GSTM1 is a glutathione S-transferase (GST) which play a role in the detoxification of metabolites of environmental carcinogens including tobacco smoke. There is some evidence to suggest that people with common polymorphisms of these genes may have an increased susceptibility to a range of different cancers. This susceptibility is often associated with a combined effect of other GST genes; GSTP1
. Polymorphisms in these genes have also been associated with pharacogenetics, toxicity to chemotherapy, and treatment outcome in some studies.
Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (11)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
|Head and Neck Cancers||GSTM1 and Head and Neck Cancers|| View Publications||275|
|Lung Cancer||GSTM1 and Lung Cancer|| View Publications||274|
|Breast Cancer||GSTM1 and Breast Cancer|| View Publications||171|
|Colorectal Cancer||GSTM1 and Colorectal Cancer|| View Publications||159|
|Bladder Cancer||GSTM1 and Bladder Cancer|| View Publications||147|
|Lung Cancer||Tabacco smoke, GSTM1 Polymorphisms and Suceptability to Lung Cancer|
There is some evidence to suggest that people with common polymorphisms of GSTM1 and other Glutathione S-transferase genes may have an increased susceptibility to lung cancer when exposed to Tobacco. In a case-control study of 136 NSCLC patients (Tang, 1998) results suggested that the effect of the GSTM1 null genotype is greatest in female smokers. Other research (Bennett, 1999) indicates that people with the GSTM1 null allele may be more suseptible to lung cancer on exposure to envoronmental tabacco smoke.
| View Publications||88|
|Oral Cavity Cancer||GSTM1 and Oral Cavity Cancer|| View Publications||86|
|Prostate Cancer||GSTM1 and Prostate Cancer|| View Publications||81|
|Acute Lymphocytic Leukemia (ALL), child||GSTM1 Polymorphisms and Susceptibility to Leukemia Prognostic|
Several studies have indicated significantly increased susceptibility to acuate leukemia, including childhood ALL, with a GSTM1 null genotype and also associated with GSTT1 polymorphisms.
| View Publications||28|
|Thyroid Cancer||GSTM1 and Thyroid Cancer|| View Publications||19|
|Acute Lymphocytic Leukemia (ALL), child||GSTM1 Polymorphisms and Treatment Response in Childhood Leukemia Therapy|
Some studies indicate that polymorphisms in genes encoding enzymes involved in drug detoxification and metabolism (including STM1,GSTP1, MTHFR, MTRR) influence treatment responce in childhood acute lymphoblastic leukemia. For example Sepe et al (2012) found that MTRR A/G and GSTM1 null genotype, significantly increased the risk of relapse.
| View Publications||8|
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: GSTM1 (cancer-related)
Zajda K, Rak A, Ptak A, Gregoraszczuk ELCompounds of PAH mixtures dependent interaction between multiple signaling pathways in granulosa tumour cells.
Toxicol Lett. 2019; 310:14-22 [PubMed
] Related Publications
Mechanism of PAH mixtures, using granulosa tumour cells, was investigated. Cells were exposed to a mixture of all 16 priority PAHs (M1) or a mixture of five PAHs not classified as human carcinogens (M2). The effect of siAHR, siAHRR and siNFKB2 on the expression of CYP1A1, CYP1B1, GSTM1, ERα, AR and cell proliferation was described. M1 decreased AhR and CYP1A1, while increased AhRR and ARNT expression. M2 also decreased AhR and CYP1A1 but had no effect on AhRR expression. siAHRR reversed the inhibitory effect of M1 on AhR and CYP1A1,while inhibitory effect of M2 was still observed. siNFKB2 reversed inhibitory effect of both mixtures on AhR and CYP1A1 expression and stimulatory effect of M1 on AhRR expression. siAHR reversed stimulatory effect of both mixtures on ERα expression. Stimulatory effect of M1 on cell proliferation was not observed in siAHR, was still observed in siESR1 cells. M2 had no effect on cell proliferation, however stimulatory effect was appeared in siAHR and siESR1cells. In conclusion: M1 by activation of AhRR and NFkB p52, but M2 only by activation of NFκB attenuated AhR signalling and ligand-induced CYP1A1 expression. Interaction between AhR and ER following M1 and M2 exposure is primarily initiated through AhR.
Moghimi M, Sobhan MR, Jarahzadeh MH, et al.Association of GSTM1, GSTT1, GSTM3, and GSTP1 Genes Polymorphisms with Susceptibility to Osteosarcoma: a Case- Control Study and Meta-Analysis
Asian Pac J Cancer Prev. 2019; 20(3):675-682 [PubMed
] Related Publications
Background: Some studies have investigated the association of GSTM1, GSTT1, GSTM3, and GSTP1
polymorphisms with susceptibility to osteosarcoma; however, these studies results are inconsistent and inconclusive. In
order to drive a more precise estimation, the present case-control study and meta-analysis was performed to investigate
association of GSTM1, GSTT1, GSTM3, and GSTP1 polymorphisms with osteosarcoma. Methods: Eligible articles
were identified by a search of several electronic databases for the period up to May 5, 2018. Odds ratios were pooled
using either fixed-effects or random effects models. Results: Finally, a total of 24 case-control studies with 2,405
osteosarcoma cases and 3,293 controls were included in the present meta-analysis. Overall, significantly increased
osteosarcoma risk was found when all studies were pooled into the meta-analysis of GSTT1 (Null vs. Present: OR= 1.247
95% CI 1.020-1.524, P= 0.031) and GSTP1 polymorphism (B vs. A: OR= 8.899 95% CI 2.722-29.094, P≤0.001). In
the stratified, significantly increased osteosarcoma risk was observed for GSTT1 polymorphism among Asians (Null
vs. Present: OR= 1.300 95% CI 1.034-1.635, P= 0.025), but not among Caucasians. Conclusions: This meta-analysis
demonstrated that GSTP1 and GSTT1 null genotype are associated with the risk of osteosarcoma. Future large welldesigned
epidemiological studies are warranted to validate our results.
