PARP1 rs1805407 Increases Sensitivity to PARP1 Inhibitors in Cancer Cells Suggesting an Improved Therapeutic Strategy.

Personalized cancer therapy relies on identifying patient subsets that benefit from a therapeutic intervention and suggest alternative regimens for those who don't. A new data integrative approach, based on graphical models, was applied on our multi-modal -omics, and clinical data cohort of metastatic melanoma patients. We found that response to chemotherapy is directly linked to ten gene expression, four methylation variables and PARP1 SNP rs1805407. PARP1 is a DNA repair gene critical for chemotherapy response and for which FDA-approved inhibitors are clinically available (olaparib). We demonstrated that two PARP inhibitors (ABT-888 and olaparib) make SNP carrier cancer cells of various histologic subtypes more sensitive to alkylating agents, but they have no effect in wild-type cells. Furthermore, PARP1 inhibitors act synergistically with chemotherapy in SNP carrier cells (especially in ovarian cancer for which olaparib is FDA-approved), but they are additive at best in wild-type cancer cells. Taken together, our results suggest that the combination of chemotherapy and PARP1 inhibition may benefit the carriers of rs1805407 in the future and may be used in personalized therapy strategies to select patients that are more likely to respond to PARP inhibitors.

A novel multi-CDK inhibitor P1446A-05 restricts melanoma growth and produces synergistic effects in combination with MAPK pathway inhibitors.

Nearly 100% of melanomas have a defect in the p16(INK4A):cyclin D-CDK4/6:RB pathway, leading to abnormal cell cycle control and unregulated cellular proliferation. Here, we report that P1446A-05, a novel multi-CDK inhibitor has significant inhibitory activity against cutaneous and uveal melanoma. Mechanistic studies revealed that P1446A-05 inhibits phosphorylation targets of CDK members, and induces cell cycle arrest and apoptosis irrespective of melanoma genotype or phenotype. Additionally, we show preclinical evidence that P1446A-05 can synergize with other small molecule inhibitors previously studied in melanoma. Collectively, these data demonstrate that targeting cell cycle and transcriptional CDKs with a small molecule multi-CDK inhibitor is a viable approach for developing novel anti-melanoma therapeutics.

MicroRNA expression profiling predicts clinical outcome of carboplatin/paclitaxel-based therapy in metastatic melanoma treated on the ECOG-ACRIN trial E2603.

BACKGROUND: Carboplatin/paclitaxel (CP), with or without sorafenib, result in objective response rates of 18-20 % in unselected chemotherapy-naïve patients. Molecular predictors of survival and response to CP-based chemotherapy in metastatic melanoma (MM) are critical to improving the therapeutic index. Intergroup trial E2603 randomized MM patients to CP with or without sorafenib. Expression data were collected from pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor tissues from 115 of 823 patients enrolled on E2603. The selected patients were balanced across treatment arms, BRAF status, and clinical outcome. We generated data using Nanostring array (microRNA (miRNA) expression) and DNA-mediated annealing, selection, extension and ligation (DASL)/Illumina microarrays (HT12 v4) (mRNA expression) with protocols optimized for FFPE samples. Integrative computational analysis was performed using a novel Tree-guided Recursive Cluster Selection (T-ReCS) [1] algorithm to select the most informative features/genes, followed by TargetScan miRNA target prediction (Human v6.2) and mirConnX [2] for network inference. RESULTS: T-ReCS identified PLXNB1 as negatively associated with progression-free survival (PFS) and miR-659-3p as the primary miRNA associated positively with PFS. miR-659-3p was differentially expressed based on PFS but not based on treatment arm, BRAF or NRAS status. Dichotomized by median PFS (less vs greater than 4 months), miR-659-3p expression was significantly different. High miR-659-3p expression distinguished patients with responsive disease (complete or partial response) from patients with stable disease. miR-659-3p predicted gene targets include NFIX, which is a transcription factor known to interact with c-Jun and AP-1 in the context of developmental processes and disease. CONCLUSIONS: This novel integrative analysis implicates miR-659-3p as a candidate predictive biomarker for MM patients treated with platinum-based chemotherapy and may serve to improve patient selection.

Inherited variation in the ATP-binding cassette transporter ABCB1 and survival after chemotherapy for stage III-IV lung cancer.

