Efficient regression analysis with ranked-set sampling

This article is motivated by a lung cancer study where a regression model is involved and the response variable is too expensive to measure but the predictor variable can be measured easily with relatively negligible cost. This situation occurs quite often in medical studies, quantitative genetics, and ecological and environmental studies. In this article, by using the idea of ranked-set sampling (RSS), we develop sampling strategies that can reduce cost and increase efficiency of the regression analysis for the above-mentioned situation. The developed method is applied retrospectively to a lung cancer study. In the lung cancer study, the interest is to investigate the association between smoking status and three biomarkers: polyphenol DNA adducts, micronuclei, and sister chromatic exchanges. Optimal sampling schemes with different optimality criteria such as A-, D-, and integrated mean square error (IMSE)-optimality are considered in the application. With set size 10 in RSS, the improvement of the optimal schemes over simple random sampling (SRS) is great. For instance, by using the optimal scheme with IMSE-optimality, the IMSEs of the estimated regression functions for the three biomarkers are reduced to about half of those incurred by using SRS.

Mammographic mass-screening and future breast cancer burden in Finland

A population-based early detection program for breast cancer has been in progress in Finland since 1987. According to regulations during the study period 1987-2001, free of charge mammography screening was offered every second year to women aged 50-59 years. Recently, the screening service was decided to be extended to age group 50-69. However, the scope of the program is still frequently discussed in public and information about potential impacts of mass-screening practice changes on future breast cancer burden is required. The aim of this doctoral thesis is to present methodologies for taking into account the mass-screening invitation information in breast cancer burden predictions, and to present alternative breast cancer incidence and mortality predictions up to 2012 based on scenarios of the future screening policy. The focus of this work is not on assessing the absolute efficacy but the effectiveness of mass-screening, and, by utilizing the data on invitations, on showing the estimated impacts of changes in an existing screening program on the short-term predictions. The breast cancer mortality predictions are calculated using a model that combines incidence, cause-specific and other cause survival on individual level. The screening invitation data are incorporated into modeling of breast cancer incidence and survival by dividing the program into separate components (first and subsequent rounds and years within them, breaks, and post screening period) and defining a variable that gives the component of the screening program. The incidence is modeled using a Poisson regression approach and the breast cancer survival by applying a parametric mixture cure model, where the patient population is allowed to be a combination of cured and uncured patients. The patients risk to die from other causes than breast cancer is allowed to differ from that of a corresponding general population group and to depend on age and follow-up time. As a result, the effects of separate components of the screening program on incidence, proportion of cured and the survival of the uncured are quantified. According to the predictions, the impacts of policy changes, like extending the program from age group 50-59 to 50-69, are clearly visible on incidence while the effects on mortality in age group 40-74 are minor. Extending the screening service would increase the incidence of localized breast cancers but decrease the rates of non-localized breast cancer. There were no major differences between mortality predictions yielded by alternative future scenarios of the screening policy: Any policy change would have at the most a 3.0% reduction on overall breast cancer mortality compared to continuing the current practice in the near future.

Tumour markers as prognostic factors of survival of gastric cancer patients

The incidence of gastric cancer in the last decades has declined rapidly in the industrialised countries. Worldwide, however, gastric cancer is still the second most common cause of cancer death. Although surgery is currently the most effective treatment, the rapid progress in adjuvant chemotherapy and radiation therapy requires a re-evaluation of prognosis assessment. The TNM staging system of the UICC is ubiquitously used; it groups patients by decreasing survival times from stage I to stage IV based on the spread of disease, i.e. depth of tumour penetration (T), extent of spread to lymph nodes (N), and the presence or absence of distant (M) metastases. This is by far the most consistent prognostic classification system today. However, even within the stage groups there are patients that follow a varying course of disease. Our knowledge of the molecular differences between tumours of the same stage and morphology has been accumulating over the years and methods for a more accurate assessment of the phenotype of neoplasias are of value when evaluating the prognosis of individual patients with gastric cancer. In this study, the immunohistochemical expression of tumour markers involved in different phases in tumourigenesis was examined. The aim was to find new markers which could provide prognostic information in addition to what is provided by the TNM variables. A total of 337 specimens from the primary tumour of patients who underwent surgery for gastric cancer were collected and the immunohistochemical expression of seven different biomarkers was analysed. DNA ploidy and S-phase fraction (SPF) was assessed by flow cytometry. Finally, all biomarkers and clinicopathological prognostic factors were combined and evaluated by a multivariate Cox regression model to elucidate which specific factors provide independent prognostic information. By univariate survival analysis the following variables were significant prognostic factors: epithelial and stromal syndecan-1 expression, stromal tenascin-C expression, expression of tumour-associated trypsin inhibitor (TATI) in cancer cells, nuclear p53 expression, nuclear p21 expression, DNA ploidy, and SPF. By multivariate survival analysis adjusted for all available clinicopathological and biomolecular variables, p53 expression, p21 expression, and DNA ploidy emerged as independent prognostic biomarkers, together with penetration depth of the tumour, presence of nodal metastases, surgical cure of the cancer, and age of the patient at the time of diagnosis.