Kalacas NA, Garcia JA, Sy Ortin T, et al.GSTM1 and GSTT1 Genetic Polymorphisms and Breast Cancer Risk in Selected Filipino Cases
Asian Pac J Cancer Prev. 2019; 20(2):529-535 [PubMed
] Related Publications
Background: The association of genetic polymorphisms with cancer development has been shown to be race- and
tumor site-specific. Thus, this study aimed to determine whether polymorphisms in the GSTM1 and GSTT1 genes
are associated with breast cancer among selected Filipinos. Methods: A total of 136 histologically confirmed breast
cancer cases were age- and sex-matched with 136 clinically healthy controls. Genomic DNA extracted from blood
samples of participants were screened for GSTM1 and GSTT1 genetic polymorphisms by multiplex PCR. Results:
The frequency of null genotypes among the cases (GSTM1: n=78; 57.4%; GSTT1: n=61; 44.9%) was not significantly
different (p>0.05) from the controls (GSTM1: n=93; 68.4%; GSTT1: n=59; 43.4%). It was also demonstrated that risk
for breast cancer was increased in passive smokers carrying the GSTM1 null (OR=2.56; 95% CI=1.38-4.75) or GSTT1
positive (OR=2.00; 95% CI=1.05-3.83) genotypes. Moreover, risk was decreased in alcohol users carrying the GSTT1
null (OR=0.39; 95% CI=0.16-0.97) genotype. Conclusion: This study suggests that variants of GSTM1 and GSTT1
may not be risk factors for breast cancer development among Filipinos. However, the risk may be increased when these
genotypes were combined with lifestyle or environmental factors.
Maccormick TM, Carvalho CES, Bravo Neto GP, Carvalho MDGDCComparative analysis of glutathione transferase genetic polymorphism, Helicobacter pylori and Epstein-Barr virus between the tumor area and the proximal and distal resection margins of gastric cancer.
Rev Col Bras Cir. 2019; 46(1):e2068 [PubMed
] Related Publications
OBJECTIVE: to compare the polymorphism of the Glutathione S-transferase theta 1 (GSTT1) and Glutathione S-transferase mu 1 (GSTM1) genes from the tumor area with the proximal and distal margins of stomach specimens resected from patients with gastric cancer, and to investigate the presence of Epstein-Barr virus (EBV) DNA and Helicobacter pylori.
METHODS: we prospectively collected tissue specimens from the tumor area and from the proximal and distal resection margins of the stomachs of ten patients with gastric adenocarcinoma who underwent gastrectomy with D2 lymphadenectomy, and submitted these specimens to DNA extraction. We compared the tumor area with the proximal and distal margins of the resected stomachs for polymorphism of GSTT1 and GSTM1 genes and investigated the presence of EBV-DNA and H. pylori. We used the p53 exon 5 gene as an internal control of the multiplex PCR reaction.
RESULTS: in one patient, we detected null GSTT1 and GSTM1 genotypes in the tumor area, in contrast to the presence of both genes in the proximal and distal margins. We found EBV-DNA and H. pylori in the tumor area and also in the proximal and distal margins. In another patient, the proximal margin was negative for GSTT1, and EBV-DNA was negative in the distal margin. In three patients, EBV-DNA was negative only in the distal margin.
CONCLUSION: this is the first report where different genotypes, EBV-DNA and H. pylori infection were observed in the same patient, indicating a probable deletion of these genes in response to tumor progression and intratumoral heterogeneity.
Cheng H, Huang C, Tang G, et al.Emerging role of EPHX1 in chemoresistance of acute myeloid leukemia by regurlating drug-metabolizing enzymes and apoptotic signaling.
Mol Carcinog. 2019; 58(5):808-819 [PubMed
] Related Publications
Microsomal epoxide hyrolase 1 (EPHX1) is a critical biotransformation enzyme and participants in both the detoxification and activation of potentially genotoxic epoxides. In this study, we firstly aimed to investigate the role of EPHX1 in the chemoresistance of acute myeloid leukemic cells to aclarubicin (ACM) and mitoxantrone (MIT). EPHX1 mRNA expression and prognosis were measured in acute myeloid leukemia (AML) patients, and the function of EPHX1 in leukemic cell viability and apoptosis induced by ACM and MIT was also measured. Our results found that EPHX1 expression is obviously associated with recurrence rate, overall survival and time of obtaining first complete remission in AML patients. EPHX1 silencing promoted ACM and MIT induced decrease in cell viability and cell apoptosis of HL-60, K562, and THP-1 that was inhibited by EPHX1 overexpression. EPHX1 reduced the susceptibility of leukemic cells to ACM and MIT by regulating drug-metabolizing enzymes (CYP1A1, GSTM1, and GSTT1) and apoptotic signaling (Bax, Bcl-2, Caspase-3, Caspase-9, and PARP1). Moreover, Nrf2 overexpression significantly increased EPHX1 expression and leukemic cell viability and decreased leukemic cell apoptosis. Taken together, we summarized the recent findings about the chemoresistance-promoting role of EPHX1, and the potential of targeting EPHX1 was proposed to counteract drug resistance in leukemia treatment.
We observed inconsistent conclusions regarding the genetic role of glutathione S-transferase gene polymorphisms, including glutathione S-transferase M1 (
Transforming growth factor (TGF)-β signaling is increasingly recognized as a key driver in cancer. In progressive cancer tissues, TGF-β promotes tumor formation, and its increased expression often correlates with cancer malignancy. In this study, we utilized adenoviruses expressing short hairpin RNAs against TGF-β1 and TGF-β2 to investigate the role of TGF-β downregulation in cancer cell death. We found that the downregulation of TGF-β increased the phosphorylation of several SAPKs, such as p38 and JNK. Moreover, reactive oxygen species (ROS) production was also increased by TGF-β downregulation, which triggered Akt inactivation and NOX4 increase-derived ROS in a cancer cell-type-specific manner. We also revealed the possibility of substantial gene fluctuation in response to TGF-β downregulation related to SAPKs. The expression levels of Trx and GSTM1, which encode inhibitory proteins that bind to ASK1, were reduced, likely a result of the altered translocation of Smad complex proteins rather than from ROS production. Instead, both ROS and ROS-mediated ER stress were responsible for the decrease in interactions between ASK1 and Trx or GSTM1. Through these pathways, ASK1 was activated and induced cytotoxic tumor cell death via p38/JNK activation and (or) induction of ER stress.
BACKGROUND: We conducted a meta-analysis to evaluate the relationship between the glutathione S-transferase μ1 (GSTM1)- and glutathione S-transferase θ1 (GSTT1)- null genotypes and susceptibility to bladder cancer.
METHODS: We identified association reports from the databases of PubMed, Embase, the Cochrane Library and the China Biological Medicine Database (CBM disc) on July 1, 2017 and synthesized eligible investigations. Results were expressed using odds ratios (ORs) for dichotomous data, and we also calculated 95% confidence intervals (CIs).