BACKGROUND: The ATP-binding cassette transporter gene ABCB1 and the glutathione S-transferase gene GSTP1 code for a multidrug resistance protein and for a detoxifying phase II metabolic enzyme, respectively, with substrate specificities that include chemotherapy drugs often used to treat lung cancer. METHODS: We genotyped 11 ABCB1 and eight GSTP1 single nucleotide polymorphisms (SNPs) in 698 white lung cancer patients (all current or former cigarette smokers) and used log-rank test statistics and proportional hazards regression to evaluate associations between SNP genotype and survival. RESULTS: Using data from all 698 cases, one SNP in ABCB1 (rs2235013) was statistically significantly associated with overall survival (p = 0.038, log-rank test). Chemotherapy and stage jointly (p = 0.025) significantly modified the association between rs2235013 and survival, with statistically significant (p = 0.013, log-rank test) association observed in the subgroup of stage III to IV lung cancer patients who received chemotherapy as part of their first course of treatment (n = 160; 93.1% nonsmall cell). Patients who inherited the minor T allele at ABCB1 rs2235013 experienced better overall survival and recurrence-free survival (hazard ratio, per minor T allele, [95% confidence interval]: 0.66 [0.49-0.90] and 0.55 [0.31-0.95], respectively; adjusted for year of diagnosis, sex, age at diagnosis, cigarette pack years, and stage). In addition, in the advanced stage chemotherapy-treated subgroup, four ABCB1 SNPs (rs6949448, rs2235046, rs1128503, and rs10276036) in mutual high linkage disequilibrium with rs2235013 and an independent ABCB1 SNP (rs1045642) showed statistically significant association (p < 0.05) with survival. CONCLUSIONS: Inherited variation in ABCB1 may affect survival specifically in advanced stage lung cancer patients who receive chemotherapy.

Polymorphisms in NAT2 and GSTP1 are associated with survival in oral and oropharyngeal cancer.

INTRODUCTION: Functional polymorphisms in drug metabolizing enzymes (DMEs) may be determinants of survival in oral and oropharyngeal squamous cell carcinoma (OOSCC). METHODS: OOSCC cases (N=159) with a history of either tobacco or alcohol use were genotyped for polymorphisms in eight DMEs. Overall and disease-specific survival were analyzed using Kaplan-Meier plots and the log-rank test. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) in exploratory analyses of patient subgroups. RESULTS: Kaplan-Meier analyses showed N-acteyltransferase-2 (NAT2) fast acetylators experienced a 19.7% higher 5-year survival rate than slow acetylators (P=0.03) and this association was similar in oropharyngeal and oral cancer. After multiple adjustment, including tumor site and stage, the NAT2 fast acetylator phenotype was associated with improved overall survival (vs. slow acetylators) provided chemotherapy or radiation were not used (HR, 0.26; 95% CI, 0.10-0.66). However, NAT2 phenotype was unrelated to survival in patients treated with chemoradiotherapy (HR, 1.21; 95% CI, 0.54-2.73) or radiotherapy (HR, 0.67; 95% CI, 0.31-1.59) (P-for-NAT2/treatment-interaction=0.04). Normal activity GSTP1 was associated with a 19.2% reduction in 5-year disease-specific survival relative to reduced activity GSTP1 (P=0.04) but this association was not modified by treatment. CONCLUSIONS: Our results suggest that functional polymorphisms in NAT2 and GSTP1 are associated with OOSCC survival. Confirmation of these results in larger studies is required.

CYP24 inhibition preserves 1α,25-dihydroxyvitamin D(3) anti-proliferative signaling in lung cancer cells.

Human lung tumors aberrantly express the 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3))-catabolizing enzyme, CYP24. We hypothesized that CYP24 reduces 1,25(OH)(2)D(3)-mediated transcription and allows lung cancer cells to escape its growth-inhibitory action. To test this, H292 lung cancer cells and the CYP24-selective inhibitor CTA091 were utilized. In H292 cells, CTA091 reduces 1,25(OH)(2)D(3) catabolism, significantly increases 1,25(OH)(2)D(3)-mediated growth inhibition, and increases 1,25(OH)(2)D(3) effects on induced and repressed genes in gene expression profiling studies. Pathway mapping of repressed genes uncovered cell cycle as a predominant 1,25(OH)(2)D(3) target. In H292 cells, 1,25(OH)(2)D(3) significantly decreases cyclin E2 levels and induces G(0)/G(1) arrest. A broader set of cyclins is down-regulated when 1,25(OH)(2)D(3) is combined with CTA091, and cell cycle arrest further increases. Effects of CTA091 on 1,25(OH)(2)D(3) signaling are vitamin D receptor-dependent. These data provide evidence that CYP24 limits 1,25(OH)(2)D(3) anti-proliferative signaling in cancer cells, and suggest that CTA091 may be beneficial in preserving 1,25(OH)(2)D(3) action in lung cancer.

