The clinical relevance of the expression of SGLT2 in lung adenocarcinoma.

PURPOSE: We aimed to elucidate the functions and clinical relevance of sodium-glucose cotransporter 2 (SGLT2) in resected lung adenocarcinoma. METHODS: The protein expression of SGLT2 in tumor samples from 199 patients with lung adenocarcinoma was analyzed by immunohistochemistry, and to the protein expression, clinical variables, and survival outcomes were compared. RESULTS: The median SGLT2 expression was significantly higher in advanced stage and more aggressive adenocarcinomas. Age≥70 (P < 0.01), BI≥600 (P < 0.01), PRDX4 < 25 (P < 0.01), and SGLT2≥12% (P = 0.03) were significant factors for RFS in multivariate analysis. Significant differences were observed in the RFS rates of the groups divided using the cutoff value of SGLT2≥12% (5-year RFS: 72.6% vs. 90%) (P<0.01). CONCLUSION: The expression of SGLT2 was more frequently detected in advanced stage and more aggressive adenocarcinomas with aggressive biological behavior than in their counterparts. The survival analysis revealed that the strong expression of SGLT2 was associated with poorer RFS. The SGLT2 expression predicts postoperative recurrence in lung adenocarcinoma patients.

Triple-negative expression (ALDH1A1-/CD133-/mutant p53-) cases in lung adenocarcinoma had a good prognosis.

Cancer stem cells (CSCs) are major contributors to the malignant transformation of cells because of their capacity for self-renewal. Aldehyde dehydrogenase1A1 (ALDH1A1) and CD133 are promising candidate of CSC markers in non-small cell lung cancer (NSCLC). Furthermore, TP53 is frequently mutated in lung cancer, and the loss of its function is associated with malignant characteristics. However, the relationship between CSCs and mutant p53 in lung adenocarcinoma is not well-established. We examined the expression of ALDH1A1, CD133, and mutant p53 in lung adenocarcinoma patients and conducted a clinicopathological study. Triple-negative cases without ALDH1A1, CD133, and mutant p53 expression in lung adenocarcinoma were shown to have a much better prognosis than others. Our present results suggest that detection of CSC markers and mutant p53 by immunohistochemical staining may be effective in therapeutic strategies for lung adenocarcinoma.

Paraneoplastic limbic encephalitis due to lung squamous cell carcinoma.

Paraneoplastic limbic encephalitis (PLE) is one of paraneoplastic neurological syndrome (PNS). We herein report a case of PLE due to lung squamous cell carcinoma. A 80-year-old woman visited because of several neurological symptoms. Brain magnetic resonance imaging revealed hyperintense signals at the splenium of the corpus callosum, suggesting limbic encephalitis. Chest X-ray and computed tomography showed a 17 × 14 mm tumor in the left lung field, suggesting lung cancer. Surgical examination revealed T1bN0M0 lung squamous cell carcinoma. She died 50 days after surgery due to the rapid progression of encephalitis. PLE is an extremely rare disorder, and even a case in the early stage of cancer shows poor prognosis. We should doubt a possibility of PLE, and detailed brain examination should be performed in case of consciousness disorder with rapid progression in the cancer patient.

Association Between CD133 Expression and Prognosis in Human Lung Adenocarcinoma.

BACKGROUND/AIM: CD133 is a promising candidate marker for cancer stem cells. However, clinical studies on CD133 expression in human lung adenocarcinoma have not yet been conducted. We hypothesized that CD133 expression in lung adenocarcinoma is a poor prognostic factor. PATIENTS AND METHODS: CD133 expression in lung adenocarcinoma was examined clinicopathologically. Then, clinicopathological parameters and patient prognosis were investigated. Moreover, CD133 expression was examined via immunohistochemical staining, and the relationship between CD133 expression and clinicopathological parameters was explored. RESULTS: Approximately 48.0% (49/102) of patients had CD133-positive cells. Based on a subgroup analysis, the CD133-positive group with pStage I+II disease had a significantly worse disease-free interval than the CD133-negative group (p<0.05). CONCLUSION: CD133 expression may be a poor prognostic factor in lung adenocarcinoma.

Simple covering technique in thoracoscopic bullectomy for spontaneous pneumothorax.

