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.^

A systematic review and analysis of the association between endometriosis and ovarian cancer

Ovarian cancer is the most lethal of the gynecologic malignancies. The development of endometriosis has been shown to increase one's risk of ovarian cancer. Numerous studies have investigated this association, yet none have synthesized the available data. In a pooled analysis of cohort and case-control studies, the association between endometriosis and ovarian cancer was strengthened. Women who developed endometriosis-associated ovarian cancer were more likely to develop an early stage clear cell or endometrioid ovarian cancer histotypes and were more likely to have a better overall prognosis. The prognostic differences between endometriosis-associated ovarian cancer and ovarian cancer without an associated endometriosis may indicate genetic and environmental differences between groups.^

A systematic review of personalized therapy in patients with advanced cancer

Background: An increased understanding of the pathogenesis of cancer at the molecular level has led to the development of personalized cancer therapy based on the mutation status of the tumor. Tailoring treatments to genetic signatures has improved treatment outcomes in patients with advanced cancer. We conducted a meta-analysis to provide a quantitative summary of the response to treatment on a phase I clinical trial matched to molecular aberration in patients with advanced solid tumors. ^ Methods: Original studies that reported the results of phase I clinical trials in patients with advanced cancer treated with matched anti-cancer therapies between January 2006 and November 2011 were identified through an extensive search of Medline, Embase, Web of Science and Cochrane Library databases. Odds Ratio (OR) with 95% confidence interval (CI) was estimated for each study to assess the strength of an association between objective response rate (ORR) and mutation status. Random effects model was used to estimate the pooled OR and their 95% CI was derived. Funnel plot was used to assess publication bias. ^ Results: Thirteen studies published between January 2006 and November 2011that reported on responses to matched phase I clinical trials in patients with advanced cancer were included in the meta-analysis. Nine studies reported on the responses seen in 538 of the 835 patients with driver mutations responsive to therapy and seven studies on the responses observed in 234 of the 306 patients with mutation predictive for negative response. Random effects model was used to estimate pooled OR, which was 7.767(95% CI = 4.199 − 14.366; p-value=0.000) in patients with activating mutations that were responsive to therapy and 0.287 (95% CI = 0.119 − 0.694; p-value=0.009) in patients with mutation predictive of negative response. ^ Conclusion: It is evident from the meta-analysis that somatic mutations present in tumor tissue of patients are predictive of responses to therapy in patients with advanced cancer in phase I setting. Plethora of research and growing evidence base indicate that selection of patients based on mutation analysis of the tumor and personalizing therapy is a step forward in the war against cancer.^

Association of TNF-alpha genetic variants with HPV-associated oral cancer risk---a case-control study

The incidence of OSCC in younger population and in those who never smoked or drank has increased since the last decade. This increase may be attributable to increase of infection with HPV. The pro-inflammatory cytokine TNF-&agr; has the role in the pathogenesis of chronic inflammatory diseases and was found to control HPV infection in cervical cancer studies. Our study aimed to investigate the association between the four polymorphisms located in TNF-&agr; promoter region, -308(rs1800629), -857(rs1799724), -863(rs1800630) and -1031(rs1799964), and the risk of HPV-related OSCC. In this hospital-based case-control study, 325 cases and 335 controls were included. We found that HPV 16 seropositivity was associated with an increased risk of oral cancer (OR = 3.1, 95% CI, 2.1–4.6). Each of the polymorphism showed to increase the risk of HPV-related OSCC. And after combining the risk genotypes and using the low-risk group (0–1 combined risk genotypes) and HPV16 seronegativity as the reference group, only the high-risk groups (3–4 combined risk genotypes) and HPV16 seronegativity were associated with a low OR of 1.8 (95% CI, 1.1–2.8), while the low-risk and high-risk groups and HPV16 seropositivity were significantly associated with a higher OR of 2.7 (95% CI, 1.3–5.8) and 8.5 (95% CI, 3.7–19.4), respectively. In addition, the joint effects were greater among the young subjects (aged<50), males, never smokers or never drinkers, and patients with oropharyngeal cancer. Overall, the four TNF-&agr; polymorphisms, individually or collectively, would result in a significantly increased risk for HPV16-associated oral cancer in a non-Hispanic white population. More large sized studies are needed for future investigation.^

"I understood what she meant when she said '21st century medicine'": A qualitative analysis of patient responses for plans for colorectal cancer screening following a recommendation from their physician