Genetic variability in DNA repair and cell cycle control pathway genes and risk of smoking-related lung cancer.

DNA repair and cell cycle control play an important role in the repair of DNA damage caused by cigarette smoking. Given this role, functionally relevant single nucleotide polymorphisms (SNPs) in genes in these pathways may well affect the risk of smoking-related lung cancer. We examined the relationship between 240 SNPs in DNA repair and cell cycle control pathway genes and lung cancer risk in a case-control study of white current and ex-cigarette smokers (722 cases and 929 controls). Additive, dominant, and recessive genetic models were evaluated for each SNP. A genetic risk summary score was also constructed. Odds ratios (OR) for lung cancer risk and 95% confidence intervals (95% CI) were estimated using logistic regression models. Thirty-eight SNPs were associated with lung cancer risk in our study population at P < 0.05. The strongest associations were observed for rs2074508 in GTF2H4 (P(additive) = 0.003), rs10500298 in LIG1 (P(recessive) = 2.7 × 10(-4)), rs747658 and rs3219073 in PARP1 (rs747658: P(additive) = 5.8 × 10(-5); rs3219073: P(additive) = 4.6 × 10(-5)), and rs1799782 and rs3213255 in XRCC1 (rs1799782: P(dominant) = 0.006; rs3213255: P(recessive) = 0.004). Compared to individuals with first quartile (lowest) risk summary scores, individuals with third and fourth quartile summary score results were at increased risk for lung cancer (OR: 2.21, 95% CI: 1.66-2.95 and OR: 3.44, 95% CI: 2.58-4.59, respectively; P(trend) < 0.0001). Our data suggests that variation in DNA repair and cell cycle control pathway genes is associated with smoking-related lung cancer risk. Additionally, combining genotype information for SNPs in these pathways may assist in classifying current and ex-cigarette smokers according to lung cancer risk.

Effects of ERCC2 Lys751Gln (A35931C) and CCND1 (G870A) polymorphism on outcome of advanced-stage squamous cell carcinoma of the head and neck are treatment dependent.

BACKGROUND: Germline variation in DNA damage response may explain variable treatment outcomes in squamous cell carcinoma of the head and neck (SCCHN). By grouping patients according to stage and radiation treatment, we compared SCCHN survival with regard to ERCC2 A35931C (Lys751Gln, rs13181) and CCND1 G870A (Pro241Pro, rs9344) genotypes. METHODS: In a hospital-based SCCHN case series (all white, 24.7% female, mean age 58.4 years), this treatment-outcome cohort study genotyped 275 stage III-IV cases that were initially treated with radiation (with or without chemotherapy) and 80 stage III-IV and 130 stage I-II cases that were initially treated without radiation or chemotherapy and used Kaplan-Meier and Cox regression analyses to compare genotype groups on the basis of overall, disease-specific, progression-free, and recurrence-free survival rates. RESULTS: ERCC2 35931 AA predicted worse survival in stage III-IV cases treated with radiation [multiply-adjusted HR = 1.66, 95% confidence interval (CI), 1.15-2.40; HR over the first 3 follow-up years = 1.92; 95% CI, 1.28-2.88] and better survival in stage III-IV cases not treated with radiation (HR = 0.26; 95% CI, 0.11-0.62). Although not associated with survival in stage III-IV cancers treated with radiation (HR = 1.00; 95% CI, 0.67-1.51), CCND1-870 GG predicted better survival in stage III-IV cancers not treated with radiation (HR = 0.14; 95% CI, 0.04-0.50). Survival in stage I-II did not depend on ERCC2 A35931C or CCND1 G870A genotype. CONCLUSIONS: Although promoting tumor progression in untreated patients, germline differences in DNA-repair or cell-cycle control may improve treatment outcome in patients treated with DNA-damaging agents. IMPACT: ERCC2 A35931C may help distinguish advanced stage SCCHN with better outcomes from radiation treatment.

