Genetic polymorphisms of CYP1A1, CYP2E1, GSTM1, and GSTT1 associated with head and neck cancer

BACKGROUND: Alcohol intake and tobacco smoke, in addition to other environmental and genetic factors, have been associated with head and neck cancer. We evaluated the role of metabolic enzyme polymorphisms on the risk of head and neck cancer in a hospital-based case-control study. METHODS: CYP1A1MspI, CYP2E1PstI, GSTM1, and GSTT1polymorphisms were evaluated in 103 histologically confirmed head and neck cancer cases and 102 controls by means of polymerase chain reaction-restriction fragment length polymorphism methods. RESULTS: GSTM1null increased the risk of head and neck cancer (odds ratio [OR], 2.2; 95% confidence interval [95% CI], 1.24-3.79), oral cancer (OR, 2.8; 95% CI, 1.28-5.98), and pharyngeal cancer (OR, 2.2; 95% CI, 1.08-4.63). CYP2E1PstI polymorphism indicated a risk for oral cancer (OR, 3.6; 95% CI, 1.29-11.56). The joint effect of GSTM1 null and CYP1A1 polymorphism increased the risk of head and neck cancer (OR, 2.4; 95% CI, 1.13-5.10). CONCLUSIONS: GSTM1 null alone or associated with CYP1A1 increased the risk of head and neck cancer; the CYP2E1PstI mutated allele increased the risk for only oral cancer.     

Prostate cancer risk and IRS1, IRS2, IGF1, and INS polymorphisms: strong association of IRS1 G972R variant and cancer risk

BACKGROUND: As cellular proliferation is central to the carcinogenic process, pathways that regulate proliferation may be important. Therefore, genes in the insulin and the insulin-like growth factor signaling pathways are plausible candidates for susceptibility genes for prostate cancer. We hypothesized that functional polymorphisms in INS, IRS1, IRS2, and IGF1 may be associated with prostate cancer. METHODS: We studied 199 incident prostate cancer cases and 267 age-matched controls. Genotyping was performed for the INS +1127 Ins-PstI, IRS1 G972R, IRS2 G1079D, and the IGF1 CA-repeat polymorphisms. Outcomes were prostate cancer, Gleason score, and AJCC stage. RESULTS: The IRS1 G972R GR/RR genotypes were associated with a significant 2.8-fold increased risk for prostate cancer (95% CI 1.5-5.1, P = 0.0007). The other variants were not significantly associated with prostate cancer. The IRS1 G972R GR/RR genotypes were also significantly associated with more advanced Gleason score (P = 0.001) and AJCC stage (P = 0.004). CONCLUSIONS: These results support a role of the insulin and/or insulin-like growth factor pathways in the etiology of prostate cancer.     

An updating meta‐analysis of the GSTM1, GSTT1, and GSTP1 polymorphisms and prostate cancer: A HuGE Review

It has been postulated that individuals with GSTM1, GSTT1 deficiency and, GSTP1 (105Ile/Val transition) have increased susceptibility to carcinogens and are more likely to develop prostate cancer. In recent years, GST status has been extensively studied as a prostate cancer risk factor; however, the results are inconsistent. To re‐examine this controversy, we have undertaken an updating meta‐analysis of 29 studies with GSTM1 genotyping (4,564 prostate cancer cases and 5,464 controls), 22 studies with GSTT1 genotyping (3,837 cases and 4,552 controls), and 24 studies with GSTP1 genotyping (5,301 cases and 5,621 controls). The random effects odds ratio was 1.33 [95% confidence interval (95% CI): 1.15, 1.55; I² = 68.9%, P for heterogeneity = 0.00] for the GSTM1 null versus present genotype and 1.05 (95% CI: 0.86, 1.27; I² = 68.2%, P for heterogeneity = 0.00) for the GSTT1 null versus present genotype, and 1.06 (95% CI: 0.91, 1.24; I² = 71.5%, P for heterogeneity = 0.00) for the GSTP1‐Val versus GSTP1‐Ile allele. For GSTM1 polymorphism, similar results reached in Caucasians and Asians, with exception for Africans. No association between GSTT1 or GSTP1 polymorphisms and prostate cancer risk was detected in different racial. In conclusion, the major finding of our study suggested that GSTM1 polymorphism conferred an increasing risk of prostate cancer on a wide population basis, however, no relationship was found between GSTT1 and GSTP1 status and the risk of prostate cancer. Prostate 69:662–688, 2009. © 2009 Wiley‐Liss, Inc.     