Although physician recommendation has been significantly associated with colorectal cancer screening (CRCS), it still does not motivate all patients to get CRCS. Although improved physician recommendation for CRCS has been shown to increase patient CRCS screening, questions remain about what elements of that discussion may lead to screening. The objective of this study is to describe patients' perceptions and interpretations about their physician's recommendation for CRCS during their annual wellness exam. A subset of patients (n=51) participating in a supplement study of a behavioral intervention trial designed to increase CRCS completed a follow-up, open-ended interview two to four weeks after their annual wellness visit. Using qualitative methods, transcripts of these interviews were analyzed. Findings suggest that most patients would follow their physician's recommendation for CRCS despite not engaging in much discussion. Patients may refrain from CRCS discussion because of a commitment to CRCS, awareness of screening guidelines, and trust in physician's honesty and beneficence. Yet many patients left their wellness exams with questions, refraining because of future plans to consult with their physicians, perceived time constraints or a lack of a patient-physician relationship. If patients are leaving their wellness exams with unanswered questions, interventions should prepare physicians for patient reticence, teaching physicians how to assure patients that CRCS is a primary care activity where all questions and concerns, including cost and scheduling, may be resolved.^

Genetic variants associated with metastatic prostate cancer

Introduction. Distant metastasis remains the leading cause of death among prostate cancer patients. Several genetic susceptibility loci associated with Prostate cancer have been identified by the Genome Wide Association Studies (GWAS). To date, few studies have explored the ability of these SNPs to identify metastatic prostate cancer. Based on the identification of genetic variants as predictors of aggressive disease, a case comparison study of prostate cancer patients was designed to explore the association of 96 GWAS single nucleotide polymorphisms (SNPs) with metastatic disease. ^ Method. 1242 histologically confirmed prostate cancer patients, with and without metastatic disease, were enrolled into the study. Data were collected from personal interviews, hospital database and abstraction of medical records. Ninety six SNPs identified from GWAS studies based on their associations with prostate cancer risk were genotyped in the study population. Univariate and multivariate logistic regression analyses were used to explore the relationships of the variants with metastatic prostate cancer in Whites and African American men. ^ Results. Four SNPs showed independent associations with metastatic prostate cancer (rs721048 in EHBP1 (2p15), rs3025039 in VEGF (6p12), rs11228565 in Intergenic(11q13.2) and rs2735839 in KLK3(19q13.33)) in the White population. For SNP rs2735839 in KLK3, genotype GA was 1.71 times as likely to be associated with metastatic prostate cancer diagnosis as genotype AA after adjusting for other significant SNPs and covariates (95% CI, 1.12-2.60; p=0.012). In men of African descent, three SNPs: rs1512268 in NKX3-1(8p21.2), rs12155172 in intergenic (7p15.3) & rs10486567 in JAZF1 (7p15.2) were positively associated with metastatic disease in the multivariate analysis. The strongest SNP was rs1512268 heterozygous genotype AG in NKX3-1(8p21.2) which was associated with 3.97-fold increased risk of metastatic prostate cancer diagnosis (95% CI, 1.69-9.34; p =0.002). ^ Conclusion. Genetic variants associated with metastatic prostate cancer were different in Whites and African American men. Given the high mortality rate recorded in men diagnosed with metastatic prostate tumor, further studies are needed to validate associations and establish their clinical application.^

Trastuzumab use and risk of congestive heart failure in older breast cancer patients

Trastuzumab is a humanized-monoclonal antibody, developed specifically for HER2-neu over-expressed breast cancer patients. Although highly effective and well tolerated, it was reported associated with Congestive Heart Failure (CHF) in clinical trial settings (up to 27%). This leaves a gap where, Trastuzumab-related CHF rate in general population, especially older breast cancer patients with long term treatment of Trastuzumab remains unknown. This thesis examined the rates and risk factors associated with Trastuzumab-related CHF in a large population of older breast cancer patients. A retrospective cohort study using the existing Surveillance, Epidemiology and End Results (SEER) and Medicare linked de-identified database was performed. Breast cancer patients ≥ 66 years old, stage I-IV, diagnosed in 1998-2007, fully covered by Medicare but no HMO within 1-year before and after first diagnosis month, received 1st chemotherapy no earlier than 30 days prior to diagnosis were selected as study cohort. The primary outcome of this study is a diagnosis of CHF after starting chemotherapy but none CHF claims on or before cancer diagnosis date. ICD-9 and HCPCS codes were used to pool the claims for Trastuzumab use, chemotherapy, comorbidities and CHF claims. Statistical analysis including comparison of characteristics, Kaplan-Meier survival estimates of CHF rates for long term follow up, and Multivariable Cox regression model using Trastuzumab as a time-dependent variable were performed. Out of 17,684 selected cohort, 2,037 (12%) received Trastuzumab. Among them, 35% (714 out of 2037) were diagnosed with CHF, compared to 31% (4784 of 15647) of CHF rate in other chemotherapy recipients (p<.0001). After 10 years of follow-up, 65% of Trastuzumab users developed CHF, compared to 47% in their counterparts. After adjusting for patient demographic, tumor and clinical characteristics, older breast cancer patients who used Trastuzumab showed a significantly higher risk in developing CHF than other chemotherapy recipients (HR 1.69, 95% CI 1.54 - 1.85). And this risk is increased along with the increment of age (p-value < .0001). Among Trastuzumab users, these covariates also significantly increased the risk of CHF: older age, stage IV, Non-Hispanic black race, unmarried, comorbidities, Anthracyclin use, Taxane use, and lower educational level. It is concluded that, Trastuzumab users in older breast cancer patients had 69% higher risk in developing CHF than non-Trastuzumab users, much higher than the 27% increase reported in younger clinical trial patients. Older age, Non-Hispanic black race, unmarried, comorbidity, combined use with Anthracycline or Taxane also significantly increase the risk of CHF development in older patients treated with Trastuzumab. ^