XPF expression correlates with clinical outcome in squamous cell carcinoma of the head and neck.

PURPOSE: Tumor-specific biomarkers that predict resistance to DNA damaging agents may improve therapeutic outcomes by guiding the selection of effective therapies and limiting morbidity related to ineffective approaches. XPF (ERCC4) is an essential component of several DNA repair pathways and XPF-deficient cells are exquisitely sensitive to DNA damaging agents. The purpose of this study was to determine whether XPF expression levels predict clinical response to DNA damaging agents in head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN: Quantitative immunohistochemistry was used to measure XPF expression in tumors from a cohort of 80 patients with newly diagnosed HNSCC treated with radiation therapy with or without platinum-based chemotherapy; samples were collected prospectively. Genomic DNA isolated from blood samples was analyzed for nine single nucleotide polymorphisms (SNP) in the XPF gene by using a custom array. The primary endpoint was progression-free survival (PFS). RESULTS: XPF expression was higher in tumors from the oral cavity than from the other sites (P < 0.01). High XPF expression correlated with early time to progression both by univariate (HR = 1.87, P = 0.03) and multivariate analysis (HR = 1.83, P = 0.05). The one year PFS for high expressers was 47% (95% CI = 31-62) compared with 72% (95% CI = 55-83) for low expressers. In addition, we identified four XPF SNPs that showed marginal association with treatment failure. CONCLUSIONS: Expression level of XPF in HNSCC tumors correlates with clinical response to DNA damaging agents. XPF has potential to guide next generation personalized cancer therapy.

Genome-wide association study of survival in non-small cell lung cancer patients receiving platinum-based chemotherapy.

BACKGROUND: Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non-small cell lung cancer (NSCLC). METHODS: To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307,260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided. RESULTS: SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10(-6)), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10(-7)). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10(-6)) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35). CONCLUSION: These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients.

A sex-specific association between a 15q25 variant and upper aerodigestive tract cancers.

BACKGROUND: Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx, and esophagus) in women (OR = 1.24, P = 0.003) with little effect in men (OR = 1.04, P = 0.35). METHODS: In a coordinated genotyping study within the International Head and Neck Cancer Epidemiology (INHANCE) consortium, we have sought to replicate these findings in an additional 4,604 cases and 6,239 controls from 10 independent UADT cancer case-control studies. RESULTS: rs16969968 was again associated with UADT cancers in women (OR = 1.21, 95% CI = 1.08-1.36, P = 0.001) and a similar lack of observed effect in men [OR = 1.02, 95% CI = 0.95-1.09, P = 0.66; P-heterogeneity (P(het)) = 0.01]. In a pooled analysis of the original and current studies, totaling 8,572 UADT cancer cases and 11,558 controls, the association was observed among females (OR = 1.22, 95% CI = 1.12-1.34, P = 7 × 10(-6)) but not males (OR = 1.02, 95% CI = 0.97-1.08, P = 0.35; P(het) = 6 × 10(-4)). There was little evidence for a sex difference in the association between this variant and cigarettes smoked per day, with male and female rs16969968 variant carriers smoking approximately the same amount more in the 11,991 ever smokers in the pooled analysis of the 14 studies (P(het) = 0.86). CONCLUSIONS: This study has confirmed a sex difference in the association between the 15q25 variant rs16969968 and UADT cancers. IMPACT: Further research is warranted to elucidate the mechanisms underlying these observations.

Chemotherapy resistance abrogation in metastatic melanoma.

Melanoma is rapidly increasing in incidence throughout the world. Based on American Cancer Society estimates, there will have been approximately 68,720 new cases of invasive melanoma diagnosed in 2009 in the United States. The increase in melanoma incidence has not been paralleled by the development of new therapeutic agents with a significant impact on survival. The promise of targeted therapy has not yet been brought to bear, making chemotherapy with alkylating agents the mainstay of therapy of metastatic melanoma despite the dismally low response rates. The resistance of tumors to these agents is in part due to DNA repair mechanisms that allow cells to survive alkylation damage. Several novel agents targeting the abrogation of DNA repair pathways alone and in combination with cytotoxic agents have been developed with varying measures of success. This review summarizes the current knowledge of the dysregulation of DNA repair pathways as mechanisms of resistance to chemotherapy in melanoma and their potential as targets for novel developmental therapeutics.