Reduced-port thoracoscopic surgery for pneumothorax has been well reported. However, the optimum method for preventing postoperative recurrence in reduced-port thoracoscopic bullectomy remains unclear. We investigated ways to improve the covering technique with reduced-port thoracoscopic bullectomy for spontaneous pneumothorax. From April to December 2016, we performed a simple covering technique with reduced-port thoracoscopic bullectomy on six patients and evaluated the surgical results and patient outcomes. All of the patients were successfully treated with the simple covering technique, and none had a postoperative ipsilateral recurrence of pneumothorax. Our method is a simple and easy technique involving the wide reinforcement of the staple line and may be effective in reducing the risk of postoperative recurrence in reduced-port thoracoscopic bullectomy.

Contralateral thoracoscopic lobectomy in postlobectomy patients.

BACKGROUND: It is difficult to perform thoracoscopic lobectomy in patients with a history of contralateral lobectomy, as stable oxygenation is not always maintained under conditions of one-lung ventilation during surgery. METHODS: This study evaluated 14 patients who underwent thoracoscopic lobectomy after previously undergoing contralateral lobectomy at a single institution between 2008 and 2015. RESULTS: Among 14 patients who had previously received contralateral lobectomy, 4 were unable to maintain sufficient perioperative oxygenation with usual one-lung ventilation. The predicted pulmonary function before surgery in these patients was as follows: both (I) predicted postoperative forced expiratory volume in 1 second <800 mL/m2; and (II) ≤5 contralateral residual segments for ventilation. Regarding special oxygenation techniques, two underwent selective ventilation using lobe-selective bronchial blockade, one underwent intermittent positive airway pressure for operative side lung, and one underwent high-frequency jet ventilation for operative residual lobe. CONCLUSIONS: When performing thoracoscopic lobectomy in patients with a history of contralateral lobectomy, a careful evaluation of the preoperative pulmonary function is needed.

The Clinical Significance of Cancer Stem Cell Markers ALDH1A1 and CD133 in Lung Adenocarcinoma.

BACKGROUND/AIM: Aldehyde dehydrogenase-1A1 (ALDH1A1) and CD133 have been identified as markers of cancer stem cells (CSCs). We investigated the expression of these markers and their clinical significance in lung adenocarcinoma. MATERIALS AND METHODS: An immunohistochemical analysis of ALDH1A1 and CD133 expression of 92 lung adenocarcinomas was performed. The association between the expression of both markers and cancer-related death and recurrence was determined. RESULTS: Cancer-related death and tumor recurrence were observed in 15 and 17 cases, respectively. The expression of CD133, but not ALDHA1A, was significantly associated with poorer overall survival (p<0.0001) and shorter disease-free interval (DFI) (p<0.0001). Multivariate analysis revealed that double negativity was independently associated with increased survival (hazard ratio(HR)=16.1, p=0.0004) and a longer DFI (HR=9.5, p=0.0007). CONCLUSION: We propose that as a functional marker, ALDH1A1 positivity may influence the viability of CSCs. The findings suggest that it is important to evaluate the expression of both markers.

Piperazine-based Alpha-1 AR Blocker, Naftopidil, Selectively Suppresses Malignant Human Bladder Cells via Induction of Apoptosis.

A retrospective observational cohort study has shown that exposure to alpha-1 adrenergic receptor (AR) blocker reduces the risk of bladder cancer (BCa). We investigated the antitumor activity of alpha-1 blockers, that are administered long-term therapeutically, in BCa. The antitumor activity of alpha-1 blockers was evaluated in terms of cell viability, cell cycle, competition, and apoptotic signaling in BCa cells. Our cell viability studies showed that naftopidil was one of the strongest alpha-1 AR blockers, regarding its antitumor action in BCa cells, independent of the grade of malignancy, but with no similar action on normal human bladder cells. Oral administration of naftopidil reduced tumor volume in a xenograft model. Our own competitive analysis using an alpha-1 AR agonist and other alpha-1 AR blockers showed that naftopidil activated cell death signaling without inhibitory action on alpha-1 ARs. We conclude that naftopidil has potential as an antitumor drug against BCa in vitro and in vivo. This finding provides a rationale for developing naftopidil in grade-independent treatment of BCa.

Protective role of ALDH2 against acetaldehyde-derived DNA damage in oesophageal squamous epithelium.

