Human DNA ligase and DNA polymerase as molecular targets for heavy metals and anticancer drugs

DNA ligase and DNA polymerase play important roles in DNA replication, repair, and recombination. Frequencies of spontaneous and chemical- and physical-induced mutations are correlated to the fidelity of DNA replication. This dissertation elucidates the mechanisms of the DNA ligation reaction by DNA ligases and demonstrates that human DNA ligase I and DNA polymerase $\alpha$ are the molecular targets for two metal ions, Zn$\sp{2+}$ and Cd$\sp{2+},$ and an anticancer drug, F-ara-ATP.^ Human DNA ligases were purified to homogeneity and their AMP binding domains were mapped. Although their AMP-binding domains are similar, there could be difference between the two ligases in their DNA binding domains.^ The formation of the AMP-DNA intermediate and the successive ligation reaction by human DNA ligases were analyzed. Both reactions showed their substrate specificity for ligases I and II, required Mg2+, and were inhibited by ATP.^ A protein inhibitor from HeLa cells and specific for human DNA ligase I but not ligase II and T4 ligase was discovered. It reversibly inhibited DNA ligation activity but not the AMP-binding activity due to the formation of a reversible ligase I-inhibitor complex.^ F-ara-ATP inhibited human DNA ligase I activity by competing with ATP for the AMP-binding site of DNA ligase I, forming a ligase I-F-ara-AMP complex, as well as when it was incorporated at 3$\sp\prime$-terminus of DNA nick by DNA polymerase $\alpha.$^ All steps of the DNA ligation reaction were inhibited by Zn$\sp{2+}$ and Cd$\sp{2+}$ in a concentration-dependent manner. Both ions did not show the ability to change the fidelity of DNA ligation reaction catalyzed by human DNA ligase I. However, Zn$\sp{2+}$ and Cd$\sp{2+}$ showed their contradictory effects on the fidelity of the reaction by human DNA polymerase $\alpha.$ Zn$\sp{2+}$ decreased the frequency of misinsertion but less affected that of mispair extension. On the contrary, Cd$\sp{2+}$ increased the frequencies of both misinsertion and mispair extension at very low concentration. Our data provided strong evidence in the molecular mechanisms for the mutagenicity of zinc and cadmium, and were comparable with the results previously reported. ^

Modification of mutagen sensitivity by chemopreventive agents {\it in vitro\/}

The clinical application of chemopreventive agents is expected to prevent the appearance of cancer by arresting carcinogenesis or reversing it in the precancerous stages. The hypothesis of the present investigations was that chemopreventive agents (retinoids and antioxidant vitamins) may counteract the clastogenic effects of bleomycin in vitro in both lymphoblastoid cell lines and primary lymphocyte cultures and that a similar phenomenon can be detected in lymphocytes from individuals treated with 13-cis-retinoic acid. The efficacy of 13-cis-retinoic acid, n-(4-hydroxyphenyl)-retinamide, ascorbic acid, n-acetyl-l-cysteine, alpha-tocopherol, and alpha-tocopherol-acid succinate was tested against bleomycin-induced chromosomal breakage.^ The results provided direct evidence of the concentration-related protective effects of these agents against bleomycin-induced clastogenicity in cultures of human lymphoblastoid cell lines in vitro. Similar anticlastogenic protection was demonstrated with 13-cis-retinoic acid, ascorbic acid, n-acetyl-l-cysteine, and alpha-tocopherol-acid succinate in primary lymphocyte cultures in vitro. The in vitro anticlastogenic effect of 13-cis-retinoic acid was also demonstrated in lymphocyte cultures from peripheral blood samples from patients treated with this retinoid.^ An important consideration is that the concentrations used in the present investigations are comparable to those achieved in clinical situations.^ The in vitro anticlastogenic effect of these retinoids and antioxidants may constitute an important element of their chemopreventive properties. The results corroborate the hypothesis that these compounds may be effective in clinical chemoprevention trials. The bleomycin-assay may also be used as a short-term test to evaluate the antimutagenic effects of various agents. ^

