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1.  Genetic variation in the serotonin pathway and smoking cessation with nicotine replacement therapy: New data from the Patch in Practice trial and pooled analyses 
Drug and alcohol dependence  2008;98(0):77-85.
The serotonin pathway has been implicated in nicotine dependence and may influence smoking cessation. Therefore, 792 cigarette smokers from the Patch in Practice trial were genotyped for the tryptophan hydroxylase (TPH1 A779C), serotonin transporter (SLC6A4 5-HTTLPR), and 5-HT1A (HTR1A C-1019G) polymorphisms. Cox regression analysis did not demonstrate significant effects of any of the three genotypes on relapse to smoking: TPH1 (Reference AA; AC: hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.78, 1.24, p = 0.90; CC: HR 0.93, 95% CI 0.73, 1.18, p = 0.55); 5-HTTLPR (Reference LL; SL: HR 1.01, 95% CI 0.85, 1.20, p = 0.90; SS: HR 1.13, 95% CI 0.91, 1.39, p = 0.27); HTR1A (Reference CC; CG: HR 1.04, 95% CI 0.86, 1.25, p = 0.70; GG: HR 1.01, 95% CI 0.82, 1.24, p = 0.93). Moreover, pooled analyses of data from all three extant pharmacogenetic NRT trials (N= 1398) found no significant effect of 5-HTTLPR genotype on continuous abstinence at 12-week (Reference LL; SL: odds ratio (OR) = 1.25, 95% CI 0.89, 1.74, p = 0.19; SS: OR= 1.31, 95% CI 0.86, 1.98, p = 0.21) or 26-week follow-up (Reference LL; SL: OR= 0.93, 95% CI 0.64, 1.33, p = 0.68; SS: OR= 1.00, 95% CI 0.63, 1.58, p = 1.00). These data do not support a statistically or clinically significant moderating effect of these specific 5-HT pathway genetic variants on smoking cessation. However, the possibility remains that other variants in these or other 5-HT genes may influence NRT efficacy for smoking cessation in treatment seeking smokers.
PMCID: PMC4439462  PMID: 18562131
Smoking cessation; Tryptophan hydroxylase; Serotonin transporter; 5-HT1A receptor; Nicotine replacement therapy; Pharmacogenetics
2.  Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium 
BMJ Open  2014;4(10):e006141.
To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach.
Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress.
Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA).
Primary outcome measures
Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis.
The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers.
Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.
PMCID: PMC4187451  PMID: 25293386
Mendelian randomisation; Smoking; Depression; Anxiety
3.  Weight Change Over Eight Years in Relation to Alcohol Consumption in a Cohort of Continuing Smokers and Quitters 
Nicotine & Tobacco Research  2011;13(11):1149-1154.
Stopping smoking results in weight gain. Avoidance of alcohol is often advocated to reduce cues to smoking, but the effect of alcohol consumption on body weight is unclear.
We used regression models to examine weight change by baseline alcohol consumption in quitting and continuing smokers. Weight was measured at baseline and at 8 years, and weekly alcohol consumption was reported at baseline in participants from the Oxfordshire general practices nicotine patch/placebo trial. Of 698 smokers attempting to stop smoking, 85 were abstinent for 8 years and 613 continued to smoke.
The association between baseline alcohol consumption and weight change depended upon smoking status (p for interaction = .019). In smokers, there was no association with weight change, 0.005 (95% CI: −0.037 to 0.056) kg per UK unit (U) (8 g of ethanol) consumed each week. This was unmodified by gender and baseline body mass index (BMI). In quitters, there was a negative association with weight change, −0.174 (95% CI: −0.315 to −0.034) kg per U consumed each week (unmodified by gender and baseline BMI). Quitters who consumed 14 U (112 g ethanol) a week weighed a mean 2.4 kg less than quitters who did not drink.
Quitting smokers who drink more alcohol appear to gain less weight after quitting than those who do not drink. This is consistent across studies, it may be accounted for by unmeasured confounders or it may be that alcohol reduces weight gain. If alcohol reduces weight gain, the advice for quitting smokers must balance the benefits and hazards of alcohol consumption. However, there is currently insufficient evidence to advise quitters who drink little or no alcohol to increase consumption.