Association of CYP17, GSTP1, and PON1 polymorphisms with the risk of prostate cancer

BACKGROUND: Dietary factors, life-style as well as environmental conditions may contribute to the risk of prostate tumor together with genetic susceptibility, that may be an important factor in determining who is more likely to develop prostate malignancy. We have undertaken a case-control study in order to elucidate the association between polymorphisms in some metabolizing genes with the risk of prostate cancer (PCa). METHODS: Polymorphisms of three xenobiotic genes (CYP17, GSTP1, PON1) were characterized in 384 patients with untreated PCa and 360 age-matched control patients with benign prostatic hyperplasia (BPH). All polymorphisms were investigated by PCR/RFLP methods using DNA from lymphocytes. RESULTS: We found that men with the CYP17/A1A1-A1A2 genotypes, GSTP1/IleVal genotype, PON192/QR and PON55/LM-MM genotypes had a significantly higher risk of PCa compared with the others genotypes. CONCLUSIONS: The three polymorphisms appear to be common genetic traits that are associated with an increased risk for PCa: the analysis of them all in each single case may be a predictable factor, particularly among groups exposed to PCa-related carcinogens.     

PD-1, PD-L1 and CTLA-4 in pregnancy-related – and in early-onset breast cancer: A comparative study

PurposeWe aimed to compare the immunohistochemical expression of PD-1, PD-L1 and CTLA-4 of pregnancy-related breast cancer (PRBC) and early onset non-PRBC (YWBC), and their prognosis prediction potential was correlated to that of conventional clinicopathological factors.MethodsTwenty-one PRBC cases were paired with 21 YWBC in this matched case-control study. Immune-checkpoint markers (ICM) were evaluated with immunohistochemistry (IHC) on whole slides using the following antibodies: PD-1 (NAT-105), PD-L1 (28-8) and CTLA-4 (F-8). IHC score was defined as the percentage of positive cells, assessed separately among tumor cells, intratumoral lymphocytes and peritumoral lymphocytes.ResultsThe optimal threshold of PD-L1 expression of tumor cells occurred at 10% for overall survival (OS, AUC = 0.847, p = 0.009), and at 1% for disease-free survival (DFS, AUC = 0.795, p = 0.010). For PD-L1 expression on intratumoral lymphocytes, the optimal cut-off was 1% (AUC = 0.763, p = 0.048). Considering PD-1, PD-L1 and CTLA-4 expression, no significant difference occurred between PRBC and YWBC (p > 0.05 for all comparisons). PD-1, PD-L1 expressed on peritumoral lymphocytes and CTLA-4 failed, but PD-L1 expressed on tumor cells and on intratumoral lymphocytes was suitable to distinguish patient cohorts with different OS and DFS (p ≤ 0.011 for all comparisons). Higher PD-L1 expression was associated with poor prognosis. PD-L1 expressed on tumor cells represented an independent association with OS (p = 0.023) and DFS (p = 0.032).ConclusionsOur results suggest that PRBC and YWBC do not differ in the expression of PD-1, PD-L1 and CTLA-4. However, our findings emphasize the relevance of PD-L1 expression in early-onset breast cancer, as an independent negative predictor of prognosis.     

Genetic polymorphism of sulfotransferase 1A1, cigarette smoking,hazardous chemical exposure and urothelial cancer risk in a Taiwanese population

Objectives: To investigate the association between genetic polymorphism of sulfotransferase1A1 (SULT1A1), cigarette smoking, hazardous chemical exposure and urothelial cancer risk in a Taiwanese population. Methods: In a hospital‐based case–control study, a total of 300 urothelial cancer (UC) cases and 300 cancer‐free controls frequency‐matched by age and gender were recruited from September 1998 to December 2005. The SULT1A1 arginine213histidine (Arg213His) polymorphism was genotyped using a polymerase chain reaction–restriction fragment length polymorphism method. Results: We found that the significantly increased UC risks of ever smokers and heavy smokers (≥28 pack‐years) were 2.1 (95% confidence interval [CI] = 1.4–3.3) and 2.2 (95% CI = 1.3–3.6), respectively. An increased UC risk of 1.8 (95% CI = 0.8–3.8) was observed among individuals with more than one item of hazardous chemical exposure, but it was not statistically significant. Compared with study subjects carrying the SULT1A1 Arg/Arg genotype, those with SULT1A1 Arg/His or His/His genotypes have a significantly decreased UC risk (Odds ratio [OR] = 0.5, 95% CI = 0.3–0.8). Heavy smokers carrying the SULT1A1 Arg/Arg genotype have a significantly increased UC risk (OR = 5.2, 95% CI = 2.3–11.6). Individuals who had been exposed to more than one item of hazardous chemicals and who carried the SULT1A1 Arg/Arg genotype have a significantly increased UC risk (OR = 3.7, 95% CI = 1.4–9.7). The highest significant increased UC risk (OR = 16.1, 95% CI = 2.9–87.2) was observed among ever smokers with hazardous chemical exposure and the SULT1A1 Arg/Arg genotype. Conclusions: SULT1A1 Arg213His polymorphism is associated with the development of UC, especially among cigarette smokers exposed to hazardous chemicals.     