Behavioral facets of cancer chemoprevention trials

Few studies have explored factors related to participation in cancer chemoprevention trials. The purpose of this dissertation was to conduct investigations in this emerging field by studying aspects of participation at three phases of cancer chemoprevention trials: at enrollment, during a placebo run-in period, and post-trial. In all three studies, subjects had a history of cancer and were at high risk of recurrence or second primary tumors.^ The first study explored correlates of enrollment in a head and neck cancer chemoprevention trial by comparing participants and eligible nonparticipants. Of 148 subjects who met the trial's preliminary eligibility criteria, 40% enrolled. In multivariate analysis, enrollment was positively associated with being male (OR 2.36) and being employed (OR 2.73). The most commonly cited reason for declining participation among nonparticipants was transportation.^ The second study examined outcomes of an eight-week placebo run-in period in a head and neck cancer chemoprevention trial. Of 391 subjects, 91.3% were randomized after the run-in. Adherence to drug capsules ranged from 0% to 120.3% (mean $\pm$ SD, 95.8% $\pm$ 15.1). In multivariate analysis, the main variable predicting run-in outcome was race; white subjects were 3.45 times more likely to be randomized than non-white subjects. Subjects with Karnofsky scores of 100 were 2.13 times more likely to be randomized than were subjects with lower scores.^ The third study used post-trial questionnaires to assess subjects' (n = 64) perceptions of participation in a cancer chemoprevention trial. The most highly rated trial benefit was the perception of potential colon cancer prevention, and the most troublesome barrier was erroneous billing for study visits. Perceived benefits were positively associated with interest in participating in future trials of the same (p = 0.05) and longer (p = 0.02) duration, and difficulty with trial pills and procedures was inversely related to interest in future placebo-controlled trials (p = 0.01).^ These are among the first behavioral studies to be completed in the rapidly growing field of cancer chemoprevention. Much work has yet to be done, however, to advance our understanding of the complex issues relating to chemoprevention trial participation. ^

INACTIVATION OF MUTAGENIC DRUGS AND THEIR METABOLITES IN THE URINE OF PATIENTS ADMINISTERED ANTINEOPLASTIC THERAPY

Urines from patients administered mutagenic antineoplastic drugs were significantly mutagenic in the Ames assay, and hence may pose a genotoxic hazard to hospital personnel or family members caring for the patient. The urines were tested for mutagenicity in several different strains of Salmonella typhimurium that were uvr positive or negative (TA98, TA100, TA102, UTH8413, UTH8414). The urines were fractionated by high pressure liquid chromatography (HPLC) and the fractions assayed for mutagenicity in the strains in which the whole urine was mutagenic. Only fractions of urines containing the parent compound (cisplatin, doxorubicin, or mitomycin) were mutagenic; no other fraction showed significant mutagenicity. However, urine containing cyclophosphamide had two fractions that were mutagenic. One fraction, the fraction containing cyclophosphamide, required metabolic activation for mutagenicity. The other fraction did not require activation for mutagenicity.^ The chemical and mutagenic stability of these urines at room temperature was assayed over a 14 day period. The parent compound degraded within the first seven days, but the urines remained mutagenic. Cis-platinum was chemically stable in the urine; however, the urine decreased in mutagenicity. The decrease was probably the result of stable ligands binding to the platinum.^ Inactivation methods were developed to reduce the genotoxic hazard. Urine containing cisplatin was inactivated by complexing the cisplatin with diethyldithiocarbamate (DDTC). Oxidation with NaOCl of urines containing mitomycin and doxorubicin (sodium thiosulfate must be added to the doxorubicin urine) results in mutagenic inactivation. Inactivation of urine containing cyclophosphamide requires oxidation with alkaline potassium permaganate and trapping of active degradation products with sodium thiosulfate. Urines containing these drugs can be inactivated, but not always by the same method that inactivates the drug alone in solution. Therefore, in the future development of inactivation methods, both chemical and mutagenic assays are necessary to determine effectiveness. Methods of inactivation of mutagenic excreta developed in this study are both effective and practical. ^

Bayesian and survival model for tumor relapse status and disease-specific survival, with applications to breast cancer