Therapeutic equivalence in survival for hepatic arterial chemoembolization and yttrium 90 microsphere treatments in unresectable hepatocellular carcinoma: a two-cohort study.

BACKGROUND: Intrahepatic arterial yttrium 90 ((90)Y) microspheres have been proposed as a less toxic, less invasive therapeutic option to transhepatic arterial chemoembolization (TACE) for patients with surgically unresectable hepatocellular carcinoma (HCC). TACE has demonstrated the ability to prolong survival. However, long-term survival remains uncertain. METHODS: In a 2-cohort experience in the treatment of North American patients who had advanced, unresectable, biopsy-proven HCC, 691 patients received repetitive, cisplatin-based chemoembolization; and a separate cohort of 99 patients who had similar treatment criteria received a planned, single dose of (90)Y. Over the study period, an additional 142 patients were followed without treatment (total, 932 patients). RESULTS: Overall survival was slightly better in the (90)Y group compared with the TACE group (median survival, 11.5 months vs 8.5 months). However, the selection criteria indicated a small but significant bias toward milder disease in the (90)Y group. By using stratification into a 3-tier model with patients dichotomized according to bilirubin levels <1.5 mg/dL, the absence of portal vein thrombosis (PVT), and low alpha-fetoprotein plasma levels (<25 U/dL), an analysis of survival in clinical subgroups indicated that the 2 treatments resulted in similar survival. In addition, patients who had PVT or high alpha-fetoprotein levels also had similar survival in both treatment groups. CONCLUSIONS: Given the current evidence of therapeutic equivalence in survival, (90)Y and TACE appeared to be equivalent regional therapies for patients with unresectable, nonmetastatic HCC.

Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: a case cohort study.

BACKGROUND AND AIMS: A total of 967 patients with unresectable and untransplantable, biopsy-proven hepatocellular carcinoma (HCC) were prospectively evaluated at baseline and followed up till death. METHODS: Survival was the end-point for all analyses. RESULTS: We found in our overall analysis, that male gender, ascites, cirrhosis, portal vein thrombosis (PVT), elevated alpha-fetoprotein (AFP) or bilirubin or alkaline phosphatases were each statistically significant adverse prognostic factors. Patients with normal AFP survived longer than those with elevated AFP, in the presence of PVT, large or bilobar tumors or cirrhosis. We used a bivariate analysis to separate patient subgroups based on poor liver function and aggressive tumor characteristics. In subgroup analysis based on these subsets, there was clear discrimination in survival between subsets; in addition both cirrhosis and presence of PVT were significant, independent but modest risk factors. The results of this large dataset show that amongst nonsurgical HCC patients, there are clear subsets with longer survival than other subsets. CONCLUSIONS: This data also supports the concept of heterogeneity of HCC.

Case-control study of oral and oropharyngeal cancer in whites and genetic variation in eight metabolic enzymes.

BACKGROUND: Genetic variation in xenobiotic metabolizing enzymes may explain differing susceptibilities to the cancer causing effects of tobacco and alcohol. METHODS: We compared 203 oral squamous cell carcinoma cases and 416 controls for single nucleotide polymorphisms (SNPs) in 8 genes (CYP1A1, CYP2E1, MPO, mEH, GSTM1, GSTT1, GSTP1, and NAT2). Except for NAT2, genotype frequencies were similar in the 2 groups. We classified subjects as fast or slow NAT2 acetylators genotyping 13 NAT2 SNPs. RESULTS: Fast acetylators were overrepresented in cases (53.7%) compared with controls (43.9%; odds ratio (OR) 1.55, 95% confidence interval (CI) 1.08-2.20; p value = .03). Gene-gene interaction testing suggested several cancer-NAT2 associations, with association strongest among persons without a CYP1A1 variant (*2C or *4) allele (OR 1.77, 95% CI 1.20-2.60, p value = .03) or with a variant MPO (463A) allele (OR 2.38, 95% CI 1.34-4.21, p value = .05). CONCLUSION: These results implicate fast NAT2 acetylation as a risk factor for oral cancer.