Joint effect among p53, CYP1A1, GSTM1 polymorphism combinations and smoking on prostate cancer risk： an exploratory genotype-environment interaction study

Aim： To assess the role of several genetic factors in combination with an environmental factor as modulators of prostate cancer risk. We focus on allele variants of low-penetrance genes associated with cell control, the detoxification processes and smoking. Methods： In a case-control study we compared people carrying p53cd72 Pro allele, CYP1A1 M1 allele and GSTM1 null genotypes with their prostate cancer risk. Results： The joint risk for smokers carrying Pro^＊ and MI^＊, Pro^＊ and GSTM1null or GSTM1 null and CYP1A1 MI^＊ variants was significantly higher （odds ratio [OR]： 13.13, 95% confidence interval [CI]： 2.41-71.36; OR： 3.97, 95% CI： 1.13-13.95 and OR： 6.87, 95% CI： 1.68-27.97, respectively） compared with that for the reference group, and for non-smokers was not significant. OR for combinations among p53cd72, GSTM1 and CYP1A1 M1 in smokers were positively and significantly associated with prostate cancer risk compared with non-smokers and compared with the putative lowest risk group （OR： 8.87, 95% CI： 1.25-62.71）. Conclusion： Our results suggest that a combination of p53cd72, CYP1A1, GSTM1 alleles and smoking plays a significant role in modified prostate cancer risk on the study population, which means that smokers carrying susceptible genotypes might have a significantly higher risk than those carrying non-susceptible genotypes.     

Solitary brain metastasis from pT1, G3 bladder cancer

Abstract:   Brain metastasis from bladder cancer occurs rarely. Particularly, solitary brain metastasis is very rare in patients who have never received systemic chemotherapy. We encountered a patient who underwent transurethral resection of bladder tumor and bacillus Calmette-Guérin bladder instillation for pT1, G3 bladder cancer accompanied by carcinoma in situ , and subsequently revealed solitary brain metastasis after 34 months while neither cystoscopy nor urine cytology revealed abnormalities during this period. To our knowledge, our experience of solitary brain metastasis from pT1 bladder cancer is the second case in the world.     

缺氧诱导因子-1与前列腺癌研究进展

缺氧诱导因子-1(HIF-1)与前列腺癌存在密切的关系。研究表明HIF-1在前列腺癌中不但与血管生成因子、增殖与存活因子、葡萄糖转运以及糖分解酶等有关,而且与p53、p21、信号转导通路等有关。通过对HIF-1的深入研究将对前列腺癌的诊断与治疗提供新的思路。现对HIF-1的结构、功能及与前列腺癌关系进行综述。     

Glutathione peroxidase 1 (GPX1) genetic polymorphism, erythrocyte GPX activity, and prostate cancer risk

Glutathione peroxidase 1 (GPX1) is a ubiquitously expressed selenium-dependent enzyme that protects cells against oxidative damage by reducing hydrogen peroxide and a wide range of organic peroxides. Some epidemiological studies have correlated low GPX activity or particular GPX1 polymorphisms with enhanced risk of cancer, although these correlations have not been consistently observed in all populations. Therefore, we conducted the present study to evaluate the possible association of GPX1 Pro198Leu polymorphism and erythrocyte GPX activity with the risk of developing prostate cancer and to clarify whether erythrocyte GPX activity levels were correlated with the GPX1 Pro198Leu genotype in the Macedonian population. The GPX1 Pro198Leu genotype was determined in 82 prostate cancer cases and 123 control individuals. We found an overall protective effect of the variant Leu allele of the GPX1 polymorphism on the prostate cancer risk. Heterozygous carriers of the variant Leu allele had a significantly lower risk of prostate cancer compared with homozygous wild-type individuals (OR, 0.38; 95% CI, 0.20–0.75; P = 0.004). Erythrocyte GPX activity was analyzed in 73 cases and 91 controls. The erythrocyte GPX activity in the cancer group was lower than in the healthy controls. Additionally, we compared the erythrocyte GPX activity in the control group of 90 subjects and found no significant differences by genotype. These findings suggest that individual susceptibility of prostate cancer may be modulated by GPX1 polymorphism and that the combination of genetic factors involved in oxidative response with environmental carcinogens may play an important role in prostate carcinogenesis.     

