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1.  Genetic variability in DNA repair and cell cycle control pathway genes and risk of smoking-related lung cancer 
Molecular carcinogenesis  2011;51(Suppl 1):E11-E20.
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 (Padditive=0.003), rs10500298 in LIG1 (Precessive=2.7×10−4), rs747658 and rs3219073 in PARP1 (rs747658: Padditive=5.8×10−5; rs3219073: Padditive=4.6×10−5), and rs1799782 and rs3213255 in XRCC1 (rs1799782: Pdominant=0.006; rs3213255: Precessive=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; Ptrend<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.
doi:10.1002/mc.20858
PMCID: PMC3289753  PMID: 21976407
SNP; case-control; lung cancer
2.  CASE–CONTROL STUDY OF ORAL AND OROPHARYNGEAL CANCER IN WHITES AND GENETIC VARIATION IN EIGHT METABOLIC ENZYMES 
Head & neck  2008;30(9):1139-1147.
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.
doi:10.1002/hed.20867
PMCID: PMC3627181  PMID: 18642288
tobacco; oral cancer; polymorphism; metabolizing enzymes; susceptibility
3.  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.
doi:10.1093/jnci/djr075
PMCID: PMC3096796  PMID: 21483023
4.  A UPLC-MS/MS assay of the “Pittsburgh Cocktail”: six CYP probe-drug/metabolites from human plasma and urine using stable isotope dilution 
The Analyst  2010;136(3):605-612.
The efficiency of drug metabolism by a single enzyme can be measured as the fractional metabolic clearance which can be used as a measure of whole body activity for that enzyme. Measurement of activity of multiple enzymes simultaneously is feasible using a cocktail approach however analytical approach using different assays for drug probes can be cumbersome. A quantitative ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based method for the rapid measurement of six cytochrome P450 (CYP) probe drugs and their relevant metabolites, is described. The six specific probe substrates/metabolites, are caffeine/paraxanthine (CYP1A2), flurbiprofen/4′-hydroxyflurbiprofen (CYP2C9), mephenytoin/4′-hydroxymephenytoin (CYP2C19), debrisoquine/4-hydroxydebrisoquine (CYP2D6), chlorzoxazone/6′-hydroxychlorzoxazone (CYP2E1) and dapsone/N-monoacetyldapsone (NAT2). These probes were quantified by stable isotope dilution from plasma and urine. The present workflow provides a robust, fast and sensitive assay for the “Pittsburgh Cocktail”, and has been successfully applied to a clinical phenotyping study of liver disease. A representative group of 17 controls and patients with chronic liver disease were administered orally caffeine (100mg), chlorzoxazone (250mg), debrisoquine (10mg), mephenytoin (100mg) flurbiprofen (50mg) and dapsone (100mg). Urine (0 through 8 h) and plasma (4 and 8 h) samples were analyzed for drug/metabolite amounts by stable isotope dilution UPLC-MS/MS. The phenotypic activity of drug metabolizing enzymes was investigated with 17 patient samples. Selected reaction monitoring (SRM) was optimized for each drug and metabolite. In the method developed, analytes were resolved by reversed-phase by development of a gradient using a water/methanol solvent system. SRM of each analyte was performed in duplicate on a triple quadrupole mass spectrometer utilizing an 8 min analytical method each, one with the source operating in the positive mode and one in the negative mode, using the same solvent system. This method enabled quantification of each drug (caffeine, chlorzoxazone, debrisoquine, mephenytoin, flurbiprofen, and dapsone) and its resulting primary metabolite in urine or plasma in patient samples. The method developed and the data herein demonstrate a robust quantitative assay to examine changes in CYP enzymes both independently or as part of a cocktail. The clinical use of a combination of probe drugs with UPLC-MS/MS is a highly efficient tool for the assessment of CYP enzyme activity in liver disease.
doi:10.1039/c0an00643b
PMCID: PMC3115584  PMID: 21107456
CYP; Mass spectrometry; stable isotope dilution; phenotyping; drug cocktail
5.  Therapeutic equivalence in survival for hepatic arterial chemoembolization and 90Yttrium microspheres (Y90) treatments in unresectable hepatocellular carcinoma: a 2 cohort study 
Cancer  2010;116(5):1305-1314.
BACKGROUND
Intra-hepatic arterial 90Yttrium (Y90) microspheres (Theraspheres) have been proposed as a less toxic, invasive therapeutic option to trans-hepatic arterial chemoembolization (TACE) for surgically unresectable hepatocellular carcinoma (HCC). TACE has been shown to prolong survival. However, long term survival remains uncertain.
METHODS
A 2 cohort experience of the treatment of advanced, unresectable and biopsy-proven HCC in North American patients is presented. 691 patients received repetitive cisplatin-based chemoembolization and a following 99 patient cohort with similar treatment criteria, received a planned single dose of Y90. Over this time period, an additional 142 patients were followed without treatment (total: 932 patients).
RESULTS
Overall survival was slightly better in the Y90 group compared to TACE, median of 11.5 vs. 8.5 months. However, selection criteria indicated a small but significant bias towards milder disease in the Y90 group. Using stratification in a 3 tier model, with cases dichotomized by bilirubin of less than 1.5 mg/dL, patients without PVT or with low alpha-fetoprotein plasma levels of less than 25 units/dL, analysis of survival in clinical subgroups showed that the 2 treatments resulted in similar survival. Similarly, patients with PVT or a high alpha-fetoprotein also had similar survival in the 2 treatment groups.
CONCLUSION
Given the present evidence of therapeutic equivalence in survival, Y90 and TACE seem to be equivalent regional therapies for patients with unresectable, non-metastatic HCC.
doi:10.1002/cncr.24884
PMCID: PMC2829376  PMID: 20066715
HCC; hepatoma; chemotherapy; Yttrium; internal radiation
6.  Gender-based outcomes differences in unresectable hepatocellular carcinoma 
Hepatology International  2007;2(1):95-101.
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.
doi:10.1007/s12072-007-9041-2
PMCID: PMC2716876  PMID: 19669284
Gender; Outcome; Unresectable hepatocellular carcinoma; Survival; Female

Results 1-6 (6)