RESULTS: In this meta-analysis, we found that the GSTM1-null genotype was associated with bladder cancer risk in the overall population, and individually in whites, Africans and Asians (overall population: OR = 1.40, 95% CI: 1.31-1.48, P<0.00001; whites: OR = 1.39, 95% CI: 1.26-1.54, P<0.00001; Africans: OR = 1.54, 95% CI: 1.16-2.05, P = 0.003; Asians: OR = 1.45, 95% CI: 1.33-1.59, P<0.00001). The GSTT1-null genotype was associated with bladder cancer risk in the overall population, but not in whites, in Africans or Asians (overall population: OR = 1.11, 95% CI: 1.01-1.22, P = 0.03; whites: OR = 1.16, 95% CI: 0.99-1.36, P = 0.07; Africans: OR = 1.07, 95% CI: 0.65-1.76, P = 0.79; Asians: OR = 1.05, 95% CI: 0.91-1.22, P = 0.51). Interestingly, a dual-null GSTM1-GSTT1 genotype was associated with bladder cancer risk in the overall population and in Asians (overall population: OR = 1.48, 95% CI: 1.15-1.92, P = 0.002; Asians: OR = 1.62, 95% CI: 1.15-2.28, P = 0.006). In conclusion, the GSTM1-null, GSTT1-null and dual-null GSTM1-GSTT1 genotypes might be associated with the onset of bladder cancer, but additional genetic-epidemiological studies should be conducted to explore this association further.
Adibhesami G, Shahsavari GR, Amiri A, et al.Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) Polymorphisms and Lung Cancer Risk among a Select Group of Iranian People
Asian Pac J Cancer Prev. 2018; 19(10):2921-2927 [PubMed
] Free Access to Full Article Related Publications
Objective(s): Lung cancer, caused primarily by smoking, is one of the leading determinants of mortality throughout
the world. Here we investigated the effects of polymorphisms in two enzymes, i.e., GSTT1 and GSTM1, related to
the antioxidant defense line against carcinogens associated with lung cancer among a select group of Iranian people.
Materials and Methods: One hundred and twenty lung cancer patients from two referral centers in Tehran, Iran, were
recruited for comparison with 120 healthy controls. Genomic DNA was extracted from the FFPE tumor tissues of
the select cases and peripheral blood buffy coats of healthy controls. The polymorphisms of GSTT1 and GSTM1 were
investigated by multiplex polymerase chain reaction. Results: With the 240 samples studied, no specific relationship
with lung cancer was discerned for the GSTM1 (P=0.35; OR=1/33; 95% CI=0.79-2.25) polymorphism, but the GSTT1
(P=0.005; OR=2.4; CI=1.32-4.35) gene polymorphism revealed a notable association on logistic regression, taking
into account age and sex factors. Furthermore, the GSTT1 genotype distribution in patients with LSCC was different
from that of healthy cases (P=0.006; OR=3.11; CI=1.38-7.04). The risk of developing lung cancer with the T0M1
genotype was 3.46 times higher than with T1M1 genotype (P=0.002; OR=3.46; CI=1.61-7.46). Moreover, the risk of
developing LSCC cancer in people with T0M1 genotypes was significantly elevated (P=0.004; OR=4.5; CI=1.62-12.52).
Conclusion: Unlike GSTM1, the GSTT1 genotype distribution is associated with the incidence of lung cancer in Iranian
people. Different types of lung cancer appear to show various correlations with GST polymorphisms in this regard.
Objective: Prostate cancer (PCa) is a major public health problem worldwide, with high morbidity and mortality
levels. Advanced age, androgen stimulation, and ethnicity have been reported to be possible risk factors. It has been
suggested that particular genetic polymorphisms in glutathione S-transferases (GST), xenobiotic-metabolising enzymes,
could predispose to prostate cancer through heritable deficiency in detoxification of environmental carcinogens.
Conflicts in the published results and the absence of similar in depth studies in Algeria prompted us to perform the
present case-control study of GSTM1 and GSTT1 polymorphisms and their possible association with PCa in an Algerian
population. Methods: We determined GSTM1 and GSTT1 genotypes for 49 histologically verified prostate cancer
patients and in 41 age-matched healthy controls by multiplex polymerase chain reaction (PCR) using peripheral blood
DNA samples. Result: While an association between the GSTM1 null genotype and PCa risk (OR= 3.69, 95% CI=
1.30-10.44; P = 0.01) was evident, the GSTT1 null genotype (OR= 0.92, 95% IC= 0.32-2.62; P = 0.49) appeared without
influence. Furthermore, no statistically significant differences between the double null genotype and PCa is detected,
also no statistically significant differences between smoking status and PCa is detected. Conclusion: The GSTM1 null
genotype may increase individual susceptibility to prostate cancer. On the other hand, the null-activity genotype of
GSTT1 did not appear to contribute to the risk of prostate cancer in our population.
AIM: To evaluate the association between polymorphisms in glutathione S transferases (GSTs) and the risk of sporadic colorectal cancer (SCRC), tumor progression and the survival of patients.
METHODS: A case-control study of 970 individuals from the Brazilian population was conducted (232 individuals from the case group with colorectal cancer and 738 individuals from the control group without a history of cancer). PCR multiplex and PCR-RFLP techniques were used to genotype the GST polymorphisms. The tumors were categorized according to the TNM classification: tumor extension (T), affected lymph nodes (N), and presence of metastasis (M). Logistic regression, multiple logistic regression and survival analysis were used to analyze the data. The results are presented in terms of odds ratio (OR) and 95% confidence interval (CI). The level of significance was set at 5% (
RESULTS: Age equal to or over 62 years (OR = 8.79; 95%CI: 5.90-13.09,
CONCLUSION: Females aged 62 years or older are more susceptible to SCRC. Polymorphisms of
Wang H, Gao X, Zhang X, et al.Glutathione S-Transferase Gene Polymorphisms are Associated with an Improved Treatment Response to Cisplatin-Based Chemotherapy in Patients with Non-Small Cell Lung Cancer (NSCLC): A Meta-Analysis.