PMCID: PMC3203131  PMID: 21622496
4.  Loss of expression of the double strand break repair protein ATM is associated with worse prognosis in colorectal cancer and loss of Ku70 expression is associated with CIN 
Oncotarget  2012;3(11):1348-1355.
Repair of double strand DNA breaks (DSBs) is pivotal in maintaining normal cell division and disruption of this system has been shown to be a key factor in carcinogenesis. Loss of expression of the DSB repair proteins have previously been shown to be associated with poorer survival in colorectal cancer. We wished to ascertain the relationship of altered expression of the DSB repair proteins γ-H2AX (gamma-H2AX), ATM and Ku70 with biological and clinico-pathological features of colorectal cancer. 908 tumours from the VICTOR clinical trial of stage II/III colorectal cancer were analysed for expression of γ-H2AX, ATM and Ku70 using immunohistochemistry. Expression levels were correlated with CIN and with disease-free survival, correcting for microsatellite instability, BRAF/KRAS mutation status, Dukes stage, chemo/radiotherapy, age, gender and tumour location. Down-regulated Ku70 expression was associated with chromosomal instability (p=0.029) in colorectal cancer. Reduced ATM expression was an independent marker of poor disease-free survival (HR=1.67, 95% CI 1.11-2.50, p=0.015). For Ku70, further studies are required to investigate the potential relationship of non-homologous end joining with chromosomal instability. Loss of ATM expression might serve as a biomarker of poor prognosis in colorectal cancer.
PMCID: PMC3717797  PMID: 23154512
Double strand break repair; ATM; γ-H2AX; colorectal cancer; prognosis
5.  CHRNA3 rs1051730 Genotype and Short-Term Smoking Cessation 
Nicotine & Tobacco Research  2011;13(10):982-988.
The rs1051730 genetic variant within the CHRNA5-A3-B4 gene cluster is associated with heaviness of smoking and has recently been reported to be associated with likelihood of stopping smoking. We investigated the potential association of rs1051730 genotype with reduced likelihood of smoking cessation in 2 cohorts of treatment-seeking smokers in primary care in the United Kingdom.
Data were drawn from 2 clinical trials on which DNA was available. One sample was a randomized placebo-controlled trial of nicotine transdermal patch and the other sample an open-label trial where all participants received nicotine transdermal patch. Smoking status was biochemically verified. Logistic regression was used to assess evidence for association in each sample, and data were combined within a meta-analysis.
There was evidence of association of rs1051730 genotype with short-term (4-week) cessation in our open-label trial sample but not our placebo-controlled trial sample. When combined in a meta-analysis, this effect remained. There was no evidence of association at later follow-up intervals. Adjustment for cigarette consumption and tobacco dependence did not alter these results substantially.
Our data, taken together with previous recent studies, provide some support for a weak association between this variant and short-term smoking cessation in treatment-seeking smokers, which does not seem to operate only among those receiving nicotine replacement therapy. Moreover, the rs1051730 variant may not merely operate as a marker for dependence or heaviness of smoking.
PMCID: PMC3179672  PMID: 21690317
6.  Association Between Genetic Variants on Chromosome 15q25 Locus and Objective Measures of Tobacco Exposure 
Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure.
We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730–rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730–rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided.
Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730–rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 × 10−6) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 × 10−11). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730–rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42).
Our data show a stronger association of rs1051730–rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure.
PMCID: PMC3352832  PMID: 22534784
7.  Effect on Adherence to Nicotine Replacement Therapy of Informing Smokers Their Dose Is Determined by Their Genotype: A Randomised Controlled Trial 
PLoS ONE  2012;7(4):e35249.
The behavioural impact of pharmacogenomics is untested. We tested two hypotheses concerning the behavioural impact of informing smokers their oral dose of NRT is tailored to analysis of DNA.
Methods and Findings
We conducted an RCT with smokers in smoking cessation clinics (N = 633). In combination with NRT patch, participants were informed that their doses of oral NRT were based either on their mu-opioid receptor (OPRM1) genotype, or their nicotine dependence questionnaire score (phenotype). The proportion of prescribed NRT consumed in the first 28 days following quitting was not significantly different between groups: (68.5% of prescribed NRT consumed in genotype vs 63.6%, phenotype group, difference  =  5.0%, 95% CI −0.9,10.8, p  =  0.098). Motivation to make another quit attempt among those (n  =  331) not abstinent at six months was not significantly different between groups (p  =  0.23). Abstinence at 28 days was not different between groups (p = 0.67); at six months was greater in genotype than phenotype group (13.7% vs 7.9%, difference  =  5.8%, 95% CI 1.0,10.7, p  =  0.018).