Breast cancer is the most common non-skin cancer and the second leading cause of cancer-related death in women in the United States. Studies on ipsilateral breast tumor relapse (IBTR) status and disease-specific survival will help guide clinic treatment and predict patient prognosis.^ After breast conservation therapy, patients with breast cancer may experience breast tumor relapse. This relapse is classified into two distinct types: true local recurrence (TR) and new ipsilateral primary tumor (NP). However, the methods used to classify the relapse types are imperfect and are prone to misclassification. In addition, some observed survival data (e.g., time to relapse and time from relapse to death)are strongly correlated with relapse types. The first part of this dissertation presents a Bayesian approach to (1) modeling the potentially misclassified relapse status and the correlated survival information, (2) estimating the sensitivity and specificity of the diagnostic methods, and (3) quantify the covariate effects on event probabilities. A shared frailty was used to account for the within-subject correlation between survival times. The inference was conducted using a Bayesian framework via Markov Chain Monte Carlo simulation implemented in softwareWinBUGS. Simulation was used to validate the Bayesian method and assess its frequentist properties. The new model has two important innovations: (1) it utilizes the additional survival times correlated with the relapse status to improve the parameter estimation, and (2) it provides tools to address the correlation between the two diagnostic methods conditional to the true relapse types.^ Prediction of patients at highest risk for IBTR after local excision of ductal carcinoma in situ (DCIS) remains a clinical concern. The goals of the second part of this dissertation were to evaluate a published nomogram from Memorial Sloan-Kettering Cancer Center, to determine the risk of IBTR in patients with DCIS treated with local excision, and to determine whether there is a subset of patients at low risk of IBTR. Patients who had undergone local excision from 1990 through 2007 at MD Anderson Cancer Center with a final diagnosis of DCIS (n=794) were included in this part. Clinicopathologic factors and the performance of the Memorial Sloan-Kettering Cancer Center nomogram for prediction of IBTR were assessed for 734 patients with complete data. Nomogram for prediction of 5- and 10-year IBTR probabilities were found to demonstrate imperfect calibration and discrimination, with an area under the receiver operating characteristic curve of .63 and a concordance index of .63. In conclusion, predictive models for IBTR in DCIS patients treated with local excision are imperfect. Our current ability to accurately predict recurrence based on clinical parameters is limited.^ The American Joint Committee on Cancer (AJCC) staging of breast cancer is widely used to determine prognosis, yet survival within each AJCC stage shows wide variation and remains unpredictable. For the third part of this dissertation, biologic markers were hypothesized to be responsible for some of this variation, and the addition of biologic markers to current AJCC staging were examined for possibly provide improved prognostication. The initial cohort included patients treated with surgery as first intervention at MDACC from 1997 to 2006. Cox proportional hazards models were used to create prognostic scoring systems. AJCC pathologic staging parameters and biologic tumor markers were investigated to devise the scoring systems. Surveillance Epidemiology and End Results (SEER) data was used as the external cohort to validate the scoring systems. Binary indicators for pathologic stage (PS), estrogen receptor status (E), and tumor grade (G) were summed to create PS+EG scoring systems devised to predict 5-year patient outcomes. These scoring systems facilitated separation of the study population into more refined subgroups than the current AJCC staging system. The ability of the PS+EG score to stratify outcomes was confirmed in both internal and external validation cohorts. The current study proposes and validates a new staging system by incorporating tumor grade and ER status into current AJCC staging. We recommend that biologic markers be incorporating into revised versions of the AJCC staging system for patients receiving surgery as the first intervention.^ Chapter 1 focuses on developing a Bayesian method to solve misclassified relapse status and application to breast cancer data. Chapter 2 focuses on evaluation of a breast cancer nomogram for predicting risk of IBTR in patients with DCIS after local excision gives the statement of the problem in the clinical research. Chapter 3 focuses on validation of a novel staging system for disease-specific survival in patients with breast cancer treated with surgery as the first intervention. ^

Genetic variants in the mammalian target of rapamycin (mTOR) signaling pathway as predictors of survival and clinical response in women with ovarian cancer