Med Sci Monit. 2018; 24:7482-7492 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND Previous studies have shown an association with glutathione S-transferase (GST) gene polymorphisms in patients with non-small cell lung cancer (NSCLC) and treatment response. This study aimed to undertake a literature review and meta-analysis of GST gene polymorphisms, including GSTT1, GSTM1, and GSTP1 IIe105Val, and the treatment response to cisplatin-based chemotherapy in patients with NSCLC. MATERIAL AND METHODS A literature search was undertaken of the main medical publication databases for publications, up to March 2017, on the association between GSTT1, GSTM1, and GSTP1 IIe105Val polymorphisms and the clinical outcome in patients with NSCLC treated with cisplatin-based chemotherapy. A random fixed-effects model was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) to evaluate the associations, considering multiple genetic models. A subgroup analysis according to ethnicity was performed. RESULTS Twenty-three published studies were identified that showed that both the null GSTM1 and the GG genotype of GSTP1 IIe105Val were associated with improved treatment response to cisplatin-based chemotherapy (GSTT1 present/null: OR=1.328; 95% CI, 1.074-1.643) (GSTP1 GG + AG vs. AA: OR=0.596; 95% CI, 0.468-0.759). In subgroup analysis, the GSTP1 polymorphism was significantly associated with treatment response in East-Asian patients, but not in Caucasian patients. CONCLUSIONS Meta-analysis showed that the GG genotype of GSTP1 IIe105Val and the null GSTM1 genotype were associated with an improved treatment response to cisplatin-based chemotherapy in patients with NSCLC, especially in East-Asian patients.
Ahmed W, Malik MFA, Saeed M, Haq FCopy number profiling of Oncotype DX genes reveals association with survival of breast cancer patients.
Mol Biol Rep. 2018; 45(6):2185-2192 [PubMed
] Related Publications
Copy number variations (CNVs) are key contributors in breast cancer initiation and progression. However, to date, no CNV-based gene signature is developed for breast cancer. 21-gene Oncotype DX, a clinically validated signature, was identified using only RNA expression data in breast cancer patients. In this study, we evaluated whether CNVs of Oncotype DX genes can be used to predict the prognosis of breast cancer patients. Transcriptomic data of 547 and genomic data of 816 of breast cancer patients were downloaded from The Cancer Genome Atlas database. To establish the prognostic relevance between the CNVs of Oncotype DX genes and clinicopathological features, statistical analysis including Pearson Correlation, Fisher-exact, Chi square, Kaplan-Meier survival and Cox regression analyses were performed. 86% genes showed positive CNV-expression correlation. CNVs in 52% and 47.6% genes showed association with ER+ and PR+ status, respectively. 71% of the genes (including ERBB2, CTSV, CD68, GRB7, MKI67, MMP1, PGR, RPLP0, TFRC, BAG1, BCL2, BIRC5, FLNB, GSTM1 and SCUBE2) showed association with poor overall survival. 14% of the genes (including CTSV, RPLP0 and BIRC5) genes showed association with disease free survival. Cox regression analysis revealed ESR1, metastasis and node stage as independent prognostic factors for overall survival of breast cancer patients. The results suggested that CNV-based assay of Oncotype DX genes can be used to predict the survival of breast cancer patients. In future, identifying new gene signatures for better breast cancer prognosis using CNV level information will be worth investigating.
Sengupta D, Guha U, Mitra S, et al.Meta-Analysis of Polymorphic Variants Conferring Genetic Risk to Cervical Cancer in Indian Women Supports CYP1A1
as an Important Associated Locus
Asian Pac J Cancer Prev. 2018; 19(8):2071-2081 [PubMed
] Free Access to Full Article Related Publications
Objective: Association of multiple polymorphic variants with cervical cancer has been elucidated by several
candidate gene based as well as genome-wide association studies. However, contradictory outcomes of those studies
have failed to estimate the true effect of the polymorphic variants on cervical cancer. Methods: Literature mining of
the PubMed database was done to gather all the publications related to genetic association with cervical cancer in India.
Out of 98 PubMed hits only 29 genetic association studies were selected for meta-analysis based on specific inclusion
criteria. A fixed-effect meta-analysis was performed to evaluate the overall association of the genetic polymorphisms
with cervical cancer. Cochran’s Q test was performed to assess between study heterogeneity. Publication bias was
also estimated by funnel plots and Egger’s regression test. Further, sub-group analysis was conducted by fixed-effect
meta-regression to assess the impact of polymorphisms on cervical cancer in the presence of Human Papilloma Virus
(HPV). Result: Following a fixed-effect model, meta-analysis was conducted that revealed 2 polymorphic variants
viz. ‘deletion polymorphism (Del2) (OR=1.79, 95% CI= 1.08-2.95, P=0.023) in GSTM1’ and ‘rs1048943 (OR = 2.34,
95% CI=1.37-3.99, P=0.0018) in CYP1A1’ to be associated with cervical cancer. However, multiple testing correction
showed only rs1048943 of CYP1A1 to be significantly associated (P-value=0.029) with cervical cancer with significant
publication bias (P-value=0.0113) as estimated by Egger’s regression test. The polymorphic variants ‘rs1801131’,
‘rs1801133’, ‘rs2430561’, ‘rs1799782’, ‘rs25486’ and ‘rs25487’ showed significant (p<0.05) evidence of heterogeneity
between studies by Cochran’s Q test and also by heterogeneity index (I2) calculation. Conclusion: Therefore, our study
revealed significant association of rs1048943 in CYP1A1, but a nominal association of deletion polymorphism (Del2)
in GSTM1 with cervical cancer, which provides a comprehensive insight on the true effect of the polymorphisms,
reported in various case-control studies, on the risk of the development of cervical cancer in Indian women.
Waś J, Karasiewicz M, Bogacz A, et al.The diagnostic potential of glutathione S-transferase (GST) polymorphisms in patients with colorectal cancer.
Adv Clin Exp Med. 2018; 27(11):1561-1566 [PubMed
] Related Publications
BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers in the world. Despite improvements in screening for early diagnosis, CRC is one of the leading causes of cancer deaths.
OBJECTIVES: The aim of the study was to determine a potential association between the frequency of GSTM1 and GSTT1 null genotypes and the risk of CRC in the Polish population. Moreover, we analyzed the clinical parameters with the glutathione S-transferase (GST) gene polymorphisms in patients with CRC.
MATERIAL AND METHODS: The study was conducted on 512 Caucasians, including 279 patients (105 women and 174 men) with CRC. DNA from peripheral blood was extracted and the multiplex polymerase chain reaction (PCR) technique was used for glutathione S-transferase theta (GSTT1) and mu (GSTM1) gene deletion genotyping.