Informing smokers their oral dose of NRT was tailored to genotype not phenotype had a small, statistically non-significant effect on 28-day adherence to NRT. Among those still smoking at six months, there was no evidence that saying NRT was tailored to genotype adversely affected motivation to make another quit attempt. Higher abstinence rate at six months in the genotype arm requires investigation.
Trial registration ISRCTN14352545.
PMCID: PMC3324463  PMID: 22509402
8.  Pharmacogenetics of Smoking Cessation in General Practice: Results From the Patch II and Patch in Practice Trials 
Nicotine & Tobacco Research  2011;13(3):157-167.
Cigarette smoking remains the leading cause of preventable death worldwide. However, the efficacy of available first-line therapies remains low, particularly in primary care practice where most smokers seek and receive treatment. These observations reinforce the notion that ‘one size fits all’ smoking cessation therapies may not be optimal. Therefore, a translational research effort was launched by the Imperial Cancer Research Fund (later Cancer Research UK) General Practice Research Group, who led a decade-long research enterprise that examined the influence of pharmacological hypothesis-driven research into genetic influences on drug response for smoking cessation with transdermal nicotine replacement therapy in general practice.
New and previously published smoking cessation genetic association results of 30 candidate gene polymorphisms genotyped for participants in two transdermal nicotine replacement clinical trials based in UK general practices, which employed an intention to analyze approach.
By this high bar, one of the polymorphisms (COMT rs4680) was robust to correction for multiple comparisons. Moreover, future research directions are outlined; and lessons learned as well as best-practice models for designing, analyzing, and translating results into clinical practice are proposed.
The results and lessons learned from this general practice-based pharmacogenetic research programme provide transportable insights at the transition to the second generation of pharmacogenetic and genomic investigations of smoking cessation and its translation to primary care.
PMCID: PMC3107615  PMID: 21330274
9.  Genome-wide association for smoking cessation success: participants in the Patch in Practice trial of nicotine replacement 
Pharmacogenomics  2010;11(3):357-367.
To confirm and extend to primary care settings prior genome-wide association results that distinguish smokers who successfully quit from individuals who were not able to quit smoking in clinical trials.
Materials & methods
Affymetrix® 6.0 Arrays were used to study DNA from successful quitters and matched individuals who did not quit from the Patch in Practice study of 925 smokers in 26 UK general practices who were provided with 15 mg/16 h nicotine-replacement therapy and varying degrees of behavioral support.
Only a few SNPs provided results near ‘genome-wide’ levels of significance. Nominally significant (p < 0.01) SNP results identify the same chromosomal regions identified by prior genome-wide association studies to a much greater extent than expected by chance.
Ability to change smoking behavior in a general practice setting appears to share substantial underlying genetics with the ability to change this behavior in clinical trials, though the modest sample sizes available for these studies provides some caution to these conclusions.
PMCID: PMC3040594  PMID: 20235792
DNA microarray; genetic susceptibility; nicotine dependence; nicotine replacement; smoking cessation
10.  Trial Protocol: Using genotype to tailor prescribing of nicotine replacement therapy: a randomised controlled trial assessing impact of communication upon adherence 
BMC Public Health  2010;10:680.
The behavioural impact of pharmacogenomics is untested; informing smokers of genetic test results for responsiveness to smoking cessation medication may increase adherence to this medication. The objective of this trial is to estimate the impact upon adherence to nicotine replacement therapy (NRT) of informing smokers that their oral dose of NRT has been tailored to a DNA analysis. Hypotheses to be tested are as follows:
I Adherence to NRT is greater among smokers informed that their oral dose of NRT is tailored to an analysis of DNA (genotype), compared to one tailored to nicotine dependence questionnaire score (phenotype).
II Amongst smokers who fail to quit at six months, motivation to make another quit attempt is lower when informed that their oral dose of NRT was tailored to genotype rather than phenotype.