Acetaldehyde is an ethanol-derived definite carcinogen that causes oesophageal squamous cell carcinoma (ESCC). Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme that eliminates acetaldehyde, and impairment of ALDH2 increases the risk of ESCC. ALDH2 is produced in various tissues including the liver, heart, and kidney, but the generation and functional roles of ALDH2 in the oesophagus remain elusive. Here, we report that ethanol drinking increased ALDH2 production in the oesophagus of wild-type mice. Notably, levels of acetaldehyde-derived DNA damage represented by N(2)-ethylidene-2'-deoxyguanosine were higher in the oesophagus of Aldh2-knockout mice than in wild-type mice upon ethanol consumption. In vitro experiments revealed that acetaldehyde induced ALDH2 production in both mouse and human oesophageal keratinocytes. Furthermore, the N(2)-ethylidene-2'-deoxyguanosine levels increased in both Aldh2-knockout mouse keratinocytes and ALDH2-knockdown human keratinocytes treated with acetaldehyde. Conversely, forced production of ALDH2 sharply diminished the N(2)-ethylidene-2'-deoxyguanosine levels. Our findings provide new insight into the preventive role of oesophageal ALDH2 against acetaldehyde-derived DNA damage.

Impairment of aldehyde dehydrogenase 2 increases accumulation of acetaldehyde-derived DNA damage in the esophagus after ethanol ingestion.

Ethanol and its metabolite, acetaldehyde, are the definite carcinogens for esophageal squamous cell carcinoma (ESCC), and reduced catalytic activity of aldehyde dehydrogenase 2 (ALDH2), which detoxifies acetaldehyde, increases the risk for ESCC. However, it remains unknown whether the ALDH2 genotype influences the level of acetaldehyde-derived DNA damage in the esophagus after ethanol ingestion. In the present study, we administered ethanol orally or intraperitoneally to Aldh2-knockout and control mice, and we quantified the level of acetaldehyde-derived DNA damage, especially N(2) -ethylidene-2'-deoxyguanosine (N(2) -ethylidene-dG), in the esophagus. In the model of oral ethanol administration, the esophageal N(2) -ethylidene-dG level was significantly higher in Aldh2-knockout mice compared with control mice. Similarly, in the model of intraperitoneal ethanol administration, in which the esophagus is not exposed directly to the alcohol solution, the esophageal N(2) -ethylidene-dG level was also elevated in Aldh2-knockout mice. This result indicates that circulating ethanol-derived acetaldehyde causes esophageal DNA damage, and that the extent of damage is influenced by knockout of Aldh2. Taken together, our findings strongly suggest the importance of acetaldehyde-derived DNA damage which is induced in the esophagus of individuals with ALDH2 gene impairment. This provides a physiological basis for understanding alcohol-related esophageal carcinogenesis.

Thoracoscopic anatomic pulmonary resection for locally advanced non-small cell lung cancer.

BACKGROUND: The safety and feasibility of thoracoscopic lobectomy for locally advanced lung cancer remain controversial. METHODS: Between April 2002 and April 2011, we retrospectively reviewed 100 consecutive patients who underwent anatomic pulmonary resection for preoperative stage II or greater non-small cell lung cancer at a single institution. After excluding 16 patients undergoing planned thoracotomy and 8 patients with preoperative stage IV disease, the remaining 76 patients who underwent thoracoscopic surgery were divided chronologically into three groups and analyzed. RESULTS: Thoracoscopic anatomic pulmonary resection was successfully performed in 74 patients (97.4%). There were 32 complications in 27 patients (35.5%), and 2 patients (2.6%) had grade 3 or higher complications. The operative, perioperative (30-day), and hospital mortality were 0%, 0%, and 2.6%, respectively. A significantly decreased operation time, a lower amount of blood loss, and increased numbers of bronchoplasty and bronchial coverage were seen, although there were no significant differences in the patient characteristics or other outcomes among the three groups. At a mean follow-up time of 40 months, the overall 3-year survival rates for pathologic stages I (n = 12), II (n = 27), III (n = 33), and IV (n = 4) were 100%, 64.2%, 36.2%, and 25.0%, respectively. CONCLUSIONS: Thoracoscopic anatomic pulmonary resection is feasible, with acceptable morbidity and mortality rates, as well as favorable oncologic outcomes, in selected patients with locally advanced non-small cell lung cancer. The learning curve for this procedure appears to be overcome after 25 consecutive patients.

Cytochrome P450 in non-small cell lung cancer related to exogenous chemical metabolism.