RESULTS: We found no statistically significant differences in the frequency of the GST gene polymorphisms in patients with CRC and controls. The prevalence of the GSTM1*0 variant in the test subjects was higher than in controls (45.9% vs 42.9%; p > 0.05). The frequency of the GSTT1*0 variant was also higher in patients with CRC compared to the control population (21.1% vs 18.9%; p > 0.05). In addition, the effect of the GSTM1 and GSTT1 polymorphisms on the incidence of CRC was also analyzed. There was a slight, but not statistically significant, increase of the risk of colon cancer for the GSTM1*0 and GSTT1*0 variants. Moreover, we examined the GST genotype due to the cancer TNM classification and the location of the primary tumor. Statistically significant differences in the distribution of the GSTT1*0 and GSTT1*1 genotypes in both the stage and the location of the primary tumor were observed.
CONCLUSIONS: It is suggested that the GSTT1 polymorphism may have an impact on the severity of the tumor and its location.
Abbas M, Kushwaha VS, Srivastava K, et al.Impact of GSTM1, GSTT1 and GSTP1 genes polymorphisms on clinical toxicities and response to concomitant chemoradiotherapy in cervical cancer.
Br J Biomed Sci. 2018; 75(4):169-174 [PubMed
] Related Publications
BACKGROUND: Certain forms of chemoradiotherapy generate toxic reactive oxygen species, which may be ameliorated by antioxidant enzymes such as glutathione S-transferase (GST). Genetic polymorphisms of GST may predict treatment outcomes and can be used as genetic marker to screen patients before treatment. We hypothesised an effect of GST polymorphisms on the response and toxicities produced by chemoradiation therapy.
MATERIALS AND METHODS: GST polymorphisms were determined by multiplex polymerase chain reaction and PCR-restriction fragment length polymorphism (PCR-RFLP) in 227 women with cervical cancer receiving cisplatin based chemoradiotherapy. Treatment response and toxicities were evaluated by standard internationally recognised criteria (RECIST and RTOG).
RESULTS: Severe (grade 3-4) gastrointestinal and haematological toxicities were present in 22 (9.4%) and 16 (7.0%) patients, respectively. GSTM1 null, GSTT1 null and GSTP1 AG genotypes brought marginally better non-significant associations. In single locus analysis GSTP1 AG and GG was linked to greatest risk of severe (grade 3-4) gastrointestinal toxicity (OR = 3.12, P = 0.035 and OR = 6.99, P = 0.01, respectively). In gene-gene interaction analysis, GSTM1 null-GSTP1 GG showed 4.2-fold higher risk of severe gastrointestinal toxicity (P = 0.014). GSTT1 null-GSTP1 AG reached statistical significance with a 3.9-fold higher risk of high grade gastrointestinal toxicity (P = 0.038).
CONCLUSIONS: Although no significant links were found between GST polymorphism and treatment response, null genotypes of GSTM1, GSTT1 and 'G' allele of GSTP1 bring a higher risk of severe gastrointestinal toxicity due to chemoradiation therapy in cervical cancer.
Zhong Z, Li H, Zhong H, et al.A systematic review and meta-analyses of the relationship between glutathione S-transferase gene polymorphisms and renal cell carcinoma susceptibility.
BMC Med Genet. 2018; 19(1):98 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Association of GSTM1- and GSTT1-null genotypes, GSTP1 A/G gene polymorphism with renal cell carcinoma (RCC) susceptibility was detected, and the relationship between the GSTM1/GSTT1-null genotype and clinical TNM stages of RCC was assessed, using meta-analysis method.
METHODS: Association investigations according to eligibility criteria were searched and identified from the databases of Cochrane Library, PubMed, and Embase from establishment time of databases to July 1, 2017, and eligible reports were analyzed by meta-analysis. 95% confidence intervals (CI) were also detected, and odds ratios (OR) was used to express the results for dichotomous data.
RESULTS: This meta-analysis indicated that there was no an association between GSTM1-null genotype, GSTT1-null genotype, GSTP1 A/G gene polymorphism and RCC risk in the overall population of Caucasians or Asians. The dual GSTM1-GSTT1-null genotype was also not associated with RCC in the overall population of Caucasians. Interestingly, there was an association between the dual GSTM1-GSTT1-null genotype and the susceptibility of RCC in Asians. Relationship of the GSTM1-null genotype with clinical TNM stage of RCC was not observed in the overall population of Asians or Caucasians. In this meta-analysis, no association between the GSTT1-null genotype and clinical TNM stage of RCC was observed in Caucasians or Asians. Interestingly, GSTT1-null genotype was detected to be associated with the clinical TNM stages in patients with RCC in the overall population.
CONCLUSION: The dual GSTM1-GSTT1-null genotype is detected to be associated with the onset of RCC in Asians, and there is an association between the GSTT1-null genotype and the clinical TNM stages in patients with RCC in the overall population.
Fernández Asensio A, Iglesias T, Cotarelo A, et al.Multiplex polymerase chain reaction in combination with gel electrophoresis-inductively coupled plasma mass spectrometry: A powerful tool for the determination of gene copy number variations and gene expression changes.
Anal Chim Acta. 2018; 1023:64-73 [PubMed
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During the last few years multiplex real-time or quantitative polymerase chain reaction PCR (qPCR) has become the method of choice for multiplex gene expression changes and gene copy number variations (CNVs) analysis. However, such determinations require the use of different fluorescent labels for the different amplified sequences, which increases significantly the costs of the analysis and limits the applicability of the technique for simultaneous amplification of many targets of interest in a single reaction. In this regard, the use of the coupling between gel electrophoresis (GE) separation with inductively coupled plasma mass spectrometry (ICP-MS) detection allows the label-free determination of multiplex PCR-amplified sequences (amplicons) by monitoring the P present in the DNA backbone. The quantitative dimension is obtained since under optimal and controlled multiplex PCR conditions the peak areas of the separated amplicons are directly proportional to the amount of DNA template in the original sample. Moreover, the calibration of the GE-ICP-MS system with a DNA ladder permits direct estimation of the size (bp) of the PCR products. The suitability of the proposed multiplex strategy has been evaluated addressing two different situations: determination of CNVs and gene expression changes in human ovarian cancer cells. In the first case, the results obtained for the simultaneous quantitation of CNVs of four genes (HER2, CCNE1, GSTM1, ACTB) on DNA obtained from OVCAR-3 cells were in accordance with the literature data, and also with the results obtained by conventional simplex qPCR. In the second case, multiplex gene expression changes of BAX, ERCC1 and CTR1 genes, using ACTB as constitutive gene, on A2780cis respect to A2780 cells, resistant and sensitive to cisplatin, respectively, provided the same information as single reaction reverse transcription (RT)-qPCR.