An open label, parallel groups randomised trial in which 630 adult smokers (smoking 10 or more cigarettes daily) using National Health Service (NHS) stop smoking services in primary care are randomly allocated to one of two groups:
i. NRT oral dose tailored by DNA analysis (OPRM1 gene) (genotype), or
ii. NRT oral dose tailored by nicotine dependence questionnaire score (phenotype)
The primary outcome is proportion of prescribed NRT consumed in the first 28 days following an initial quit attempt, with the secondary outcome being motivation to make another quit attempt, amongst smokers not abstinent at six months. Other outcomes include adherence to NRT in the first seven days and biochemically validated smoking abstinence at six months. The primary outcome will be collected on 630 smokers allowing sufficient power to detect a 7.5% difference in mean proportion of NRT consumed using a two-tailed test at the 5% level of significance between groups. The proportion of all NRT consumed in the first four weeks of quitting will be compared between arms using an independent samples t-test and by estimating the 95% confidence interval for observed between-arm difference in mean NRT consumption (Hypothesis I). Motivation to make another quit attempt will be compared between arms in those failing to quit by six months (Hypothesis II).
This is the first clinical trial evaluating the behavioural impact on adherence of prescribing medication using genetic rather than phenotypic information. Specific issues regarding the choice of design for trials of interventions of this kind are discussed.
Trial details
Funder: Medical Research Council (MRC)
Grant number: G0500274
ISRCTN: 14352545
Date trial stated: June 2007
Expected end date: December 2009
Expected reporting date: December 2010
PMCID: PMC2996370  PMID: 21062464
11.  Weekly versus basic smoking cessation support in primary care: a randomised controlled trial 
Thorax  2007;62(10):898-903.
There is insufficient and conflicting evidence about whether more intensive behavioural support is more effective than basic behavioural support for smoking cessation and whether primary care nurses can deliver effective behavioural support.
A randomised controlled trial was performed in 26 UK general practices. 925 smokers of ⩾10 cigarettes per day were randomly allocated to basic or weekly support. All participants were seen before quitting, telephoned around quit day, and seen 1 and 4 weeks after the initial appointment (basic support). Participants receiving weekly support had an additional telephone call at 10 days and 3 weeks after the initial appointment and an additional visit at 2 weeks to motivate adherence to nicotine replacement and renew quit attempts. 15 mg/16 h nicotine patches were given to all participants. The outcome was assessed by intention to treat analyses of the percentage confirmed sustained abstinence at 4, 12, 26 and 52 weeks after quit day.
Of the 469 and 456 participants in the basic and weekly arms, the numbers (%) who quit and the percentage difference were 105 (22.4%) vs 102 (22.4%), 0.1% (95% CI −5.3% to 5.5%) at 4 weeks, 66 (14.1%) vs 52 (11.4%), −2.6% (95% CI −6.9% to 1.7%) at 12 weeks, 50 (10.7%) vs 40 (8.8%), −1.9% (95% CI −5.7% to 2.0%) at 26 weeks and 36 (7.7%) vs 30 (6.6%), −1.1% (95% CI −4.4% to 2.3%) at 52 weeks.
The absolute quit rates achieved are those expected from nicotine replacement alone, implying that neither basic nor weekly support were effective. Primary care smoking cessation treatment should provide pharmacotherapy with sufficient support only to ensure it is used appropriately, and those in need of support should be referred to specialists.
PMCID: PMC2094265  PMID: 17483139
12.  A cost-effectiveness analysis of genetic testing of the DRD2 Taq1A polymorphism to aid treatment choice for smoking cessation 
We conducted a cost-effectiveness analysis of genetic testing for smoking cessation, based on data available from the published pharmacogenetic studies of nicotine replacement therapy and bupropion, and a previous cost-effectiveness analysis of smoking cessation treatments. We use multiparameter evidence synthesis methods to combine evidence on cessation by genotype with evidence on cessation irrespective of genotype (which can be written as a function of genotype-specific parameters). Our intention was to explore the most cost-effective approach to prescribing smoking cessation pharmacotherapy, given the hypothetical availability of a test based on a single-gene variant that has been reported to predict treatment response. We considered four types of treatment: nicotine replacement therapy (NRT) pharmacotherapy, bupropion SR pharmacotherapy, combination NRT and bupropion, and standard care as the control. Two scenarios were investigated, one in which the control represented brief advice and the other in which the control represented individual counseling. Strategies that either do not test for dopamine D2 receptor (DRD2) genotype (each individual receives the same treatment), or do test for DRD2 genotype (treatment allocated according to genotype), were evaluated. Our results indicated that the most cost-effective strategy in our hypothetical example of a single-gene test to aid prescription of smoking cessation pharmacotherapy is to prescribe both NRT and bupropion regardless of genotype, as a first-line treatment for smoking cessation. We conclude that it should not be assumed that genetic tailoring will necessarily be more cost-effective than applying the current “one-size-fits-all” model of pharmacotherapy for smoking cessation. In addition, single-gene tests are unlikely to be cost-effective, partly because the predictive value of these tests is likely to be modest.