Metabolic susceptibility genes and prostate cancer risk in a southern European population: the role of glutathione S-transferases GSTM1, GSTM3, and GSTT1 genetic polymorphisms

BACKGROUND: Glutathione S-transferase (GST) metabolic enzymes may be involved in the development of human cancer. Genetic polymorphisms have been reported in GSTM1, GSTM3, and GSTT1 with functional alterations and influencing cancer risk. METHODS: We analyzed DNA samples from 335 (670 alleles) unrelated individuals, 185 community control subjects, and 150 prostate cancer (PC) patients, for GSTM1, GSTM3, and GSTT1 genotypes using polymerase chain reaction (PCR). RESULTS: The analysis of the frequencies from the 670 alleles indicates that men carrying two B-alleles (GSTM3) have increased risk for PC (OR = 5.50, 95% confidence interval (CI) 1.2-25.8; P = 0.016). Multivariate logistic regression analysis confirmed this association (OR = 5.2, 95% CI 1.1-25.0; P = 0.036). No increased PC risk was observed for men carrying any of the GSTM1 or GSTT1 genotypes (OR = 1.20, 95% CI 0.75-1.90; P = 0.420 for GSTM1 null and OR = 0.87, 95% CI 0.50-1.51; P = 0.550 for GSTM1 null). However, GSTT1 null was overrepresented in men with advanced PC disease (P = 0.038). CONCLUSIONS: Our results indicate that polymorphism in the GSTM3 may be an important biomarker for PC risk, especially in the definition of the genetic risk profile of populations of southern Europe.     

Overexpression of protease-activated receptors-1,-2, and-4 (PAR-1, -2, and -4) in prostate cancer

BACKGROUND: Although protease-activated receptors (PARs) have been described to play a role in different malignancies, their expression and biological activity in prostate cancer are mostly unknown. METHODS: PAR expression in radical prostatectomy specimens was investigated by immunohistochemistry (IHC, 40 patients) and RT-PCR. Their role in LNCaP prostate cancer cell migration and Rac1/Cdc42 signaling was assessed with Boyden chamber analysis and Western blot, respectively. RESULTS: PAR mRNA expression was higher in cancer, and protein expression was increased in PAR-1 (45%), PAR-2 (42%), and PAR-4 (68%), compared to normal glands. Increased PAR-1 (periglandular stroma) was associated with higher rates of biochemical recurrence (median follow-up, 5 years; P = 0.006). LNCaP migration was enhanced twofold and Rac1/Cdc42 signaling was activated by stimulation of PAR-1 and PAR-2. CONCLUSIONS: PARs are overexpressed in prostate cancer and may serve as potential predictors of recurrence. The data suggest potential role of PARs in autocrine and paracrine mechanisms of prostate cancer.     

Breast cancer risk associated with CYP1A1 genetic polymorphisms in Japanese women

Although several reports are available on the association between CYP1A1 polymorphisms and breast cancer risk in Caucasian women, it has never been reported in Japanese women. Since breast cancer incidence and clinicopathologic features of breast cancers are different between Japanese and Caucasian women, it is conceivable that the risk factors of breast cancer might also differ. In addition, a preliminary study has shown that the frequencies of the variant allele in the CYP1A1 gene are different among ethnic groups. Therefore, in the present study, we investigated the association of CYP1A1 polymorphisms with breast cancer risk in Japanese women. The association of two CYP1A1 polymorphisms, that is, 3' noncoding region (6235(T/C)) and codon 462 (Ile/Val), with breast cancer risk was analyzed by a case-control study (195 cases and 272 controls). Variant allele 6235C carriers at the 3' noncoding region polymorphism showed a significantly ( p < 0.01) reduced breast cancer risk (odds ratio 0.60; 95% CI 0.41–0.88) as compared with noncarriers, and variant allele 462Val carriers at the codon 462 polymorphism also showed a significantly ( p < 0.05) reduced risk (odds ratio 0.66; 95% CI 0.45–0.96) as compared with noncarriers. The relationship between the genetic polymorphisms and clinicopathologic characteristics of breast cancers was also investigated. Variant allele 6235C carriers showed a significantly ( p < 0.02) higher positivity of lymph node metastasis than noncarriers (54% versus 36%), and tumors measuring less than 2 cm were significantly ( p < 0.03) more frequently observed in variant allele 462Val carriers than noncarriers (50% versus 33%). These results suggest that the CYP1A1 polymorphisms would be useful for predicting breast cancer risk as well as some tumor characteristics in Japanese women.