Fathi Z, Syn NL, Zhou JG, Roudi RMolecular epidemiology of lung cancer in Iran: implications for drug development and cancer prevention.
J Hum Genet. 2018; 63(7):783-794 [PubMed
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Epidemiological studies undertaken over the past decades reveal a gradual but progressive increase in the incidence and mortality attributable to lung cancer in the Islamic Republic of Iran, a sovereign state geographically situated at the crossroads of Central Eurasia and Western Asia. We identified references published in English and Persian through searches of PubMed, EMBASE, Web of Science, Scopus, and the Scientific Information Database (SID)-a specialized Iranian database, which indexes Iranian scientific journals-between inception and 15 September 2017. Of 1475 references identified through electronic searches, we reviewed the full text of 88 studies, and included 38 studies in the review. Potentially druggable NSCLC targets, which have been studied in Iran include EGFR, ALK, ERBB2, and KIT; but no studies were found, which examined the impact of MET, ROS1, BRAF, PIK3CA, and FGFR1 aberrations. We were able to identify some literature on DNA repair genes and xenobiotic metabolism, including TP53, TP63, ERCC2, XRCC2, SIRT1, PTEN, CYP1A1, CYP1B1, GSTT1, and GSTM1. We also found an increasing amount of research performed in relation to the tumor microenvironment and immune contexture, including CTLA4, MAGE, FOXP3, IFN-γ, and various interleukins, chemokines, and transcription factors; but did not identify any publication concerning the expression of PD-1/PD-L1 in lung cancer. Our survey of research performed in Iran has revealed a dearth of studies in topics, which are otherwise highly pursued in developed countries, but nevertheless, has begun to hint at a distinct biology of lung cancer in this part of the world.
Background: Epidemiological research has highlighted the global burden of primary liver cancer cases due to
alcohol consumption, even in a low consumption country like India. Alcohol detoxification is governed by ADH1B,
ALDH2, GSTM1 and GSTT1 genes that encode functional enzymes which are coordinated with each other to remove
highly toxic metabolites i.e. acetaldehyde as well as reactive oxygen species generated through detoxification processes.
Some communities in the population appears to be at greater risk for development of the liver cancer due to genetic
predispositions. Methods: The aim of this study was to screen the arcadian population of central India in order to
investigate and compare the genotype distribution and allele frequencies of alcohol metabolizing genes (ADH1B,
ALDH2, GSTM1 and GSTT1) in both alcoholic (N=121) and control (N=145) healthy subjects. The gene polymorphism
analysis was conducted using PCR and RFLP methods. Results: The allele frequency of ALDH2 *1 was 0.79 and of
ALDH2*2 was 0.21 (OR:1.12; CI (95%): 0.74-1.71). The null allele frequency for GSTM1 was 0.28 (OR:0.85; CI
(95%): 0.50-1.46) and for GSTT1 was 0.20 (OR:1.93; CI (95%): 1.05-3.55). No gene polymorphism for ADH1B was
not observed. The total prevalence of polymorphisms was 3.38% for ALDH2, GSTM1 and GSTT1. Conclusion: The
results of this study suggested that individuals of the Central India population under study are at risk for liver disorders
due to ALDH2, GSTM1 and GSTT1 gene polymorphisms. This results may have significance for prevention of alcohol
dependence, alcoholic liver disorders and the likelihood of liver cancer.
Huang M, Zeng Y, Zhao F, Huang YAssociation of glutathione S-transferase M1 polymorphisms in the colorectal cancer risk: A meta-analysis.
J Cancer Res Ther. 2018; 14(1):176-183 [PubMed
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Purpose: The glutathione S-transferase M1 (GSTM1) as a member of phase II detoxification enzymes is expressed in many tissues and plays a critical role in preventing the occurrence of cancer. Published data regarding the associations between the GSTM1 polymorphism and colorectal cancer (CRC) risk are inconclusive.
Materials and Methods: A meta-analysis of 55 case-control studies involving 17,498 cases and 26,441 controls were performed to assess the strength of association using odds ratio (OR) with 95% confidence interval (CI).
Results: The meta-analysis of those studies suggested that GSTM1 null genotype was significantly associated with CRC risk (OR = 1.13, 95% CI = 1.06-1.20, P < 0.0001). In the subgroup analysis by ethnicity, significant risks were associated with GSTM1 null genotype in Caucasians (OR = 1.18, 95% CI = 1.07-1.29, P = 0.001), Asians (OR = 1.11, 95% CI = 1.02-1.22, P = 0.02), and mixed group (OR = 1.01, 95% CI = 0.90-1.14, P = 0.85). In the subgroup analysis by study design, significant elevated risks were associated with GSTM1 null genotype in hospital-based case-control study group (OR = 1.20, 95% CI = 1.10-1.31, and P < 0.0001) but not in population-based case-control study group (OR = 1.03, 95% CI = 0.96-1.10, P = 0.43).
Conclusions: Based on our meta-analysis, the GSTM1 null genotype is a risk factor for CRC.
Bhardwaj A, Bahl C, Sharma S, et al.Interactive potential of genetic polymorphism in Xenobiotic metabolising and DNA repair genes for predicting lung cancer predisposition and overall survival in North Indians.
Mutat Res Genet Toxicol Environ Mutagen. 2018; 826:15-24 [PubMed
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INTRODUCTION: Cancer, a multi-step, multifactorial and multi-gene disease, not only damages the genomic integrity of the cell but also hinders the DNA repair mechanisms of the body. Gene-gene and gene environment interactions amongst the genetic polymorphisms together modulate the susceptibility towards a cancer. We have studied the high order gene interactions between the genetic polymorphism of detoxifying genes (CYP1A1, Ahr, XRCC and GST1) that play a key role in the metabolism of the xenobiotics and have been proved to be prognostic markers for lung cancer METHODS: 237 cases and 250 controls have been genotyped using PCR-RFLP technique. In order to find out the association, unconditional logistic regression approach was used and to analyse high order interactions MDR and CART was used.