The occurrence of lung cancer is associated with smoking, which exposes smokers to a series of carcinogenic chemicals. CYP (cytochrome P450) usually metabolizes carcinogens to their inactive derivatives, but occasionally convert the chemicals to more potent carcinogens. In addition to the metabolism of carcinogenic compounds, CYP also participates in the activation and/or inactivation of anti-carcinogenic agents, suggesting that the local CYP expression in lung cancer and surrounding tissues could be an important determinant of efficacy of anticancer drugs. Furthermore, CYP19 (aromatase), estrogen synthase P450, expressed in more than 80 percent of non-small cell lung cancers. It suggests an association between estrogens and cancer development, which makes aromatase an attractive therapeutic target for the treatment of lung cancer. 1alpha,25-Dihydroxyvitamin D3 has an inhibitory effect on the proliferation of cancer tissues, and is converted to its inactive 24-hydroxylated derivatives by CYP24, which is frequently expressed in lung cancer tissues. Therefore, understanding the CYP expression in tumor tissues is important in developing better therapies for lung cancer, and may lead us to standardized, tailor-made therapies for individuals.

The effect of ethanol on the formation of N2-ethylidene-dG adducts in mice: implications for alcohol-related carcinogenicity of the oral cavity and esophagus.

The present study aimed to experimentally confirm that long-term alcohol drinking causes a high risk of oral and esophageal cancer in aldehyde dehydrogenase 2 (ALDH2)-deficient individuals. Aldh2 knockout mice, an animal model of ALDH2-deficiency, were treated with 8% ethanol for 14 months. Levels of acetaldehyde-derived DNA adducts were increased in esophagus, tongue and submandibular gland. Our finding that a lack of Aldh2 leads to more DNA damage after chronic ethanol treatment in mice supports epidemiological findings on the carcinogenicity of alcohol in ALDH2-deficient individuals who drink chronically.

Detection of EGFR and K-ras mutations for diagnosis of multiple lung adenocarcinomas.

The incidence of multiple primary lung adenocarcinoma (MPLA) is increasing, and it is important to distinguish MPLA from intrapulmonary metastasis (IPM) in order to determine the therapeutic strategy. However, there is no reliable method to differentiate between the two. The purpose of this study was to distinguish MPLA from IPM based on the gene status of EGFR and K-ras and the morphological Noguchi classification system. Sixty-eight tumors from 34 cases of clinical MPLA were evaluated. Of them, 11 cases (32.4%) were diagnosed as biological MPLA (bMPLA) by EGFR/K-ras mutation analyses, and 12 cases (35.3%) by morphological analysis. In all, 23 of the 34 cases (67.6%) were diagnosed as bMPLA. The remaining 11 cases were diagnosed as biological IPM (bIPM). The 5-year survival rates of bMPLA and bIPM were 90.9% and 63.6%, respectively (p=0.04). These findings suggest that the combination method including gene mutation and morphological analysis can guide treatment decisions and that there is a need for systemic chemotherapy, and surveillance monitoring.

Molecular diagnosis of MACC1 status in lung adenocarcinoma by immunohistochemical analysis.

BACKGROUND: Recently, we reported that overexpression of metastasis-associated colon cancer-1 (MACC1) mRNA may be a useful marker for predicting postoperative recurrence in patients with lung adenocarcinoma following surgery. However, the biological significance of mRNA overexpression is difficult to determine and is not widely used because mRNA expression analysis is relatively expensive and time- and labor-intensive. On the other hand, immunohistochemical (IHC) staining is easy to perform, well-established, inexpensive, and is a useful method which can be routinely applied in solid tumor diagnosis in clinical laboratories. PATIENTS AND METHODS: Tumor specimens were collected from 197 consecutive patients who underwent a complete resection for lung adenocarcinoma from 1998 to 2007. We analyzed the MACC1 status of the primary lung adenocarcinoma by IHC analysis. RESULTS: The average postoperative observation period was 46.7 months. Forty (20.3%) of the 197 patients developed recurrences after surgery. Positive expression of MACC1 was identified in 129 (65.5%) patients. Furthermore, MACC1 IHC was positive in 33 (82.5%) out of the 40 patients and 96 (61.1%) out of the 157 patients, with and without recurrence, respectively (p=0.011). Both univariate and multivariate logistic regression models indicated that positive staining for MACC1 was an independent factor for tumor recurrence. Furthermore, positive staining for MACC1 was associated with poorer disease-free survival (DFS), according to the univariate survival analysis (p=0.080). CONCLUSION: Positive staining for MACC1 expression in resected specimens was associated with a poorer DFS. Therefore, positive staining of IHC for MACC1 may be a useful marker for predicting postoperative recurrence in patients with lung adenocarcinoma following surgery.

Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells.

Cancer cells show constitutive upregulation of glycolysis, and the concentration of lactate thus produced correlates with prognosis. Here, we examined whether lactate concentration and lactate transporter expression are related to migration and invasion activity. We found that the expression of the monocarboxylate transporters MCT1 and MCT4, but not MCT5, in human lung cancer cell lines was significantly correlated with invasiveness. To clarify the effects of MCT1 and MCT4 expression on invasion, we performed migration and invasion assays after transfection with siRNA specific for MCT1 or MCT4. Knockdown of MCT1 or MCT4 did not influence cell migration but reduced invasion; this was also observed for knockdown of the lactate transporter-associated protein basigin. We also demonstrated that both expression and activity of MMP9 and MMP2 were not correlated with invasion activity and not regulated by MCT1, MCT4 and basigin. Furthermore, the addition of lactate did not increase migration and invasion activity, but low concentration of 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), a general anion channel blocker, as well as other MCT inhibitors quercetin and simvastatin, inhibited cell invasion without influencing migration activity and the cellular expression of MCT1 and MCT4. This is the first report suggesting that lactate transporters are involved in human cancer cell invasiveness. As such, these proteins may be promising targets for the prevention of cancer invasion and metastasis.

Reduced bone formation in alcohol-induced osteopenia is associated with elevated p21 expression in bone marrow cells in aldehyde dehydrogenase 2-disrupted mice.

INTRODUCTION: High consumption of alcohol is one of the risk factors for osteoporosis. Approximately 45% of Chinese and Japanese individuals have the inactive aldehyde dehydrogenase 2 (Aldh2) phenotype. The absence of the ALDH2*2 allele is found to adversely influence the risk of osteoporosis. The aim of this study is to clarify the effects of alcohol consumption on osteoblast differentiation in bone marrow and trabecular bone formation in Aldh2-disrupted mice. MATERIALS AND METHODS: Seven-week-old male Aldh2 knockout mice (Aldh2(-/-)) and wild-type (Aldh2(+/+)) mice were fed with water (groups Aldh2(-/-)/Wa and Aldh2(+/+)/Wa) or with 5% ethanol (groups Aldh2(-/-)/Al and Aldh2(+/+)/Al) for 4 weeks. At the age of 12 weeks, bone histomorphometry was performed at the secondary spongiosa of the tibias. Bone marrow cells from the bilateral femurs and tibias were used for mRNA expression analysis. RESULTS: Histomorphometrical study revealed that trabecular bone was significantly reduced in the Aldh2(-/-)/Al group compared with that in the Aldh2(-/-)/Wa and Aldh2(+/+)/Wa groups. Bone formation rate was significantly decreased in Aldh2(-/-)/Al compared with the other three groups. Quantitative RT-PCR revealed a significant decrease in type I collagen, osterix, osteopontin, and osteocalcin mRNA expressions in Aldh2(-/-)/Al compared with Aldh2(-/-)/Wa. In bone marrow cell cultures, mineralized nodule formation in Aldh2(-/-)/Al was significantly decreased compared with that in Aldh2(+/+)/Wa and Aldh2(-/-)/Wa, while PAK18, a p21-activated kinase inhibitor, recovered the decreased mineralized nodule formation in Aldh2(-/-)/Al. CONCLUSION: Alcohol consumption suppressed the differentiation and mineralization of osteoblasts and then reduced trabecular bone formation and bone volume in association with the elevated p21 expression in bone marrow cells, especially in aldehyde dehydrogenase 2-disrupted mice.

TS gene tandem repeats in esophageal cancer patients receiving chemoradiotherapy.

5-Fluorouracil (5-FU) interferes with tumor-cell proliferation by inhibiting thymidylate synthase (TS). We examined the relationship between tandem repeat (TR) variations in the TS gene and survival following concurrent chemoradiotherapy in patients with esophageal squamous cell carcinoma (ESCC). TS-TR variations were analyzed in 57 stage II-IV ESCC patients undergoing chemoradiotherapy combined with 5-FU and cisplatinum (CDDP), and in 106 controls. Pretreatment non-neoplastic biopsy specimens from ESCC patients and lymphocytes from controls were used for analysis. Variations were identified by the size of DNA fragments amplified by polymerase chain reaction. Two to five TRs were found in Japanese individuals. TR3 homozygotes were predominant in 74% of ESCC patients and 61% of controls. Three-year survival rates were significantly longer in patients with TR2/2 or TR2/3 genotypes (38%) than in patients with TR3/3, 3/4, or 3/5 genotypes (9%; p=0.011). In the Cox proportional hazard model, the TR2/2 or TR2/3 genotypes were the only independent predictor for survival (Hazard ratio, 2.647; 95% confidence interval, 1.271-5.513). The TS-TR variations exert an important influence on survival following chemoradiotherapy in ESCC patients.