Prognostic tumour markers in pancreatic cancer

Background. Pancreatic cancer is one of the major causes of cancer death in the industrialised world. The overall survival of patients with ductal pancreatic adenocarcinoma is poor: 5-year survival is only 0.2 to 4%. Tumour stage and histological grade are used as prognostic markers in pancreatic cancer. However, there are differences in survival within stages and histological grades. New, additional and more accurate prognostic tools are needed. Aims. The purpose of this study was to investigate whether the tissue expression of potential and promising tumour markers p27, tenascin C, syndecan-1, COX-2 and MMP-2 are associated with clinicopathological parameters in pancreatic cancer. The expression of p27, tenascin C and syndecan-1 was also evaluated in acute and chronic pancreatitis. The main purpose in the study was to find new prognostic markers for pancreatic adenocarcinoma. Patients. The study included 147 patients with histologically verified pancreatic adenocarcinoma treated at Helsinki University Central Hospital from 1974 to1998. Methods. The expression of tumour marker antigens was demonstrated by immunohistochemistry using monoclonal antibodies against p27, syndecan-1, tenascin C, COX-2 and MMP-2. The results were compared with clinicopathological variables, i.e. age, sex, TNM stage and histological grade. Survival analyses were performed with univariate Kaplan-Meier life-tables and the log-rank test, while multivariate analyses were performed using Cox regression. Results. Pancreatic adenocarcinomas expressed p27, syndecan-1, tenascin C, COX-2 and MMP-2 in 30, 94, 92, 36 and 50% of the samples, respectively. Loss of p27 expression was associated with poor prognosis in stage I and II pancreatic cancer. Stromal syndecan-1 expression was an independent prognostic marker in pancreatic cancer, whereas epithelial syndecan-1 expression predicted better prognosis only in stage I and II disease. Tenascin C expression did not correlate with survival but was associated with differentiation. COX-2 expression was associated with poor outcome and was an independent prognostic factor. Epithelial MMP-2 correlated with poor prognosis in pancreatic cancer. Conclusion: p27 and epithelial syndecan-1 are prognostic markers in early (stage I and II) pancreatic cancer. Stromal syndecan-1, COX-2 and epithelial MMP-2 are prognostic factors in ductal pancreatic adenocarcinoma.

Estramustine and its Derivatives in Potentiating Radiotherapy of Prostate Cancer

The purpose of this study was to deepen our knowledge of the combined use of estramustine and radiotherapy in the treatment of prostate cancer. Prostate cancer is a common disease, with a high variability between subjects in its malignant potential. In many cases, the disease is an incidental finding with little or no clinical significance. In other cases, however, prostate cancer may be an aggressive malignant disease, which, if the initial treatment fails, lacks an effective cure and may lead to severe symptoms, metastasis, and death despite all treatment. In many cases, the methods of treatment available at the moment provide cure or significant regression of symptoms, but often at the cost of considerable side effects. Estramustine, a cytostatic drug used for treating advanced cancer of the prostate, has been shown to inhibit prostate cancer progression and also to increase the sensitivity of cancer cells to radiotherapy. The goals of this study were, first, to find out whether it is possible to use either estramustine or an antibody against estramustine binding protein as carrier molecules for bringing therapeutic radioisotopes into prostate cancer cells, and, secondly, to gain more understanding of the mechanisms behind the known radiosensitising effect of estramustine. Estramustine and estramustine binding protein antibody were labelled with iodine-125 to study the biodistribution of these substances in mice. In the first experiment, both of the substances accumulated in the prostate, but radioiodinated estramustine also showed affinity to the liver and the lungs. Since the radiolabelled antibody was found out to accumulate more selectively to the prostate, we studied its biodistribution in nude mice with DU-145 human prostate cancer implants. In this experiment, the prostate and the tumour accumulated more radioactivity than other organs, but we concluded that the difference in the dose of radiation compared to other organs was not sufficient for the radioiodinated antibody to be advocated as a carrier molecule for treating prostate cancer. Mice with similar DU-145 prostate cancer implants were then treated with estramustine and external beam irradiation, with and without neoadjuvant estramustine treatment. The tumours responded to the treatment as expected, showing the radiation potentiating effect of estramustine. In the third experiment, this effect was found without an increase in the amount of apoptosis in the tumour cells, despite previous suggestions to the contrary. In the fourth experiment, we gave a similar treatment to the mice with DU-145 tumours. A reduction in proliferation was found in the groups treated with radiotherapy, and an increased amount of tumour hypoxia and tumour necrosis in the group treated with both neoadjuvant estramustine and radiation. This finding is contradictory to the suggestion that the radiation sensitising effect of estramustine could be attributed to its angiogenic activity.

