Head and neck squamous cell carcinoma (HNSCC) is treated with cisplatin (CDDP) and radiotherapy (RT), and distinct results are observed among patients with similar clinicopathological aspects. This prospective study aimed to investigate whether MLH1 c.-93G>A (rs1800734), MSH2 c.211+9C>G (rs2303426), MSH3 c.3133G>A (rs26279), EXO1 c.1765G>A (rs1047840), and EXO1 c.2270C>T (rs9350) single nucleotide polymorphisms (SNPs) of the mismatch repair (MMR) pathway change side effects and response rate of 90 HNSCC patients treated with CDDP and RT. DNA from peripheral blood was analyzed by PCR-based methods to obtain genotypes. It was observed 4.27-fold and 4.69-fold increased risks of presenting pronounced nephrotoxicity with treatment in patients with MSH3 GG and EXO1 rs9350 CC genotypes compared with patients with GA or AA and CT or TT genotypes, respectively. MSH3 GG or GA and GT haplotype of EXO1 rs1047840 and rs9350 SNPs conferred to patients 10.29 and 4.00 more chances of presenting pronounced ototoxicity after treatment than MSH3 AA genotype and other EXO1 haplotypes, respectively. Patients with EXO1 rs1047840 GA or AA genotype and AC haplotype of EXO1 rs1047840 and rs9350 SNPs had both 9.55-fold increased risks of achieving partial response or stable disease instead of complete remission after treatment than patients with EXO1 GG genotype and other EXO1 haplotypes, respectively. For the first time, our data show preliminary indication that inherited alterations of DNA MMR pathway, related to MSH3 rs26279, EXO1 rs1047840 and EXO1 rs9350 SNPs, modify toxicity and response to chemoradiation in HNSCC, and may contribute to future personalized treatment of patients.

We examined the influence of MLH1 c.293G>A, MSH2 c.211 1 9C>G, MSH3 c.3133G>A and EXO1 c.1765G>A polymorphisms, involved in DNA mismatch repair (MMR), on head and neck (HN) squamous cell carcinoma (SCC) risk and prognosis. Aiming to identify genotypes, DNA from 450 HNSCC patients and 450 controls was analyzed by PCR-RFLP or real time PCR. MSH2 GG plus MSH3 GG (31.7% vs. 18.7%, p 5 0.003) genotypes were higher in laryngeal SCC (LSCC) patients than in controls. Carriers of the respective combined genotype were under a 3.69 (95% CI: 1.54-8.81)-fold increased risk of LSCC. Interactions of tobacco and tobacco plus all the above-mentioned polymorphisms on HNSCC and LSCC risk were also evident in study (p 5 0.001). At 60 months of follow-up, relapse-free survival (RFS) was shorter in patients with EXO1 GG genotype (54.8% vs. 61.1%, p 5 0.03) and overall survival (OS) was shorter in patients with MSH3 GG genotype (42.8% vs. 52.5%, p 5 0.02) compared to those with other genotypes, respectively. After multivariate Cox analysis, patients with EXO1 GG and MSH3 GG genotypes had worst RFS (HR: 1.50, 95% CI: 1.03-2.20, p 5 0.03) and OS (HR: 1.59, 95% CI: 1.19-2.13, P 5 0.002) than those with the remaining genotypes, respectively. Our data present, for the first time, evidence that inherited MLH1 c.-93G>A, MSH2 c.211 1 9C>G, MSH3 c.3133G>A, and EXO1 c.1765G>A abnormalities of DNA MMR pathway are important determinants of HNSCC, particularly among smokers, and predictors of patient outcomes.Exposure to tobacco smoke is considered the most important etiological factor in the development of head and neck (HN) squamous cell carcinoma (SCC). 1 Carcinogens present in tobacco, such as benzo(a)pyrene, could bind to DNA from epithelial cells of the upper aerodigestive tract, forming covalent DNA adducts and inducing replication errors, which can be associated with HNSCC origin. 2,3 However, not all smokers develop HNSCC suggesting that individual genetic background may also participate in the tumor etiology. 4 DNA mismatch repair (MMR) pathway contributes to maintain genetic stability. 5 MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MutS homolog 3 (MSH3) and exonuclease 1 (EXO1) proteins play important roles in this process, recognizing DNA damage induced by carcinogens from tobacco, and enabling its excision. 6,7 The ability to promote DNA repair of damaged cells is variable in humans, since several DNA repair proteins, such as MLH1, MSH2, MSH3 and EXO1, are encoded by polymorphic genes. 8,9 Variant alleles of MLH1 c.293G>A, 10 MSH2 c.211 1 9C>G 11 and EXO1 c.1765G>A 12 single nucleotide polymorphisms (SNPs) reduce the expression of encoded proteins when compared with the respective wild-type alleles, and have decrease in DNA repair as consequence. The role of MSH3 c.3133G>A in protein activity is not totally clarified. 13-15 GG genotype of MLH1 c.293G>A and variant allele A of EXO1 c.1765G>A SNP were associated with increased risk of oral SCC only in India 16 and Taiwan, 17 respectively. To the best of our knowledge, the roles of the ...