Background. The mTOR pathway is commonly altered in human tumors and promotes cell survival and proliferation. Preliminary evidence suggests this pathway's involvement in chemoresistance to platinum and taxanes, first line therapy for epithelial ovarian cancer. A pathway-based approach was used to identify individual germline single nucleotide polymorphisms (SNPs) and cumulative effects of multiple genetic variants in mTOR pathway genes and their association with clinical outcome in women with ovarian cancer. ^ Methods. The case-series was restricted to 319 non-Hispanic white women with high grade ovarian cancer treated with surgery and platinum-based chemotherapy. 135 SNPs in 20 representative genes in the mTOR pathway were genotyped. Hazard ratios (HRs) for death and Odds ratios (ORs) for failure to respond to primary therapy were estimated for each SNP using the multivariate Cox proportional hazards model and multivariate logistic regression model, respectively, while adjusting for age, stage, histology and treatment sequence. A survival tree analysis of SNPs with a statistically significant association (p<0.05) was performed to identify higher order gene-gene interactions and their association with overall survival. ^ Results. There was no statistically significant difference in survival by tumor histology or treatment regimen. The median survival for the cohort was 48.3 months. Seven SNPs were significantly associated with decreased survival. Compared to those with no unfavorable genotypes, the HR for death increased significantly with the increasing number of unfavorable genotypes and women in the highest risk category had HR of 4.06 (95% CI 2.29–7.21). The survival tree analysis also identified patients with different survival patterns based on their genetic profiles. 13 SNPs on five different genes were found to be significantly associated with a treatment response, defined as no evidence of disease after completion of primary therapy. Rare homozygous genotype of SNP rs6973428 showed a 5.5-fold increased risk compared to the wild type carrying genotypes. In the cumulative effect analysis, the highest risk group (individuals with ≥8 unfavorable genotypes) was significantly less likely to respond to chemotherapy (OR=8.40, 95% CI 3.10–22.75) compared to the low risk group (≤4 unfavorable genotypes). ^ Conclusions. A pathway-based approach can demonstrate cumulative effects of multiple genetic variants on clinical response to chemotherapy and survival. Therapy targeting the mTOR pathway may modify outcome in select patients.^

The role and impact of transitional care utilization in colorectal cancer

BACKGROUND Although one out of every five gastrointestinal cancer patients needs transitional care (home-based skilled care or placement in skilled nursing or rehabilitation facilities) following treatment, few studies have examined outcomes in this population compared to patients who return home without assistance. This study has two primary goals: 1. To evaluate long-term cancer-specific outcomes in colorectal cancer patients utilizing transitional care compared to those that return home without assistance following therapy 2. To compare results using standard regression techniques and propensity scores. ^ METHODS Patients undergoing curative surgery for colorectal adenocarcinoma will be identified using data from a tertiary care Veterans Administration hospital. Survival and recurrence will then be determined from VA records and the Social Security Death Index. ^ The association between transitional care utilization and overall and disease-free survival will be evaluated using Cox proportional hazards regression to adjust for confounding factors. Predictors of transitional care utilization will be assessed using multiple logistic regression to generate a propensity score which will also be used to assess differences in survival based on transitional care use. ^ POTENTIAL SIGNIFICANCE If transitional care utilization is associated with worse survival and recurrence following therapy then it will be important to subsequently assess the mechanism in order to target interventions to improve outcomes. If there is no difference in cancer-specific outcomes, then this project can potentially highlight benefits of supportive therapy following colorectal cancer resection.^

Bisphosphonates for metastatic bone disease in lung cancer

Bisphosphonates have proven effectiveness in preventing skeletal-related events (SREs) in advanced breast cancer, prostate cancer and multiple myeloma. The purpose of this study was to assess efficacy of bisphosphonates in preventing SREs, in controlling pain, and in increasing life expectancy in lung cancer patients with bone metastases.^ We performed an electronic search in MEDLINE, EMBASE, Web of Science, and Cochrane library databases up to April 4, 2010. Hand searching and searching in clinicaltrials.gov were also performed. Two independent reviewers selected all clinical trials that included lung cancer patients with bone metastases treated with bisphosphonates. We excluded articles that involved cancers other than lung, patients without bone metastasis and treatment other than bisphosphonates. Outcome questions answered were efficacy measured as overall pain control, overall improvement in survival and reduction in skeletal-related events or SREs (fracture, cord compression, radiation or surgery to the bone, hypercalcemia of malignancy). The quality of each study was evaluated using the Cochrane Back Review group questionnaire to assess risk of bias (0-worst to 11-best). Data extraction and quality assessments were independently performed by two assessors. Meta-analyses were performed where more than one study with similar outcomes were found.^ We identified eight trials that met our inclusion criteria. Three studies evaluated zoledronic acid, three pamidronate, three clodronate and two ibandronate. Two were placebocontrol trials while two had multi-group comparisons (radiotherapy, radionucleotides, and chemotherapy) and two had different bisphosphonate as active controls. Quality scores ranged from 1-4 out of 11 suggesting high risk of bias. Studies failed to report adequate explanation of randomization procedures, concealment of randomization and blinding. Metaanalysis showed that patients treated with zoledronic acid alone had lower rates of developing SREs compared to placebo at 21 months (RR=0.80, 95% CI=0.66-0.97, p=0.02). Meta-analyses also showed increased pain control when a bisphosphonate was added to the existing treatment modality like chemotherapy or radiation (RR=1.17, 95% CI=1.03-1.34, p=0.02). However, pain control was not statistically significantly different among various bisphosphonates when other treatment modalities were not present. Despite improvement in SRE and pain control, bisphosphonates failed to show improvement in overall survival (Difference in means=109.1 days, 95% CI= -51.52 – 269.71, p=0.183).^ Adding biphosphonates to standard care improved pain control and reduced SREs. Biphosphonates did not improve overall survival. Further larger studies with higher quality are required to stengthen the evidence.^ Keywords/MeSH terms Bisphosphonates/diphosphonates: generic, chemical and trade names.^

