severe may include chronic inflammatory processes, vascular changes, fibrosis, and atrophy. Time is required for these late effects to evolve. After RT, an acutely increased expression of transforming

Genetic Basis of Normal Tissue Radiosensitivity

Ionizing radiation produces its biological effects mainly through the generation of short-lived but highly reactive DNA radicals that evolve into stable/long-lived DNA lesions, such as DSBs⁶ or through interactions with the plasma membrane,⁷ leading to cell death. Researchers interested in the prediction of normal tissue damage have naturally turned their attention to the evaluation of the expression or status of genes whose encoded proteins are known or suspected to affect intrinsic cellular

Polymorphisms in Candidate Genes Encoding Proteins Relevant to Cellular Radiosensitivity and Tissue Injury After RT

Variations in the sequence of the human genome can comprise repeating sequences, such as variable number of tandem repeats, short tandem repeats, and SNPs.⁹ Although the human genome is ∼99.9% identical among individuals, the ∼0.1% variations (the vast majority of which are SNPs) tend to be heritable and stable.¹⁰ A SNP will have a major allele (allele [AT] or [CG] more frequent) and a minor allele (allele [AT] or [CG] less frequent). For each SNP, any one individual will be either homozygous

Genetic Versus Genomic Approaches and Newer Platforms

In approaching the daunting task of searching for links between variants in an individual's genes and the radiation sensitivity of their cancers and/or normal tissues, historically the use of knowledge from DNA damage recognition, processing, and repair pathways has made perfect sense to provide direction. The existence of rare, naturally occurring mutations associated with marked radiosensitivity (eg, AT) has provided a starting point for many studies of variants in candidate genes. Typically,

Association of DNA Repair SNPs With Acute and Late RT Normal Tissue Effects in Breast Cancer Patients

Radiogenomics studies are most numerous in the domain of breast cancer adjuvant RT patients. Although the survival benefits documented for early breast cancer patients receiving RT¹⁶ make it unlikely that breast RT would be completely avoidable for a given patient if SNP profiles were successful in identifying radiosensitive patients, this information would be nonetheless important to stratify participants of prospective clinical trials in which toxicity was an endpoint. The interpretation of

Association of DNA Repair SNPs With Late RT Normal Tissue Effects in Prostate Cancer Patients

Long-term genitourinary, sexual, and gastrointestinal quality of life are paramount issues guiding patient and physician co–decision making processes with respect to curative management of prostate cancer. Radiogenomic studies in localized prostate cancer are therefore of great interest to practitioners who would benefit from the individualized toxicity risk information that could be available if validated genetic and clinical risk-based predictive models were available.

The radiogenomics

Association of DNA Repair SNPs With Acute and Late Normal Tissue Effects in Head and Neck and Gynecologic Cancer Patients

Few studies have examined patient populations other than those with carcinomas of the breast or prostate. However, because of the high doses of RT necessary for treatment with curative intent, significant acute and late toxicities frequently occur in patients with squamous carcinomas of the head and neck (SCCHN), including mucositis, xerostomia, dysphagia, and subcutaneous fibrosis, making this an important site for investigation. However, potential confounding variables need to be considered

Association of DNA Repair SNPs With Radiotherapy Efficacy and Cancer Treatment Outcome in Head and Neck, Esophagus, Lung, Gastrointestinal, and Bladder Cancer Patients

As noted earlier, human tumors in the clinic vary dramatically even within 1 histopathological subtype with respect to features, such as genetic changes and gene expression profiles. Some of these differences may be related to microenvironmental heterogeneity within a tumor, with different regions experiencing completely different growth states because of gradients of oxygen and glucose availability and pH, with consequent effects on transcriptional and translational activity. The phenomenon of

Conclusions

Multiple reviews, including this one, have highlighted the rapid expansion of knowledge in the domain of SNPs in DNA repair genes and tumor or normal tissue outcomes in RT patients. At a meeting in Manchester, UK, in November 2009 of interested clinicians and scientists in the radiogenomics field, an international Radiogenomics Consortium was established (personal communication, B Rosenstein and C West, November 2009). This move bodes well for the rapid translation of burgeoning genomic