Detecting genetic and nutritional lung cancer risk factors related to folate metabolism using Bayesian generalized linear models

Complex diseases, such as cancer, are caused by various genetic and environmental factors, and their interactions. Joint analysis of these factors and their interactions would increase the power to detect risk factors but is statistically. Bayesian generalized linear models using student-t prior distributions on coefficients, is a novel method to simultaneously analyze genetic factors, environmental factors, and interactions. I performed simulation studies using three different disease models and demonstrated that the variable selection performance of Bayesian generalized linear models is comparable to that of Bayesian stochastic search variable selection, an improved method for variable selection when compared to standard methods. I further evaluated the variable selection performance of Bayesian generalized linear models using different numbers of candidate covariates and different sample sizes, and provided a guideline for required sample size to achieve a high power of variable selection using Bayesian generalize linear models, considering different scales of number of candidate covariates. ^ Polymorphisms in folate metabolism genes and nutritional factors have been previously associated with lung cancer risk. In this study, I simultaneously analyzed 115 tag SNPs in folate metabolism genes, 14 nutritional factors, and all possible genetic-nutritional interactions from 1239 lung cancer cases and 1692 controls using Bayesian generalized linear models stratified by never, former, and current smoking status. SNPs in MTRR were significantly associated with lung cancer risk across never, former, and current smokers. In never smokers, three SNPs in TYMS and three gene-nutrient interactions, including an interaction between SHMT1 and vitamin B12, an interaction between MTRR and total fat intake, and an interaction between MTR and alcohol use, were also identified as associated with lung cancer risk. These lung cancer risk factors are worthy of further investigation.^

Fibulin-2 stabilizes tumor extracellular matrix and drives malignant progression of lung adenocarcinoma

The ECM of epithelial carcinomas undergoes structural remodeling during periods of uncontrolled growth, creating regional heterogeneity and torsional stress. How tumors maintain ECM integrity in the face of dynamic biophysical forces is still largely unclear. This study addresses these deficiencies using mouse models of human lung adenocarcinoma. Spontaneous lung tumors were marked by disorganized basement membranes, dense collagen networks, and increased tissue stiffness. Metastasis-prone lung adenocarcinoma cells secreted fibulin-2 (Fbln2), a matrix glycoprotein involved in ECM supra-molecular assembly. Fibulin-2 depletion in tumor cells decreased the intra-tumoral abundance of matrix metalloproteinases and reduced collagen cross-linking and tumor compressive properties resulting in inhibited tumor growth and metastasis. Fbln2 deposition within intra-tumoral fibrotic bands was a predictor of poor clinical outcome in patients. Collectively, these findings support a feed-forward model in which tumor cells secrete matrix-stabilizing factors required for the assembly of ECM that preferentially favors malignant progression. To our knowledge, this is the first evidence that tumor cells directly regulate the integrity of their surrounding matrix through the secretion of matrix-stabilizing factors such as fibulin-2. These findings open a new avenue of research into matrix assembly molecules as potential therapeutic targets in cancer patients.

SABR for early-stage lung cancer: Early-adoption and future directions

Early-stage lung cancer incidence among older adults is expected to increase due to demographic trends and CT-based screening, yet optimal treatment of lung cancer in the elderly remains controversial. There are several accepted strategies for treating lung cancer including surgery, conventional radiation, and stereotactic ablative body radiotherapy (SABR). However, there are currently no randomized controlled trials to help distinguish the comparative effectiveness of these various strategies. This is an unfortunate omission as lung cancer causes the most deaths among all cancers in the United States (as well as the entire world). SABR holds particular promise as it is a completely non-invasive, ambulatory technique for achieving cure without an operation, thus avoiding the risks of surgery and the associated pre-operative and post-operative costs. To provide fair view of the potential effect on SABR on controlling lung cancer in the United States, a systematic review of SABR with a focus on its achieved outcomes, toxicities, and comparison to conventional radiation and surgical options is presented. ^