Lawson Eng

p53 Arg72Pro Polymorphism, HPV Status and Initiation, Progression, and Development of Cervical Cancer: A Systematic Review and Meta-Analysis

Cervical cancer develops through progression from normal cervical epithelium through squamous intraepithelial lesions (SIL) to invasive cancer. Cervical cancer is associated with oncogenic human papillomavirus (HPV). The HPV E6 oncoprotein binds to the tumor suppressor gene product p53, promoting its degradation; the Arg allele of p53 Arg72Pro polymorphism binds more ardently with HPV E6 than the Pro variant. Here we evaluate the role of p53 Arg72Pro polymorphism and HPV status on the initiation, progression, and development of cervical cancer. A systematic review and meta-analysis were conducted. Events of interest were the initiation of neoplasia (SIL vs. normal), progression to invasive cancer (cervical cancer vs. SIL), and risk of invasive cancer (cervical cancer vs. normal) by HPV status. OR were extracted from individual studies and pooled using generic inverse variance and random effects modeling. Forty-nine studies were included. In individuals showing HPV positivity, there was a significantly higher odds of progression from SIL to cervical cancer with the p53 Arg allele [OR 1.37; 95% confidence intervals (CI), 1.15–1.62; P < 0.001]. This association was not seen in HPV-negative individuals. p53 Arg72Pro was not associated with the risk of cervical cancer or initiation of SIL in either HPV-positive or HPV-negative patient subsets. The Arg variant of p53 Arg72Pro is associated with progression of SIL to cervical cancer only in the presence of HPV positivity. There were no associations of this variant with overall risk or initiation of cancer in either HPV-positive or HPV-negative patients. Clin Cancer Res; 18(23); 6407–15. ©2012 AACR.

Vascular Endothelial Growth Factor Pathway Polymorphisms as Prognostic and Pharmacogenetic Factors in Cancer: A Systematic Review and Meta-analysis

Angiogenesis is an important host process that interacts with cancer cells to promote growth, invasion, and metastasis. Numerous therapeutic agents targeting the VEGF pathway have been developed. Host variability in VEGF pathway can influence angiogenesis-dependent signaling, altering sensitivity to antiangiogenic drugs and prognosis. A systematic review and meta-analysis was conducted (May 1990–July 2011). Eligible studies involved cancer patients and compared polymorphisms in the VEGF pathway [VEGF and molecules directly interacting with VEGF: KDR, FLT1, FGF, FGF2, FGFR, NRP1, endostatin (encoded by COL18A1)], and reported one of the following outcomes: overall survival, progression-free survival, time to recurrence, disease-free survival, response rate, or drug toxicity. We identified 48 cancer studies assessing prognosis and 12 cancer studies exploring pharmacogenetics of anti-VEGF therapy across various VEGF pathway polymorphisms. There was marked inter- and intradisease site heterogeneity in the effect of polymorphisms on both outcome and response to therapy. Meta-analyses of 5 VEGF polymorphisms (+936C>T, −460T>C, +405G>C, −1154G>A, and −2578C>A) identified a significant prognostic relationship: VEGF +405G>C variants showed a highly statistically significant improvement in overall survival [HR, 0.74; 95% confidence interval, 0.60–0.91; P = 0.004]. Variants (heterozygotes and/or homozygotes) of VEGF +405G>C were significantly associated with improved survival in a meta-analysis of multiple cancer sites. Clin Cancer Res; 18(17); 4526–37. ©2012 AACR.

Second-Hand Smoke As a Predictor of Smoking Cessation Among Lung Cancer Survivors

PURPOSE Second-hand smoke (SHS; ie, exposure to smoking of friends and spouses in the household) reduces the likelihood of smoking cessation in noncancer populations. We assessed whether SHS is associated with cessation rates in lung cancer survivors. PATIENTS AND METHODS Patients with lung cancer were recruited from Princess Margaret Cancer Centre, Toronto, ON, Canada. Multivariable logistic regression and Cox proportional hazard models evaluated the association of sociodemographics, clinicopathologic variables, and SHS with either smoking cessation or time to quitting. RESULTS In all, 721 patients completed baseline and follow-up questionnaires with a mean follow-up time of 54 months. Of the 242 current smokers at diagnosis, 136 (56%) had quit 1 year after diagnosis. Exposure to smoking at home (adjusted odds ratio [aOR], 6.18; 95% CI, 2.83 to 13.5; P < .001), spousal smoking (aOR, 6.01; 95% CI, 2.63 to 13.8; P < .001), and peer smoking (aOR, 2.49; 95% CI, 1.33 to 4.66; P = .0043) were each associated with decreased rates of cessation. Individuals exposed to smoking in all three settings had the lowest chances of quitting (aOR, 9.57; 95% CI, 2.50 to 36.64; P < .001). Results were similar in time-to-quitting analysis, in which 68% of patients who eventually quit did so within 6 months after cancer diagnosis. Subgroup analysis revealed similar associations across early- and late-stage patients and between sexes. CONCLUSION SHS is an important factor associated with smoking cessation in lung cancer survivors of all stages and should be a key consideration when developing smoking cessation programs for patients with lung cancer.