PMCID: PMC2257987  PMID: 18188764
13.  The serotonin transporter 5-HTTLPR polymorphism and treatment response to nicotine patch: Follow-up of a randomized controlled trial 
In this follow-up of a randomized placebo-controlled clinical trial of nicotine replacement transdermal patch for smoking cessation, 741 smokers of European ancestry who were randomized to receive active patch or placebo patch were genotyped for the serotonin transporter gene-linked polymorphic region. The study setting was a primary care research network in Oxfordshire, United Kingdom. The primary outcome measures were biochemically verified sustained abstinence from cigarette smoking at end of treatment and 24-week follow-up. The main effect of genotype was not associated with sustained abstinence from smoking at either end of treatment (SL: p=.33; SS: p=.81) or 24-week follow-up (SL: p=.05; SS: p=.21), and we found no evidence for a genotype×treatment interaction effect. In summary, despite the theoretically important contribution of serotonin neurotransmission to smoking cessation, the serotonin transporter gene was not associated with treatment response to nicotine patch for smoking cessation in this primary care–based trial.
PMCID: PMC2031912  PMID: 17365753
14.  Association of COMT Val108/158Met Genotype with Smoking Cessation in a Nicotine Replacement Therapy Randomized Trial 
We investigated the association of catechol O-methyltransferase (COMT) genotype with abstinence following a smoking cessation attempt among a large cohort of smokers who attempted to quit using either the nicotine transdermal patch or placebo and were followed up over an 8-year period following their initial cessation attempt. In addition, we examined the possible moderating influence of sex on any association. The genotype × treatment interaction effect at 12-week follow-up indicated a greater benefit of active nicotine replacement treatment compared with placebo on likelihood of abstinence in the COMT Met/Met genotype group (33% versus 12%), in comparison to the Met/Val + Val/Val group (22% versus 16%). Our results indicate that COMT genotype may moderate the effect of active transdermal nicotine patch compared with placebo, with reduced relative benefit of nicotine replacement therapy in individuals with Met/Val or Val/Val genotype. Our data follow an emerging pattern of results suggesting that genetic variation in the dopamine pathway may provide a future basis for tailored smoking cessation therapies, but indicate that different genes influencing various components of this pathway may have different effects on response to smoking cessation pharmacotherapy.
PMCID: PMC2031911  PMID: 17548664
15.  A Functional Genetic Variation of the Serotonin (5-HT) Transporter Affects 5-HT1A Receptor Binding in Humans 
In humans, 5-HT1A receptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT1A receptor expression in the living human brain was assessed using the 5-HT1A-selective positron emission tomography (PET) ligand [ 11C]WAY 100635. After the genotyping of 140 healthy volunteers to study population frequencies of known single nucleotide polymorphisms (SNPs) in the 5-HT1A receptor gene, the influence of the common SNP [(−1018) C>G] on 5-HT1A receptor expression was examined in a group of 35 healthy individuals scanned with [ 11C]WAY 100635. In the PET group, we also studied the influence of a common variable number tandem repeat polymorphism [short (S) and long (L) alleles] of the 5-HT transporter (5-HTT) gene on 5-HT1A receptor density. Whereas, the 5-HT1A receptor genotype did not show any significant effects on [ 11C]WAY 100635 binding, 5-HT1A receptor binding potential values were lower in all brain regions in subjects with 5-HTTLPR short (SS or SL) genotypes than those with long (LL) genotypes. Although the PET groups are necessarily a small sample size for a genetic association study, our results demonstrate for the first time that a functional polymorphism in the 5-HTT gene, but not the 5-HT1A receptor gene, affects 5-HT1A receptor availability in man. The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states.
