E.M. Thurner

Association between single nucleotide polymorphisms in the gene for XRCC1 and radiation-induced late toxicity in prostate cancer patients

BACKGROUND AND PURPOSE Polymorphisms in genes responsible for DNA damage signaling and repair might modulate DNA repair capacity and, therefore, affect cell and tissue response to radiation and influence individual radiosensitivity. The purpose of the present prospective investigation was to evaluate the association of single nucleotide polymorphisms in XRCC1 with radiation-induced late side effects in prostate cancer patients treated with radiotherapy. MATERIAL AND METHODS To analyze the role of XRCC1 polymorphisms for late toxicity 603 participants from the Austrian PROCAGENE study treated with three-dimensional conformal radiotherapy were included in the present investigation. Three non-synonymous candidate polymorphisms in the X-ray repair cross-complementing group 1 (XRCC1) gene (Arg194Trp; Arg280His; Arg399Gln) were selected and determined by 5´-nuclease (TaqMan) assays. RESULTS Within a median follow-up time of 35 months, 91 patients (15.7%) developed high-grade late toxicities (defined as late bladder and/or rectal toxicity RTOG≥2). In a Kaplan-Meier analysis, carriers of the XRCC1 Arg280His polymorphism were at decreased risk of high-grade late toxicity (p=0.022), in multivariate analysis including clinical and dosimetric parameters as potential confounders the XRCC1 Arg280His polymorphism remained a significant predictor for high-grade late toxicity (HR=0.221, 95% CI 0.051-0.956; p=0.043). No significant associations were found for the remaining polymorphisms. CONCLUSIONS We conclude that the XRCC1 Arg280His polymorphism may be protective against the development of high-grade late toxicity after radiotherapy in prostate cancer patients.

Impact of VEGF gene polymorphisms and haplotypes on radiation-induced late toxicity in prostate cancer patients.

Background and PurposeVascular endothelial growth factor (VEGF) is an important determinant of microvascular permeability and angiogenesis and has been shown to be up-regulated during the late phase of radiation injury. The present prospective study was performed to evaluate the role of VEGF gene polymorphisms and haplotypes in the development of radiation-induced late side effects in prostate cancer patients.Patients and MethodsThe association of VEGF gene polymorphisms and haplotypes with high-grade late rectal or urinary toxicity (defined as late toxicity EORTC/RTOG ≥2) was analyzed using 493 prostate cancer patients from the Austrian PROCAGENE study treated with definitive radiotherapy. Seven candidate polymorphisms in the VEGF gene were selected and determined by 5’-nuclease (TaqMan) assays.ResultsWithin a median follow-up time of 48 months, 42 patients (8.6%) developed high-grade late rectal and 47 patients (9.6%) urinary toxicity, respectively. In a Kaplan–Meier analysis, carriers of the VEGF -7C > T polymorphism were at increased risk of high-grade late rectal toxicity (p = 0.003) and in a multivariate analysis including clinical and dosimetric parameters as potential confounders the VEGF -7C > T polymorphism remained a significant predictor (HR = 2.8, 95% CI 1.349–5.813; p = 0.006). Furthermore, the ATTGT haplotype formed by five polymorphisms upstream of the coding sequence demonstrated a significant association with late rectal toxicity grade ≥2 (p = 0.001). No significant associations were found for the remaining polymorphisms and haplotypes.ConclusionWe conclude that genetic variants in the VEGF gene may influence the risk of high-grade late rectal toxicity after definitive radiotherapy for prostate cancer.ZusammenfassungHintergrundVascular endothelial growth factor (VEGF) ist ein wichtiger Regulator der Gefäßpermeabilität und Angiogenese, und in der chronischen Strahlenreaktionsphase wurde die Hochregulation von VEGF gezeigt. Ziel der vorliegenden prospektiven Studie war die Analyse des Zusammenhangs von VEGF-Genpolymorphismen und -Haplotypen mit dem Auftreten von radiogenen Spätfolgen bei Prostatakarzinompatienten.Patienten und MethodenDer Zusammenhang zwischen VEGF-Genpolymorphismen und -Haplotypen und höhergradigen rektalen und urogenitalen Spätfolgen (definiert als Spättoxizität EORTC/RTOG ≥2) wurde bei 493 Prostatakarzinompatienten der PROCAGENE-Studie, die einer definitiven Strahlentherapie unterzogen wurden, untersucht. 7 Kandidatenpolymorphismen wurden ausgewählt und mittels 5´-Nuklease-Assays (TaqMan) analysiert.ErgebnisseWährend einer medianen Nachbeobachtungszeit von 48 Monaten entwickelten 42 Patienten (8,6%) höhergradige rektale und 47 Patienten (9,6%) urogenitale Nebenwirkungen. In der Kaplan-Meier-Analyse zeigten Träger des VEGF -7C > T-Poly-morphismus ein erhöhtes Risiko für höhergradige rektale Spätfolgen (p = 0,003; Abbildung 2) und in der multivariaten Analyse, in welche klinische und dosimetrische Faktoren eingeschlossen wurden, blieb der VEGF -7C > T-Polymorphismus ein signifikanter Prediktor (HR = 28; 95%-CI 1,349–5,813; p = 0,006, Tabelle 4). Zusätzlich zeigte sich für den ATTGT-Haplotyp, bestehend aus 5 vor der kodierenden Sequenz liegenden Polymorphismen, eine signifikante Assoziation mit höhergradiger rektaler Spättoxizität (p = 0,001; Abbildung 3). Keine signifikanten Assoziationen wurden für die übrigen untersuchten Polymorphismen und Haplotypen gefunden (Tabellen 3 und 4).SchlussfolgerungDie vorliegenden Daten zeigen, dass Varianten im VEGF-Gen möglicherweise das Auftreten von höhergradigen rektalen Spätfolgen nach definitiver Radiotherapie des Prostatakarzinoms beeinflussen.