Social environment, secondary smoking exposure, and smoking cessation among head and neck cancer patients

Smoking during treatment of squamous cell head and neck cancer (HNC) has adverse affects on toxicity, treatment, and survival. The purpose of this report was to evaluate sociodemographic predictors of smoking cessation in HNC patients to support the development of a smoking cessation program.

An evaluation of Wikipedia as a resource for patient education in nephrology.

Wikipedia, a multilingual online encyclopedia, is a common starting point for patient medical searches. As its articles can be authored and edited by anyone worldwide, the credibility of the medical content of Wikipedia has been openly questioned. Wikipedia medical articles have also been criticized as too advanced for the general public. This study assesses the comprehensiveness, reliability, and readability of nephrology articles on Wikipedia. The International Statistical Classification of Diseases and Related problems, 10th Edition (ICD‐10) diagnostic codes for nephrology (N00–N29.8) were used as a topic list to investigate the English Wikipedia database. Comprehensiveness was assessed by the proportion of ICD‐10 codes that had corresponding articles. Reliability was measured by both the number of references per article and proportion of references from substantiated sources. Finally, readability was assessed using three validated indices (Flesch‐Kincaid grade level, Automated readability index, and Flesch reading ease). Nephrology articles on Wikipedia were relatively comprehensive, with 70.5% of ICD‐10 codes being represented. The articles were fairly reliable, with 7.1 ± 9.8 (mean ± SD) references per article, of which 59.7 ± 35.0% were substantiated references. Finally, all three readability indices determined that nephrology articles are written at a college level. Wikipedia is a comprehensive and fairly reliable medical resource for nephrology patients that is written at a college reading level. Accessibility of this information for the general public may be improved by hosting it at alternative Wikipedias targeted at a lower reading level, such as the Simple English Wikipedia.

Bioinformatic analyses identifies novel protein- coding pharmacogenomic markers associated with paclitaxel sensitivity in NCI60 cancer cell lines

BackgroundPaclitaxel is a microtubule-stabilizing drug that has been commonly used in treating cancer. Due to genetic heterogeneity within patient populations, therapeutic response rates often vary. Here we used the NCI60 panel to identify SNPs associated with paclitaxel sensitivity. Using the panels GI50 response data available from Developmental Therapeutics Program, cell lines were categorized as either sensitive or resistant. PLINK software was used to perform a genome-wide association analysis of the cellular response to paclitaxel with the panels SNP-genotype data on the Affymetrix 125 k SNP array. FastSNP software helped predict each SNPs potential impact on their gene product. mRNA expression differences between sensitive and resistant cell lines was examined using data from BioGPS. Using Haploview software, we investigated for haplotypes that were more strongly associated with the cellular response to paclitaxel. Ingenuity Pathway Analysis software helped us understand how our identified genes may alter the cellular response to paclitaxel.Results43 SNPs were found significantly associated (FDR < 0.005) with paclitaxel response, with 10 belonging to protein-coding genes (CFTR, ROBO1, PTPRD, BTBD12, DCT, SNTG1, SGCD, LPHN2, GRIK1, ZNF607). SNPs in GRIK1, DCT, SGCD and CFTR were predicted to be intronic enhancers, altering gene expression, while SNPs in ZNF607 and BTBD12 cause conservative missense mutations. mRNA expression analysis supported these findings as GRIK1, DCT, SNTG1, SGCD and CFTR showed significantly (p < 0.05) increased expression among sensitive cell lines. Haplotypes found in GRIK1, SGCD, ROBO1, LPHN2, and PTPRD were more strongly associated with response than their individual SNPs.ConclusionsOur study has taken advantage of available genotypic data and its integration with drug response data obtained from the NCI60 panel. We identified 10 SNPs located within protein-coding genes that were not previously shown to be associated with paclitaxel response. As only five genes showed differential mRNA expression, the remainder would not have been detected solely based on expression data. The identified haplotypes highlight the role of utilizing SNP combinations within genomic loci of interest to improve the risk determination associated with drug response. These genetic variants represent promising biomarkers for predicting paclitaxel response and may play a significant role in the cellular response to paclitaxel.

The role of second-hand smoke exposure on smoking cessation in non-tobacco-related cancers.