PMCID: PMC1942077  PMID: 15758168
serotonin; 5-HT1A receptor; serotonin transporter; genetics; polymorphisms; positron emission tomography
18.  Use of multivariate analysis to suggest a new molecular classification of colorectal cancer 
The Journal of Pathology  2013;229(3):441-448.
Molecular classification of colorectal cancer (CRC) is currently based on microsatellite instability (MSI), KRAS or BRAF mutation and, occasionally, chromosomal instability (CIN). Whilst useful, these categories may not fully represent the underlying molecular subgroups. We screened 906 stage II/III CRCs from the VICTOR clinical trial for somatic mutations. Multivariate analyses (logistic regression, clustering, Bayesian networks) identified the primary molecular associations. Positive associations occurred between: CIN and TP53 mutation; MSI and BRAF mutation; and KRAS and PIK3CA mutations. Negative associations occurred between: MSI and CIN; MSI and NRAS mutation; and KRAS mutation, and each of NRAS, TP53 and BRAF mutations. Some complex relationships were elucidated: KRAS and TP53 mutations had both a direct negative association and a weaker, confounding, positive association via TP53–CIN–MSI–BRAF–KRAS. Our results suggested a new molecular classification of CRCs: (1) MSI+ and/or BRAF-mutant; (2) CIN+ and/or TP53– mutant, with wild-type KRAS and PIK3CA; (3) KRAS- and/or PIK3CA-mutant, CIN+, TP53-wild-type; (4) KRAS– and/or PIK3CA-mutant, CIN–, TP53-wild-type; (5) NRAS-mutant; (6) no mutations; (7) others. As expected, group 1 cancers were mostly proximal and poorly differentiated, usually occurring in women. Unexpectedly, two different types of CIN+ CRC were found: group 2 cancers were usually distal and occurred in men, whereas group 3 showed neither of these associations but were of higher stage. CIN+ cancers have conventionally been associated with all three of these variables, because they have been tested en masse. Our classification also showed potentially improved prognostic capabilities, with group 3, and possibly group 1, independently predicting disease-free survival. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
PMCID: PMC3588155  PMID: 23165447
colorectal cancer; genetic pathways; clinico-pathological associations; prognostic markers; somatic mutations; molecular classification
19.  A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS 
Gut  2014;64(1):111-120.
Capecitabine is an oral 5-fluorouracil (5-FU) pro-drug commonly used to treat colorectal carcinoma and other tumours. About 35% of patients experience dose-limiting toxicity. The few proven genetic biomarkers of 5-FU toxicity are rare variants and polymorphisms, respectively, at candidate loci dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS).
We investigated 1456 polymorphisms and rare coding variants near 25 candidate 5-FU pathway genes in 968 UK patients from the QUASAR2 clinical trial.
We identified the first common DPYD polymorphisms to be consistently associated with capecitabine toxicity, rs12132152 (toxicity allele frequency (TAF)=0.031, OR=3.83, p=4.31×10−6) and rs12022243 (TAF=0.196, OR=1.69, p=2.55×10−5). rs12132152 was particularly strongly associated with hand-foot syndrome (OR=6.1, p=3.6×10−8). The rs12132152 and rs12022243 associations were independent of each other and of previously reported DPYD toxicity variants. Next-generation sequencing additionally identified rare DPYD variant p.Ala551Thr in one patient with severe toxicity. Using functional predictions and published data, we assigned p.Ala551Thr as causal for toxicity. We found that polymorphism rs2612091, which lies within an intron of ENOSF1, was also associated with capecitabine toxicity (TAF=0.532, OR=1.59, p=5.28×10−6). ENSOF1 is adjacent to TYMS and there is a poorly characterised regulatory interaction between the two genes/proteins. Unexpectedly, rs2612091 fully explained the previously reported associations between capecitabine toxicity and the supposedly functional TYMS variants, 5′VNTR 2R/3R and 3′UTR 6 bp ins-del. rs2612091 genotypes were, moreover, consistently associated with ENOSF1 mRNA levels, but not with TYMS expression.
DPYD harbours rare and common capecitabine toxicity variants. The toxicity polymorphism in the TYMS region may actually act through ENOSF1.
PMCID: PMC4283622  PMID: 24647007
Cancer; Cancer Genetics; Chemotherapy; Pharmacogenetics

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