Association between Normal Tissue Complications after Radiotherapy and Polymorphic Variations inTGFB1andXRCC1Genes

Abstract

Genetic predictive biomarkers of radiosensitivity are being sought to individualize radiation treatment of cancer patients. In this pilot case-control study, we tested the association between TGFB1 T869C codon 10 Leu/Pro (rs1982073), XRCC1 G28152A codon 399 Arg/Gln (rs25487), and XRCC3 C18067T codon 241 Thr/Met (rs861539) single-nucleotide polymorphisms (SNPs) and late reaction to radiotherapy in 60 nasopharyngeal cancer patients. Subcutaneous and deep tissue fibrosis was scored using the RTOG/EORTC grading system. Patients with moderate to severe fibrosis (radiosensitive cases, G2-3, n = 30) were matched and compared to those with little or no reaction (controls, G0-1, n = 30). The three nonsynonymous SNPs were genotyped by direct DNA sequencing. Significant association was observed for TGFB1 T869C and XRCC1 G28152A genotypes (P < or = 0.05). Both variant alleles, TGFB1 869C and XRCC1 28152A, were associated with a lower grade of fibrosis (odds ratios were 0.41, 95% CI: 0.20-0.86, P = 0.02 and 0.30, 95% CI: 0.10-0.89, P = 0.02, respectively), and therefore the wild-types were the risk alleles. Interestingly, there was a significant difference in the median number of risk alleles between the radiosensitive and the control groups (P = 0.006). We conclude that radiotherapy complications are associated with genetic variations in our nasopharynx cancer patients. Our findings support the assumption of the combined effects of multiple SNPs. Large-scale studies are required to confirm these findings before polymorphisms can be used as predictive markers to individualize radiation therapy on genetic bases.

Association of XRCC1 and XRCC3 gene haplotypes with the development of radiation-induced fibrosis in patients with nasopharyngeal carcinoma

“…Our results were in line with findings reported by other studies with relatively large sample sizes (16,17). However, our results were in contrast to those reported by 3 studies performed in Saudi Arabian NPC patients by Alsbeih et al (4,5,18). Our results indicated a trend of possible association between rs861539 of XRCC3 and radiation-induced fibrosis in Chinese NPC patients, but not rs25487 of XRCC1.…”

“…Since different patients may present with different degrees of skin fibrosis despite receiving identical treatment, it was hypothesized that the severity of such complications may be genetically determined. Previous studies investigated the association of single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair, such as X-ray repair cross-complementing protein 1 (XRCC1) rs25487 (c.1196A>G, p.Gln399Arg) and X-ray repair cross-complementing protein 3 (XRCC3) rs861539 (c.722C>T, p.Thr241Met) with late complications in various types of cancer (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

Involvement of Single-Nucleotide Polymorphisms in Predisposition to Head and Neck Cancer in Saudi Arabia

“…In the last decade, cancer researchers have investigated the link between SNPs and various endpoints such as drug resistance in chemotherapy, radiosensitivity in radiation therapy, and cancer susceptibility (Alsbeih et al, 2010). A number of studies have suggested that SNPs might contribute along with other factors to the development of various human malignancies (Zhou et al, 2007;Chiu et al, 2008).…”

A simulated SNP experiment indicates a high risk of over-fitting and false positive results when a predictive multiple SNP model is established and tested within the same dataset

“…Some of these studies establish predictive models based on multiple SNPs. Examples are given in references [5][6][7][8][9][10][11][12]. For several reasons, such approach seems attractive.…”

“…We have taken a closer look at four different studies that established predictive models based on multiple SNPs [5][6][7][8]. All studies were relatively small with sample sizes between 37 and 69 patients.…”