Gender-based outcomes differences in unresectable hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. HCC is notably more prevalent in males worldwide, with reported male:female ratios ranging from 2:1 to 8:1. The reasons for sex differences in the incidence of HCC are unclear. Furthermore, differences in rates of disease progression and longevity are not well studied and few series have compared the clinicopathologic characteristics of patients and their impact on survival with specific reference to gender in a large sample set. METHODS: The present study is a large single-institution study of 1138 HCC cases referred to a single individual carried out over a period of 17 years. The primary endpoint measure was over-all survival measured in months, which was defined as the time between the date of diagnosis and date of death. Differences in median survival for each subgroup analysis in survival rates were compared by log rank test. RESULTS: There are differences in both the distribution of evidence of disease progression at the time of diagnosis and the time for survival following diagnosis in patients with HCC between the two genders. Females had a longer survival than males in subsets matched for residual liver function and tumor extension, suggesting that the natural history of HCC is different between men and women. CONCLUSION: The present study provides evidence that female gender provides a distinct survival advantage over males in unresectable HCC presenting with similar tumor characteristics, liver function, and coexisting liver disease.

Association of polymorphisms in the cyclin D1 and XPD genes and susceptibility to cancers of the upper aero-digestive tract.

DNA repair enzyme genetic polymorphisms have been postulated to increase the risk of certain cancers in the presence of tobacco carcinogen exposures. The XPD protein is an important component of the TFIIH transcription factor complex. XPD genetic polymorphisms resulting in amino acids substitutions may lead to alterations in TFIIH helicase activity, resulting in repair and transcription defects. Cyclin D1 is a key regulatory protein for the transition of cells from the G(1)-S cell cycle phase. The CCND1 G870A polymorphism has been reported to enhance alternate splicing of a stable mRNA variant, which may result in the bypass of the G(1)/S cell cycle checkpoint. In this study, XPD G23591A (Asp312Asn) and A35931C (Lys751Gln) polymorphisms and the CCND1 G870A splice variant frequencies were determined in 273 upper aero-digestive tract cancer cases and 269 controls. The XPD Asp312Asn variant frequency was significantly different among cases and controls and conferred an odds ratio (OR) of 1.3 (95% CI 1.0-1.8). However, individuals with the CCND1 G870A and XPD Lys751Gln variants had higher age adjusted ORs of 3.2 (95% CI 2.2-4.6) and 2.2 (95% CI 1.5-3.2), respectively. Furthermore, a significant gene-gene interaction was observed among cases with at least two variant alleles for both CCND1 and XPD genes [OR 7.09 (95% CI 4.03-12.5)]. Smokers with a combination of at least one variant allele of both CCND1 and XPD genes also had an elevated risk as compared to nonsmokers. This is the first study to suggest an associative interaction between XPD and CCND1 genetic polymorphisms, tobacco exposure, and cancer risk.

Polymorphism at GSTM1, GSTM3 and GSTT1 gene loci and susceptibility to oral cancer in an Indian population.

This study evaluates the influence of genetic polymorphism at GSTM1, GSTM3 and GSTT1 gene loci on oral cancer risk among Indians habituated to the use of, smokeless tobacco, bidi or cigarette. DNA extracted from white blood cells of 297 cancer patients and 450 healthy controls by the proteinase K phenol-chloroform extraction procedure were analyzed by the polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) analyses. Lifetime tobacco exposure was evaluated as a risk factor in relation to the polymorphism at the GST gene loci using logistic regression analysis. There was no significant difference in the distribution of the GSTM3 and GSTT1 genotypes between oral cancer patients and controls. In contrast, a significant 3-fold increase in risk was seen for patients with the GSTM1 null genotype (age adjusted OR = 3.2, 95% CI 2.4-4.3). The impact of the GSTM1 null genotype on oral cancer risk was also analyzed in separate groups of individuals with different tobacco habits. The odds ratio associated with the GSTM1 null genotype was 3.7 (95% CI 2.0-7.1) in tobacco chewers, 3.7 (5% CI 1.3-7.9) in bidi smokers and 5.7 (95% CI 2.0-16.3) in cigarette smokers. Furthermore, increased lifetime exposure to chewing tobacco appeared to be associated with a 2-fold increase in oral cancer risk in GSTM1 null individuals. The results suggest that the GSTM1 null genotype is a risk factor for development of oral cancer among Indian tobacco habitues.