Our data present, for the first time, evidence that inherited OGG1 c.977C>G; XRCC1 c.-77T>C, c.580C>T, c.839G>A and c.1196G>A abnormalities of DNA BER pathway are important determinants of OPSCC and predictors of patient outcomes.

The wild and the variant alleles of the C936T and G634C vascular endothelial grow factor (VEGF) polymorphisms seem to be linked to higher angiogenic phenotype than the remaining alleles and may act on breast cancer (BC) origin. We investigated the influence of the VEGF C936T and G634C polymorphisms on the occurrence and clinicopathologic characteristics of sporadic breast cancer (SBC) in 235 patients and 235 controls. Peripheral blood samples of all individuals were analysed by the polymerase chain reaction for identification of genotypes and by enzyme-linked immunosorbent assay (ELISA) for quantification of serum VEGF levels. The variant 634CC genotype isolated (16.2% versus 10.7%, P  = 0.01) and in combination with the wild 936CC genotype (10.6% versus 5.5%, P  = 0.01) were more common in patients than in controls. The carriers of the respective genotypes were under a 2.20-fold and a 3.08-fold increased risks for the disease. Additionally, the frequency of the wild 936CC genotype was higher in patients with tumours of histological grade III compared to those with tumours of I+II histological grades (84.0% versus 64.7%, P  = 0.004) and in patients with positive oestrogen receptor tumours compared to those with tumours lacking oestrogen receptor expression (84.7% versus 73.9%, P  = 0.02). Similar serum values of VEGF were seen in patients and controls with the distinct genotypes of the VEGF. The data suggest that the VEGF wild 936CC and the variant 634CC genotypes constitute inherited determinants of SBC and SBC aggressiveness in Brazil, but are not significant predictors of circulating VEGF levels.

Cisplatin (CDDP) combined with radiotherapy (RT) is employed in head and neck squamous cell carcinoma (HNSCC) with variable toxicities and clinical response. Glutathione S-transferases (GSTs) participate in CDDP excretion from cells, and genes encoding GSTs, GSTM1 , GSTT1 and GSTP1 , are polymorphic in humans. This prospective study aimed to evaluate the roles of GSTM1 , GSTT1 , and GSTP1 Ile105Val polymorphisms in outcomes of HNSCC patients treated with CDDP chemoradiation. Ninety patients were genotyped by multiplex PCR. Urinary CDDP measurements were performed by HPLC. Treatment side effects and response were analysed by conventional criteria. Patients with GSTT1 genes showed 7.23- and 5.37-fold higher likelihood of presenting vomiting and ototoxicity, lower glomerular filtration rate (GFR), and lower elimination of CDDP in urine relative to patients with deleted genes. Patients harbouring the GSTP1 IleVal or ValVal genotypes showed 4.28-fold higher likelihood of presenting grade 2 or 3 vomiting and lower GFR with treatment than those harbouring the IleIle genotype. In multivariate Cox analysis, patients with the GSTP1 105ValVal genotype had 3.87 more chance of presenting disease progression than those with the IleIle or IleVal genotype ( p < 0.01). Our findings provide preliminary evidence that inherited abnormalities in CDDP metabolism, related to GSTT1 and GSTP1 Ile105Val polymorphisms, alter outcomes of HNSCC patients treated with CDDP and RT.