Overexpression of MACC1 mRNA in lung adenocarcinoma is associated with postoperative recurrence.

OBJECTIVE: The purpose of this study was to clarify the role and clinical significance of metastasis associated in colon cancer 1 in resected stage I non-small cell lung cancers. METHODS: Tumor specimens were collected from 146 consecutive patients who underwent a complete resection for stage I lung adenocarcinoma from 1998 to 2007 at the University of Occupational and Environmental Health. We analyzed the expression of metastasis associated in colon cancer 1 mRNA of primary lung adenocarcinomas by real-time reverse transcriptase-polymerase chain reaction. RESULTS: The average postoperative observation period was 49.4 months. Thirteen (8.9%) of 146 patients had recurrences after surgery. Overexpression of metastasis associated in colon cancer 1 mRNA was identified in 62 patients (42.5%). Metastasis associated in colon cancer 1 was overexpressed in 9 (69.2%) of 13 patients and 53 (39.9%) of 133 patients with and without recurrence, respectively (P = .004). The median metastasis associated in colon cancer 1 copy number was 3.0 and 1.4 in patients with and without tumor recurrence, respectively. Metastasis associated in colon cancer 1 overexpression was associated with poorer disease-free survival according to the survival analysis (P = .033). CONCLUSIONS: Metastasis associated in colon cancer 1 gene overexpression may be a useful marker for predicting postoperative recurrence in patients with lung adenocarcinoma after surgery.

Formation of acetaldehyde-derived DNA adducts due to alcohol exposure.

Epidemiological studies have identified chronic alcohol consumption as a significant risk factor for cancers of the upper aerodigestive tract, including the oral cavity, pharynx, larynx and esophagus, and for cancer of the liver. Ingested ethanol is mainly oxidized by the enzymes alcohol dehydrogenase (ADH), cytochrome P-450 2E1 (CYP2E1), and catalase to form acetaldehyde, which is subsequently oxidized by aldehyde dehydrogenase 2 (ALDH2) to produce acetate. Polymorphisms of the genes which encode enzymes for ethanol metabolism affect the ethanol/acetaldehyde oxidizing capacity. ADH1B*2 allele (ADH1B, one of the enzyme in ADH family) is commonly observed in Asian population, has much higher enzymatic activity than ADH1B*1 allele. Otherwise, approximately 40% of Japanese have single nucleotide polymorphisms (SNPs) of the ALDH2 gene. The ALDH2 *2 allele encodes a protein with an amino acid change from glutamate to lysine (derived from the ALDH2*1 allele) and devoid of enzymatic activity. Neither the homozygote (ALDH2*2/*2) nor heterozygote (ALDH2*1/*2) is able to metabolize acetaldehyde promptly. Acetaldehyde is a genotoxic compound that reacts with DNA to form primarily a Schiff base N(2)-ethylidene-2'-deoxyguanosine (N(2)-ethylidene-dG) adduct, which may be converted by reducing agents to N(2)-ethyl-2'-deoxyguanosine (N(2)-ethyl-dG) in vivo, and strongly blocked translesion DNA synthesis. Several studies have demonstrated a relationship between ALDH2 genotypes and the development of certain types of cancer. On the other hand, the drinking of alcohol induces the expression of CYP2E1, resulting in an increase in reactive oxygen species (ROS) and oxidative DNA damage. This review covers the combined effects of alcohol and ALDH2 polymorphisms on cancer risk. Studies show that ALDH2*1/*2 heterozygotes who habitually consume alcohol have higher rates of cancer than ALDH2*1/*1 homozygotes. Moreover, they support that chronic alcohol consumption contributes to formation of various DNA adducts. Although some DNA adducts formation is demonstrated to be an initiation step of carcinogenesis, it is still unclear that whether these alcohol-related DNA adducts are true factors or initiators of cancer. Future studies are needed to better characterize and to validate the roles of these DNA adducts in human study.