Breast cancer risk with aromatase inhibition and phytoestrogen-free diet

In this thesis a mouse model was used to examine the effect of pubertal estrogen inhibition and a phytoestrogen-free diet on the development of mammary glands. The study question was does treatment with aromatase inhibitor during puberty increase susceptibility to breast cancer among cohorts that consumed a diet free of phytoestrogens. The study design consisted of a cohort of mice treated with aromatase inhibitor, letrozole, during puberty and a vehicular group that was used as a control. Both groups were fed a diet free of phytoestrogens from the time of weaning until sacrifice during adulthood. The study aimed to assess mammary gland development in terms of breast cancer risk. The methods employed in this research included morphological and histological analysis of mammary glands, as well as estradiol, RNA and protein analysis. The main finding of the study was that mice exposed to aromatase inhibitor during puberty developed mammary glands with specific characteristics suggestive of vulnerability to oncogenesis such as increased lateral branching, increased number of glands, increase ductal hyperplasia, and diminished expression of TGFβ and p27 protein levels. The conclusions suggest that puberty is a critical period in which the mammary gland is susceptible to environmental threats that may result in deleterious epigenetic effects leading to an increased breast cancer risk in adulthood. This study has several public health implications; the most significant is that environmental threats during puberty may result in adverse mammary gland development and that phytoestrogen sources in the diet are necessary for normal maturation of the mammary glands.^

Identification of micro-RNAs targeting genes of PI3K/AKT pathway in ovarian cancer

Ovarian cancer is the leading cause of cancer-related death for females due to lack of specific early detection method. It is of great interest to find molecular-based biomarkers which are sensitive and specific to ovarian cancer for early diagnosis, prognosis and therapeutics. miRNAs have been proposed to be potential biomarkers that could be used in cancer prevention and therapeutics. The current study analyzed the miRNA and mRNA expression data extracted from the Cancer Genome Atlas (TCGA) database. Using simple linear regression and multiple regression models, we found 71 miRNA-mRNA pairs which were negatively associated between 56 miRNAs and 24 genes of PI3K/AKT pathway. Among these miRNA and mRNA target pairs, 9 of them were in agreement with the predictions from the most commonly used target prediction programs including miRGen, miRDB, miRTarbase and miR2Disease. These shared miRNA-mRNA pairs were considered to be the most potential genes that were involved in ovarian cancer. Furthermore, 4 of the 9 target genes encode cell cycle or apoptosis related proteins including Cyclin D1, p21, FOXO1 and Bcl2, suggesting that their regulator miRNAs including miR-16, miR-96 and miR-21 most likely played important roles in promoting tumor growth through dysregulated cell cycle or apoptosis. miR-96 was also found to directly target IRS-1. In addition, the results showed that miR-17 and miR-9 may be involved in ovarian cancer through targeting JAK1. This study might provide evidence for using miRNA or miRNA profile as biomarker.^

Molecular epidemiological studies on genetic predispositions to squamous cell carcinoma of the head and neck