Association of vascular endothelial growth factor--a gene polymorphisms and haplotypes with breast cancer metastases.

Abstract Background. Vascular endothelial growth factor (VEGF-A) is a key regulator of tumor-induced angiogenesis and essential for tumor growth and distant tumor spread. The aim of the present study was to evaluate the role of VEGF-A polymorphisms and haplotypes for metastatic progression in breast cancer patients. Material and methods. We performed a prospective study including 801 breast cancer patients. Occurrence of metastases was examined in regular follow-up investigations. Seven VEGF-A polymorphisms were selected and determined by 5′-nuclease assays (TaqMan). The selection of VEGF-A variants was based upon their location (promoter or UTR) as well as a minor allele frequency of at least 0.10. Haplotypes and linkage disequilibrium were determined using the Haploview program. Results. Within a median follow-up time of 84 months, 165 (21%) patients developed distant metastases. In univariate analysis, carriers of the CCCCC haplotype formed by five polymorphisms upstream the coding region were at decreased risk of distant metastases [hazard ratio (HR) = 0.743; 95% CI 0.579–0.953; p = 0.019]. Univariate analysis also revealed a decreased risk of distant metastases for postmenopausal patients carrying the -634G> C polymorphism (HR 0.704; 95% CI 0.514–0.965; p = 0.029) and the CCCCC haplotype (HR = 0.645; 95% CI 0.464–0.898; p = 0.009). After adjustment for other co-variates, the HR for distant metastases was 0.651 (95% CI 0.447–0.948) for postmenopausal carriers of the -634G> C polymorphism (p = 0.025; corrected p-value = 0.262), and 0.586 (95% CI 0.393–0.873) for postmenopausal patients with the CCCCC haplotype (p = 0.009, corrected p-value = 0.189). Conclusion. The results from univariate and multivariate analyses suggest an influence of VEGF-A gene variants on the development of distant metastases in breast cancer patients. However, none of the observed associations reached statistical significance after correction for the effects of multiple testing. Additional prospective and sufficiently powered studies are essential before firm conclusions about the role of VEGF-A gene variants for distant progression in breast cancer can be drawn.