RESULTS: In the MDR analysis, the best model was one factor model which included GSTM1 (CVC 10/10, Prediction error = 0.43, p < .001). The best three factor model comprised of XRCC1 632, XRCC1 206, GSTM1 (CVC 10/10, Prediction error = 0.45, p < .0001). The CART analysis exhibited that Node 1 carrying mutant type of GSTM1 imposed the highest risk towards lung cancer (OR = 11.0, 95%C.I. = 6.05-20.03, p = .000001). Wild type of GSTM1 when combined with mutant type of CYP1A1 M2 and XRCC1 632, an 8 fold risk towards lung cancer was observed (95%C.I. = 4.07-16.29, p = .00001). The high order interactions were used to predict the prognosis of lung cancer patients. Of all the genetic variants, XRCC1 632, GSTM1 and AhR rs2066853 was the most important determinant of overall survival of lung cancer patients CONCLUSION: Through the study we introduced the concept of polygenic approach to get an insight about the various polymorphic variants in determining cancer susceptibility. Lesser number of subjects were found in the high risk subgroups. Further studies with larger sample size are required to warranty the above findings.
Endo-Tsukude C, Sasaki JI, Saeki S, et al.Population Pharmacokinetics and Adverse Events of Erlotinib in Japanese Patients with Non-small-cell Lung Cancer: Impact of Genetic Polymorphisms in Metabolizing Enzymes and Transporters.
Biol Pharm Bull. 2018; 41(1):47-56 [PubMed
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Determinants of interindividual variability in erlotinib pharmacokinetics (PK) and adverse events remain to be elucidated. This study with 50 Japanese non-small-cell lung cancer patients treated with oral erlotinib at a standard dose of 150 mg aimed to investigate whether genetic polymorphisms affect erlotinib PK and adverse events. Single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, and GSTT1) or efflux transporters (ABCB1, and ABCG2) were analyzed as covariates in a population PK model. The ABCB1 1236C>T (rs1128503) polymorphism, not ABCB1*2 haplotype (1236TT-2677TT-3455TT, rs1128503 TT-rs2032582 TT-rs1045642 TT), was a significant covariate for the apparent clearance (CL/F), with the TT genotype showing a 29.4% decrease in CL/F as compared with the CC and the CT genotypes. A marginally higher incidence of adverse events (mainly skin rash) was observed in the TT genotype group; however, patients with high plasma erlotinib exposure did not always experience skin rash. None of the other SNPs affected PK or adverse events. The ABCB1 genotype is a potential predictor for erlotinib adverse events. Erlotinib might be used with careful monitoring of adverse events in patients with ABCB1 polymorphic variants.
García-Martínez A, Gamboa-Loira B, Tejero ME, et al.CYP1A1, CYP1B1, GSTM1 and GSTT1 genetic variants and breast cancer risk in Mexican women.
Salud Publica Mex. 2017 Sep-Oct; 59(5):540-547 [PubMed
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OBJECTIVE: To evaluate if variants in the genes CYP1A1 (T3801C and A4889G), CYP1B1 (G119T), GSTM1 (indel) and GSTT1 (indel) are associated with breast cancer (BC) among Mexican women.
MATERIALS AND METHODS: 952 incident cases with histologically confirmed BC were matched by age (± 5 years) and zone of residence with 998 healthy population controls. Genetic variants in genes CYP1A1, CYP1B1, GSTM1 and GSTT1were genotyped by allelic discrimination and multiplex PCR. In a subsample of women, 105 markers for ancestry were determined.
RESULTS: An increased BC risk, independent of other BC risk factors, was observed among carriers of CYP1B1 G119T genotype (T/T vs. G/G: OR=1.9; 95%CI 1.4-2.5).
CONCLUSION: Our results support the existence of genetic susceptibility for BC conferred by CYP1B1 G119T variant among Mexican women.
Ma L, Lan B, Guo L, et al.GSTM1 and GSTT1 Gene Polymorphisms, Gene-Gene Interaction, and Esophageal Carcinoma Risk: Evidence from an Updated Meta-Analysis.
Genet Test Mol Biomarkers. 2018; 22(1):11-19 [PubMed
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BACKGROUND: Published data regarding the association between GSTM1 and/or GSTT1 gene polymorphisms and esophageal cancer (EC) susceptibility remain inconclusive. To clarify these associations, a meta-analysis was conducted.
METHODS: We conducted a comprehensive search in PubMed, Embase, and the China National Knowledge Infrastructure (CNKI) for all such manuscripts published as of May 1, 2017. The pooled odds ratio (ORs) with confidence intervals (95% CI) were estimated for each study to assess the strength of the association. A subgroup analysis, a sensitivity analysis, and a publication bias analysis were also performed.
RESULTS: Data from 41 studies comprising 5291 EC cases and 8191 controls were available for analysis of the GSTM1 polymorphism, and data from 31 studies comprising 4330 EC cases and 6558 controls were available for analysis of the GSTT1 polymorphism. Analyses of the GSTM1 polymorphisms demonstrated that there was a significantly increased EC risk in GSTM1 null genotype carriers (OR = 1.319, 95% CI = 1.125-1.546, p for heterogeneity <0.001). In subgroup analyses by ethnicity, and categories of EC, a significantly increased EC risk was found in Asians (OR = 1.457, 95% CI = 1.212-1.751, p for heterogeneity <0.001) and patients whose histological type was unknown. Analyses of the GSTT1 polymorphisms indicated a positive correlation between the GSTT1 null genotype and the EC risk (OR = 1.233, 95% CI = 1.044-1.455, p for heterogeneity <0.001). In subgroup analyses stratified by ethnicity and categories of EC, similar statistical associations were observed in Asians, esophageal squamous cell carcinoma (ESCC) patients, and ESCC on Asian population. In the GSTM1-GSTT1 interaction analysis, we discovered remarkably enhanced EC risk for patients with the GSTM1 and GSTT1 dual null genotypes (OR = 1.962, 95% CI = 1.178-3.268, p for heterogeneity <0.001) compared with the reference GSTM1 and GSTT1 dual positive genotype.
CONCLUSIONS: We conclude that the GSTM1 and GSTT1 null genotypes are associated with increased genetic susceptibility to EC in the overall human population, particularly among Asians. In addition, our findings suggest that persons with a null genotype for both the GSTM1 and GSTT1 genes are at higher risk of developing EC. Further well-designed studies are needed to confirm these associations.