Two molecular epidemiological studies were conducted to examine associations between genetic variation and risk of squamous cell carcinoma of the head and neck (SCCHN). In the first study, we hypothesized that genetic variation in p53 response elements (REs) may play roles in the etiology of SCCHN. We selected and genotyped five polymorphic p53 REs as well as a most frequently studied p53 codon 72 (Arg72Pro, rs1042522) polymorphism in 1,100 non-Hispanic White SCCHN patients and 1,122 age-and sex-matched cancer-free controls recruited at The University of Texas M. D. Anderson Cancer Center. In multivariate logistic regression analysis with adjustment for age, sex, smoking and drinking status, marital status and education level, we observed that the EOMES rs3806624 CC genotype had a significant effect of protection against SCCHN risk (adjusted odds ratio= 0.79, 95% confidence interval =0.64–0.98), compared with the -838TT+CT genotypes. Moreover, a significantly increased risk associated with the combined genotypes of p53 codon 72CC and EOMES -838TT+CT was observed, especially in the subgroup of non-oropharyneal cancer patients. The values of false-positive report probability were also calculated for significant findings. In the second study, we assessed the association between SCCHN risk and four potential regulatory single nucleotide polymorphisms (SNPs) of DEC1 (deleted in esophageal cancer 1) gene, a candidate tumor suppressor gene for esophageal cancer. After adjustment for age, sex, and smoking and drinking status, the variant -606CC (i.e., -249CC) homozygotes had a significantly reduced SCCHN risk (adjusted odds ratio = 0.71, 95% confidence interval = 0.52–0.99), compared with the -606TT homozygotes. Stratification analyses showed that a reduced risk associated with the -606CC genotype was more pronounced in subgroups of non-smokers, non-drinkers, younger subjects (defined as ≤ 57 years), carriers of TP53 Arg/Arg (rs1042522) genotype, patients with oropharyngeal cancer or late-stage SCCHN. Further in silico analysis revealed that the -249 T-to-C change led to a gain of a transcription factor binding site. Additional functional analysis showed that the -249T-to-C change significantly enhanced transcriptional activity of the DEC1 promoter and the DNA-protein binding activity. We conclude that the DEC1 promoter -249 T>C (rs2012775) polymorphism is functional, modulating susceptibility to SCCHN among non-Hispanic Whites. Additional large-scale, preferably population-based studies are needed to validate our findings.^

Predictors of Contralateral Breast Cancer in BRCA Negative Women

Breast cancer is the most common cancer diagnosis and second leading cause of death in women. Risk factors associated with breast cancer include: increased age, alcohol consumption, cigarette smoking, white race, physical inactivity, benign breast conditions, reproductive and hormonal factors, dietary factors, and family history. Hereditary breast and ovarian cancer syndrome (HBOC) is caused by mutations in the BRCA1 and BRCA2 genes. Women carrying a mutation in these genes are at an increased risk to develop a second breast cancer. Contralateral breast cancer is the most common second primary cancer in patients treated for a first breast cancer. Other risk factors for developing contralateral breast cancer include a strong family history of breast cancer, age of onset of first primary breast cancer, and if the first primary was a lobular carcinoma, which has an increased risk of being bilateral. A retrospective chart review was performed on a select cohort of women in an IRB approved database at MD Anderson Cancer Center. The final cohort contained 572 women who tested negative for a BRCA1 or BRCA2 mutation, had their primary invasive breast cancer diagnosed under the age of 50, and had a BRCAPro risk assessment number over 10%. Of the 572 women, 97 women developed contralateral breast cancer. A number of predictors of contralateral breast cancer were looked at between the two groups. Using univariable Cox Proportional Hazard model, thirteen statistically interesting risk factors were found, defined as having a p-value under 0.2. Multivariable stepwise Cox Proportional Hazard model found four statistically significant variables out of the thirteen found in the univariable analysis. In our study population, the incidence of contralateral breast cancer was 17%. Four statistically significant variables were identified. Undergoing a prophylactic mastectomy was found to reduce the risk of developing contralateral breast cancer, while not having a prophylactic mastecomy, a young age at primary diagnosis, having a positive estrogen receptor status of the primary tumor, and having a family history of breast cancer increased a woman’s risk to develop contralateral breast cancer.

