Marzanna Ciesielka

Predictive value of ERCC1 and RRM1 gene single-nucleotide polymorphisms for first-line platinum- and gemcitabine-based chemotherapy in non-small cell lung cancer patients

Platinum-based chemotherapy with third generation drugs (such as gemcitabine) is an efficacious regimen of first-line treatment of patients with advanced, unresectable non-small cell lung cancer (NSCLC), without activating EGFR mutations. Mechanism of action of cytostatics are distortions in the DNA. ERCC1 and RRM1 are key proteins involved in the repair of DNA, thus, they may be responsible for the ineffectiveness of therapy. We investigated whether ERCC1 (19007C>T) and RRM1 (-37C>A) polymorphisms impact response to chemotherapy and survival in 62 patients with NSCLC treated with platinum and gemcitabine. Single nucleotide polymorphisms (SNPs) were assessed using a PCR-RFLP method in DNA isolated from PBLs. There were no statistically significant relationships between ERCC1 genotypes and response to therapy (p=0.581, χ2=1.09) as well as patient overall survival (OS). Carriers of the RRM1 AC genotype showed disease progression significantly more frequently (p=0.019, χ2=5.473) compared to carriers of the AA or CC genotypes. Carriers of the ERCC1/RRM1TT/CC genotype combination showed disease control significantly more frequently (p=0.047, χ2=3.95) compared to carriers of other genotype combinations. Patients with AA or CC genotypes of RRM1 showed significantly higher progression-free survival probability (p=0.0001, HR=0.39, 95% CI, 0.22-0.70) and OS probability (p=0.0104, HR=0.39, 95% CI, 0.18-0.82) compared to those with the AC genotype. In Cox regression model, poor performance status (p=0.0016, HR=4.78, 95% CI, 1.82-12.56), AC genotype of RRM1 gene (p=0.0414, HR=2.47, 95% CI, 1.04-5.87), lack of prior surgical treatment (p=0.0425, HR=4.71, 95% CI, 1.06-20.92) and lack of subsequent lines of treatment (p=0.0127, HR=3.23, 95% CI, 1.29-8.11) were significantly associated with shortening of patient survival. The analysis of RRM1 (-37C>A) more than ERCC1 (19007C>T) polymorphism may be a promising tool in the qualification of NSCLC patients for chemotherapy containing platinum compounds and gemcitabine.

Allele frequency distributions of D1S80 in the Polish population.

The polymorphism of the D1S80 locus has been analyzed in a population sample of 208 unrelated individuals in the Southeast Poland and 103 mother/child pairs. PCR amplified alleles were separated by a vertical discontinuous polyacrylamide gel electrophoresis system. Nineteen different alleles and 52 phenotypes could be distinguished. The alleles 18 (f = 0.267) and 24 (f = 0.300) were most common in Poland. D1S80 genotype frequencies of Poland population do not deviate from Hardy-Weinberg equilibrium. All mother/child pairs shared at least one D1S80 allele.

Polymorphism of Promoter Region of TNFRSF1A Gene (−610 T > G) as a Novel Predictive Factor for Radiotherapy Induced Oral Mucositis in HNC Patients

Every year, about 650 thousand new cases of Head and Neck Cancer (HNC) are diagnosed globally. Apart from surgery, radiotherapy (RTH), chemotherapy (CHT) or its combination is used in the treatment of HNC. One of the most frequent complications and, at the same time, limitations of RTH is oral mucositis (OM). Proinflammatory cytokines (including TNF-α) play a key role in the development of OM. Genetic alterations, i.e. single nucleotide polymorphisms (SNPs) within genes encoding for receptors for TNF (ie. TNFRSF1A) may change their function. The aim of this study was to investigate relationship between a polymorphism of TNFRSF1A and occurrence and severity of acute reaction after RTH for HNC patients. Data from 58 HNC patients (stages I-IV) were analyzed. All of them were irradiated using IMRT technique with doses 50-70Gy. Oral mucositis (OM) was evaluated according to RTOG/EORTC guidelines. DNA from HNC patients were isolated from whole blood and genotypes were determined by sequencing method. Patients with TT or GT genotype demonstrated higher risk of manifestation of grade 3 OM in 5th week of RTH (p=0.041; OR=9.240; 95% CI: 1.101–77.581) compared to GG carriers. Similarly, high risk of grade 3 OM in patients with T allele presence was noted in 6th week (p=0.030; OR=10.50; 95%CI:1.257–87.690) and in 7th week (p=0.008; OR=5.625; 95% CI: 1.584–19.975) of treatment compared to patients with GG homozygote. Our results indicate an association between SNP of TNFRSF1A (rs4149570) gene and risk of more severe OM related to radiation therapy for HNC patients.

Polymorphism of regulatory region of APEH gene (c.-521G>C, rs4855883) as a relevant predictive factor for radiotherapy induced oral mucositis and overall survival in head neck cancer patients

Background The study purpose was to examine the correlation between SNP in the regulatory region (c.-521G>C, rs4855883) of APEH gene as well as the incidence and severity of radiotherapy (RTH) induced oral mucositis (OM) and overall survival (OS) in head and neck cancer (HNC) patients. Methods OM in 62 HNC patients subjected to irradiation was assessed using RTOG/EORTC scale. DNA was isolated from whole blood of HNC patients. Mini-sequencing method (SNaPshot PCR) was used to determine the genotype. Results The following frequency of occurrence of APEH gene was observed: CC: 37.1%, CG: 43.6% and GG: 19.3%. It was established that the presence of CC genotype reduced the risk of occurrence of grade 2 and 3 OM symptoms: 3-fold in RTH week 2 (in case of CC vs GC or GG it was: 26.8% vs 73.2% patients, respectively, OR = 0.27, 95 CI: 0.09–0.83; p = 0.0222), 6-fold in RTH week 3 (in case of CC vs GC or GG it was: 29.4% vs 70.6% patients, respectively, OR = 0.16, 95 CI: 0.04–0.67; p = 0.0125) and grade 3 OM symptoms 4-fold in RTH week 6 (in case of CC vs GC or GG it was: 19.2% vs 80.8% patients, respectively, OR = 0.23, 95 CI: 0.07–0.77; p = 0.0166). CC genotype was associated with lower OS (CC vs GG or GC: 29 months vs 38 months; HR = 2.48, 95% CI: 0.90–6.85; p = 0.0266). Conclusion CC genotype of APEH gene was correlated with the risk of more severe radiotherapy-induced OM in HNC patients and lower rates of survival.

Polymorphism of regulatory region of GHRL gene (-2531C>T) as a promising predictive factor for radiotherapy-induced oral mucositis in patients with head neck cancer

The purpose of this study was to investigate the relationship between single nucleotide polymorphisms (SNP; rs1629816) in the regulatory region (c.‐2531C>T) of the ghrelin (GHRL) gene and the occurrence and severity of oral mucositis caused by radiotherapy (RT) in patients with head and neck cancer.