Breast cancer is one of the most common cancers among women, and susceptibility is explained by genetic, lifestyle and environmental components. Copy Number Variants (CNVs) are structural DNA variations that contribute to diverse phenotypes via gene-dosage effects or cis-regulation. In this study, we aimed to identify germline CNVs associated with breast cancer susceptibility and their relevance to prognosis. We performed whole genome CNV genotyping in 422 cases and 348 controls using Human Affymetrix SNP 6 array. Principal component analysis for population stratification revealed 84 outliers leaving 366 cases and 320 controls of Caucasian ancestry for association analysis; CNVs with frequency > 10% and overlapping with protein coding genes were considered for breast cancer risk and prognostic relevance. Coding genes within the CNVs identified were interrogated for gene- dosage effects by correlating copy number status with gene expression profiles in breast tumor tissue. We identified 200 CNVs associated with breast cancer (q-value < 0.05). Of these, 21 CNV regions (overlapping with 22 genes) also showed association with prognosis. We validated representative CNVs overlapping with APOBEC3B and GSTM1 genes using the TaqMan assay. Germline CNVs conferred dosage effects on gene expression in breast tissue. The candidate CNVs identified in this study warrant independent replication.
Liu C, Cui H, Gu D, et al.Genetic polymorphisms and lung cancer risk: Evidence from meta-analyses and genome-wide association studies.
Lung Cancer. 2017; 113:18-29 [PubMed
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A growing number of studies investigating the association between Single Nucleotide Polymorphisms (SNPs) and lung cancer risk have been published since over a decade ago. An updated integrative assessment on the credibility and strength of the associations is required. We searched PubMed, Medline, and Web of Science on or before August 29
Sengupta D, Guha U, Bhattacharjee S, Sengupta MAssociation of 12 polymorphic variants conferring genetic risk to lung cancer in Indian population: An extensive meta-analysis.
Environ Mol Mutagen. 2017; 58(9):688-700 [PubMed
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Candidate gene as well as genome-wide association studies identified several polymorphic variants to be associated with lung cancer worldwide including in India. However, contradictory results have failed to estimate the overall effect of the polymorphic variants on the disease. Textmining was conducted on PubMed following specific search strings to gather all the publications related to genetic association with lung cancer in India. Out of 211 PubMed hits only 30 studies were selected for meta-analysis following specific inclusion criteria. Heterogeneity between studies was calculated by Cochran's Q-test (P < 0.05) and heterogeneity index (I
Sharma V, Nandan A, Sharma AK, et al.Signature of genetic associations in oral cancer.
Tumour Biol. 2017; 39(10):1010428317725923 [PubMed
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Oral cancer etiology is complex and controlled by multi-factorial events including genetic events. Candidate gene studies, genome-wide association studies, and next-generation sequencing identified various chromosomal loci to be associated with oral cancer. There is no available review that could give us the comprehensive picture of genetic loci identified to be associated with oral cancer by candidate gene studies-based, genome-wide association studies-based, and next-generation sequencing-based approaches. A systematic literature search was performed in the PubMed database to identify the loci associated with oral cancer by exclusive candidate gene studies-based, genome-wide association studies-based, and next-generation sequencing-based study approaches. The information of loci associated with oral cancer is made online through the resource "ORNATE." Next, screening of the loci validated by candidate gene studies and next-generation sequencing approach or by two independent studies within candidate gene studies or next-generation sequencing approaches were performed. A total of 264 loci were identified to be associated with oral cancer by candidate gene studies, genome-wide association studies, and next-generation sequencing approaches. In total, 28 loci, that is, 14q32.33 (AKT1), 5q22.2 (APC), 11q22.3 (ATM), 2q33.1 (CASP8), 11q13.3 (CCND1), 16q22.1 (CDH1), 9p21.3 (CDKN2A), 1q31.1 (COX-2), 7p11.2 (EGFR), 22q13.2 (EP300), 4q35.2 (FAT1), 4q31.3 (FBXW7), 4p16.3 (FGFR3), 1p13.3 (GSTM1-GSTT1), 11q13.2 (GSTP1), 11p15.5 (H-RAS), 3p25.3 (hOGG1), 1q32.1 (IL-10), 4q13.3 (IL-8), 12p12.1 (KRAS), 12q15 (MDM2), 12q13.12 (MLL2), 9q34.3 (NOTCH1), 17p13.1 (p53), 3q26.32 (PIK3CA), 10q23.31 (PTEN), 13q14.2 (RB1), and 5q14.2 (XRCC4), were validated to be associated with oral cancer. "ORNATE" gives a snapshot of genetic loci associated with oral cancer. All 28 loci were validated to be linked to oral cancer for which further fine-mapping followed by gene-by-gene and gene-environment interaction studies is needed to confirm their involvement in modifying oral cancer.
The bladder is an important organ for the storage of excreted water and metabolites. If metabolites with carcinogenic characteristics are present in urine, the urothelial lining of the bladder could be damaged and genetically altered. In this study, we analyzed the interaction of arsenic and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) on mouse bladder carcinogenesis. Our previous study found that arsenic affects BBN-altered urothelial enzymatic activity, protein expression, DNA oxidation and global DNA CpG methylation levels. In this study, two mouse models were used. First, after administering a co-treatment of BBN and arsenic for 20 weeks, BBN alone led to a urothelial carcinoma formation of 20%, and arsenic promoted a BBN-induced urothelial carcinoma formation of 10%. The protein expression of GSTM1, GSTO1, NQO1, and p21 did not change by arsenic along with the BBN co-treatment, but the Sp1 expression increased. In the second mouse model, BBN was a pretreatment promoter; arsenic dose-dependently deteriorated BBN-promoted dysplasia by 10% and 40% at 10 ppm and 100 ppm, respectively. Conversely, BBN pretreatment also accelerated arsenic-induced dysplasia by 30%. The urothelial carcinogenic effect reversed after ceasing BBN for a period of 20 weeks. In summary, three conclusions were drawn from this study. The first is the mutual promotion of arsenic and BBN in bladder carcinogenesis. Second, arsenic dosages without bladder carcinogenicity (10 ppm) or with slight carcinogenicity (100 ppm) promote BBN-induced mice bladder cancer progression. Finally, the dysplastic urothelium had reverted to near-normal morphology after ceasing BBN intake for 20 weeks, providing a good suggestion for people who want to quit smoking.