Knowledge, Attitudes, and Utilization of BRCA Testing Among Obstetricians and Gynecologists

Hereditary breast and ovarian cancer (HBOC) is an inherited cancer syndrome that is associated with mutations in the BRCA1 and BRCA2 genes. Carriers of BRCA mutations, both men and women, are at an increased risk for developing certain cancers. Carriers are most notably at an increased risk to develop breast and ovarian cancers; however an increased risk for prostate cancer, melanoma, and pancreatic cancers has also been associated with these mutations. In 2009 the American Congress of Obstetricians and Gynecologists (ACOG) released a practice bulletin stating that evaluating a patient’s risk for HBOC should be a routine part of obstetric and gynecologic practice. A survey was created and completed by 83 obstetricians and gynecologists in the greater Houston, TX area. The survey consisted of four sections designed to capture demographic information, attitudes towards HBOC and BRCA testing, utilization of BRCA testing, and the overall knowledge of respondents with regards to HBOC and BRCA testing. This study found that the majority of participants indicated that they felt that obstetricians and gynecologists should have the primary responsibility of identifying patients who may be at increased risk of carrying a BRCA mutation. Moreover, this study found that the majority of participants indicated that they felt comfortable or very comfortable in identifying patients at an increased risk of carrying a BRCA mutation. However, only about a quarter of participants indicated that they order BRCA genetic testing one to two times per month or more. Lastly, this study demonstrates that the overall knowledge of HBOC and BRCA testing among this population of obstetricians and gynecologists is poor. The results of this study stress the need for more education regarding HBOC, genetic testing, and strategies for identifying patients that may be at risk for having a mutation in a BRCA gene. Furthermore, it reiterates the importance of raising awareness to current practice guidelines and recommendations that can assist obstetricians and gynecologist to better identify and manage patients that may be at an increased risk of having HBOC.

Is there an association between choline/betaine dietary intake and lung cancer?

Choline and betaine are important methyl donors that contribute to protein and phospholipid synthesis and DNA methylation. They can either be obtained through diet or synthesized de novo. Evidence from human and animal research indicates that choline metabolic pathways may be activated during a variety of diseases, including cancer. Studies have been conducted to investigate the role of dietary intake of choline and betaine on cancers, but results vary among studies by cancer types, and no such study had been conducted for lung cancer. We conducted a case-control study to explore the association between choline and betaine dietary intake and lung cancer. A total of 2807 cases and 2919 controls were included in the study. After adjusting for total calorie intake, age, sex, race and smoking status, multivariable logistic regression analysis revealed a significant negative association between choline/betaine intake and lung cancer. Specifically, we observed that higher choline intake was associated with reduced lung cancer odds, and the association did not differ significantly by smoking status. A similar negative trend was observed in the association between betaine intake and lung cancer after adjusting for total calorie intake, age, sex, smoking status, race, and pack-years of smoking. However, this association was strongly affected by smoking. No significant association was observed with increased betaine intake and lung cancer among never smokers, but higher betaine intake was strongly associated with reduced lung cancer odds among smokers, and lower odds ratios were observed among current smokers than among former smokers. Our results suggest that high intake of choline may be protective for lung cancer independent of smoking status, while high betaine intake may mitigate the adverse effect of smoking on lung cancer, and help prevent lung cancer among smokers.^

Colorectal cancer: An insight on dietary factors

Aim. To assess the relationships between dietary factors and colorectal cancer risk. ^ Methods. We looked at all the systematic reviews published in last ten years on the topic. ^ Results. For fruits-vegetables some studies1 were significant for heterogeneity and others2 were not. In study by Aune at al3 only fruits were significant, although all the studies had protective RR between 0.90 to 0.94. For folate only case-control group of studies, the study by Sanjoaquin et al4 was significant with p heterogeneity being 0.01 and all of them had protective effect with RR between 0.75 to 0.95, for dietary as well as total folate. For fiber study by Park et al5 p was insignificant at 0.14 an RR was 0.84. Vitamin B6 study by Larsson et al6 had significant p with RR 0.90. For dietary fat both Alexander7 and Liu8 concluded that there is insufficient evidence that dietary fat is an independent causative risk factor. Only one study by Norat et al9 out of three was able to achieve significant p heterogeneity for meat. All the studies reported RR between 1.14 to 1.35, clearly implicating meat as culprit for increasing the risk of colorectal cancer. ^ Conclusions. We would recommend the use of fruits and vegetables to be protective against colorectal cancer. Also meat consumption increases the risk of colorectal cancer.^ *Please refer to dissertation for references/footnotes.^