Second‐hand smoke (SHS) is a significant barrier to smoking cessation after a diagnosis of cancer in patients with lung as well as head and neck cancers. In the current study, the authors evaluated the effect of SHS on smoking cessation among patients with those cancers not traditionally perceived to be strongly associated with smoking.

Lifestyle Behaviors in Elderly Cancer Survivors: A Comparison With Middle-Age Cancer Survivors

PURPOSE Improved cancer screening and treatment have led to a greater focus on cancer survivorship care. Older cancer survivors may be a unique population. We evaluated whether older cancer survivors (age ≥ 65 years) had lifestyle behaviors, attitudes, and knowledge distinct from younger survivors. PATIENTS AND METHODS Adult cancer survivors with diverse cancer subtypes were recruited from Princess Margaret Cancer Centre (Toronto, Ontario, Canada). Multivariable models evaluated the effect of age on smoking, alcohol, and physical activity habits, attitudes toward and knowledge of these habits on cancer outcomes, and lifestyle information and recommendations received from health care providers, adjusted for sociodemographic and clinicopathologic covariates. RESULTS Among the 616 survivors recruited, 23% (n = 139) were older. Median follow-up since diagnosis was 24 months. Older survivors were more likely ex-smokers and less likely current smokers than younger survivors, but they were less likely to know that smoking could affect cancer treatment (adjusted odds ratio [OR], 0.53; P = .007) or prognosis (adjusted OR, 0.53; P = .008). Older survivors were more likely to perceive alcohol as improving overall survival (adjusted OR, 2.39; P = .02). Rates of meeting moderate-to-vigorous physical activity guidelines 1 year before diagnosis (adjusted OR, 0.55; P = .02) and maintaining and improving their exercise levels to meet these guidelines after diagnosis (adjusted OR, 0.48; P = .02) were lower in older survivors. Older and younger cancer survivors reported similar rates of receiving lifestyle behavior information from health care providers (P = .36 to .98). CONCLUSION Older cancer survivors reported being less aware of the impact of smoking on their overall health, more likely perceived alcohol as beneficial to survival, and were less likely to meet exercise goals compared with younger survivors. Survivorship programs need to consider age when counseling on lifestyle behaviors.

VEGF pathway polymorphisms as prognostic and pharmacogenetic factors in cancer: a 2013 update.

With the recent advances in genomic medicine and the development of targeted antiangiogenic therapy for cancer patients, there has been an increased interest in the role of predictive and prognostic markers for antiangiogenic therapy. Here, we provide a summary of the angiogenesis pathway, the role of predictive and prognostic markers in cancer and a summary of the current literature and studies on predictive and prognostic markers for antiangiogenic therapy. Our aim is to summarize those studies that are currently in the literature with an emphasis on the future directions of the field from 2013 and beyond. We conclude by providing our perspective on the future directions of this growing field, as well as possible challenges and pitfalls along the way.

Discovery and validation of vascular endothelial growth factor (VEGF) pathway polymorphisms in esophageal adenocarcinoma outcome

Polymorphisms in the vascular endothelial growth factor (VEGF)/angiogenesis pathway have been implicated previously in cancer risk, prognosis and response to therapy including in esophageal adenocarcinoma. Prior esophageal adenocarcinoma studies focused on using candidate polymorphisms, limiting the discovery of novel polymorphisms. Here, we applied the tagSNP (single nucleotide polymorphism) approach to identify new VEGF pathway polymorphisms associated with esophageal adenocarcinoma prognosis and validated them in an independent cohort of esophageal adenocarcinoma patients. In 231 esophageal adenocarcinoma patients of all stages/treatment plans, 58 genetic polymorphisms (18 KDR, 7 VEGFA and 33 FLT1) selected through tagging and assessment of predicted function were genotyped. Cox-proportional hazard models adjusted for important socio-demographic and clinico-pathological factors were applied to assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then validated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis and median OS and PFS were 20 and 12 months, respectively. KDR rs17709898 was found significantly associated with PFS (adjusted hazard ratio, aHR = 0.69, 95% confidence interval (CI): 0.53-0.90; P = 5.9E-3). FLT1 rs3794405 and rs678714 were significantly associated with OS (aHR = 1.44, 95% CI: 1.04-1.99; P = 0.03 and aHR = 1.50, 95% CI: 1.01-2.24; P = 0.045, respectively). No VEGFA polymorphisms were found significantly associated with either outcome. Upon validation, FLT1 rs3794405 remained strongly associated with OS (aHR = 1.59, 95% CI: 1.04-2.44; P = 0.03). FLT1 rs3794405 is significantly associated with OS in esophageal adenocarcinoma, whereby each variant allele confers a 45-60% increased risk of mortality. Validation and evaluation of this association in other cancer sites are warranted.