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Citation Excerpt :
Even if attempts have been made to identify patients liable to benefit from combined chemoRT [23], no GWAS is available for HNSCC patients. Most RT studies have focused on SNPs with known or presumed functionality linked with radiation pharmacodynamics [2,24–26]. The candidate-gene approach, studying common SNPs in genes encoding proteins associated with response to radiation, is more cost-effective than GWAS approaches provided that SNPs are validated [22,27].
Single nucleotide polymorphisms (SNPs) of DNA repair and apoptosis genes have been associated with outcome in head and neck squamous cell carcinoma (HNSCC) patients receiving radiotherapy (RT). Our goal was to conduct a candidate gene study in HNSCC patients receiving RT or chemoRT.
122 non-resectable HNSCC patients undergoing RT (N = 38) or chemoRT (N = 84) between 1992 and 2006 were retrospectively analyzed. ERCC1 Lys259Thr (rs735482), ERCC2 Lys751Gln (rs13181), ERCC5 His46His C > T (rs1047768), XRCC1 Arg399Gln (rs25487), TP53 Arg72Pro (rs1042522) and MDM2 309T > G (rs2279744) were analyzed on tumor DNA. SNP profile was considered to assess RT-related toxicity.
All 120 evaluable patients experienced RT-related toxicity at any time. Among them, 83% had G3-4 acute side-effects during RT, mainly dysphagia, mucositis, epithelitis and/or xerostomia (DMEX). 28/105 patients (27%) had early G3-4 toxicity up to 3 months after the end of RT. 29/96 patients (30%) had G3-4 late toxicity thereafter. The presence of G allele of MDM2 or Thr allele of ERCC1 was associated with a significantly higher risk of acute and/or early DMEX toxicity. The MDM2 309GG genotype was linked to a higher risk of acute G3-4 dermatitis. The ERCC5 TT genotype was associated with more frequent G3-4 late cervical skin fibrosis or xerostomia. Pro allele of TP53 72 was associated with a higher risk of G3-4 osteoradionecrosis.
Relevant SNPs in DNA repair (ERCC1 and ERCC5) and apoptosis (MDM2 and TP53) genes might influence the severity of radiation-related side-effects in HNSCC patients. Prospective clinical SNP-based validation studies are needed on these bases.

View all citing articles on Scopus

: Supported in part by an operating grant to MBP from the Alberta Cancer Research Institute, Alberta, Canada.

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Single Nucleotide Polymorphisms of DNA Repair Genes as Predictors of Radioresponse

Section snippets

Normal Tissue Complications of RT for Cancer

Genetic Basis of Normal Tissue Radiosensitivity

Polymorphisms in Candidate Genes Encoding Proteins Relevant to Cellular Radiosensitivity and Tissue Injury After RT

Genetic Versus Genomic Approaches and Newer Platforms

Association of DNA Repair SNPs With Acute and Late RT Normal Tissue Effects in Breast Cancer Patients

Association of DNA Repair SNPs With Late RT Normal Tissue Effects in Prostate Cancer Patients

Association of DNA Repair SNPs With Acute and Late Normal Tissue Effects in Head and Neck and Gynecologic Cancer Patients

Association of DNA Repair SNPs With Radiotherapy Efficacy and Cancer Treatment Outcome in Head and Neck, Esophagus, Lung, Gastrointestinal, and Bladder Cancer Patients

Conclusions

Mutat Res

Radiother Oncol

Radiother Oncol

Semin Radiat Oncol

Gene

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

J Gastrointest Surg

Int J Radiat Oncol Biol Phys

Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype

Nat Rev Cancer

Preventing or reducing late side effects of radiation therapy: Radiobiology meets molecular pathology

Nat Rev Cancer

Radiation-induced signal transduction and stress response

Radiat Res

DNA repair genes and radiosensitivity

Single nucleotide polymorphismsFrom the evolutionary past

Nature