Oncogenic MicroRNA-155 Down-regulates Tumor Suppressor CDC73 and Promotes Oral Squamous Cell Carcinoma Cell Proliferation IMPLICATIONS FOR CANCER THERAPEUTICS

The CDC73 gene is mutationally inactivated in hereditary and sporadic parathyroid tumors. It negatively regulates beta-catenin, cyclin D1, and c-MYC. Down-regulation of CDC73 has been reported in breast, renal, and gastric carcinomas. However, the reports regarding the role of CDC73 in oral squamous cell carcinoma (OSCC) are lacking. In this study we show that CDC73 is down-regulated in a majority of OSCC samples. We further show that oncogenic microRNA-155 (miR-155) negatively regulates CDC73 expression. Our experiments show that the dramatic up-regulation of miR-155 is an exclusive mechanism for down-regulation of CDC73 in a panel of human cell lines and a subset of OSCC patient samples in the absence of loss of heterozygosity, mutations, and promoter methylation. Ectopic expression of miR-155 in HEK293 cells dramatically reduced CDC73 levels, enhanced cell viability, and decreased apoptosis. Conversely, the delivery of a miR-155 antagonist (antagomir-155) to KB cells overexpressing miR-155 resulted in increased CDC73 levels, decreased cell viability, increased apoptosis, and marked regression of xenografts in nude mice. Cotransfection of miR-155 with CDC73 in HEK293 cells abrogated its pro-oncogenic effect. Reduced cell proliferation and increased apoptosis of KB cells were dependent on the presence or absence of the 3'-UTR in CDC73. In summary, knockdown of CDC73 expression due to overexpression of miR-155 not only adds a novelty to the list of mechanisms responsible for its down-regulation in different tumors, but the restoration of CDC73 levels by the use of antagomir-155 may also have an important role in therapeutic intervention of cancers, including OSCC.

Multimodal therapy for complete regression of malignant melanoma using constrained nonlinear optimal dynamic inversion

Using a realistic nonlinear mathematical model for melanoma dynamics and the technique of optimal dynamic inversion (exact feedback linearization with static optimization), a multimodal automatic drug dosage strategy is proposed in this paper for complete regression of melanoma cancer in humans. The proposed strategy computes different drug dosages and gives a nonlinear state feedback solution for driving the number of cancer cells to zero. However, it is observed that when tumor is regressed to certain value, then there is no need of external drug dosages as immune system and other therapeutic states are able to regress tumor at a sufficiently fast rate which is more than exponential rate. As model has three different drug dosages, after applying dynamic inversion philosophy, drug dosages can be selected in optimized manner without crossing their toxicity limits. The combination of drug dosages is decided by appropriately selecting the control design parameter values based on physical constraints. The process is automated for all possible combinations of the chemotherapy and immunotherapy drug dosages with preferential emphasis of having maximum possible variety of drug inputs at any given point of time. Simulation study with a standard patient model shows that tumor cells are regressed from 2 x 107 to order of 105 cells because of external drug dosages in 36.93 days. After this no external drug dosages are required as immune system and other therapeutic states are able to regress tumor at greater than exponential rate and hence, tumor goes to zero (less than 0.01) in 48.77 days and healthy immune system of the patient is restored. Study with different chemotherapy drug resistance value is also carried out. (C) 2014 Elsevier Ltd. All rights reserved.

MicroRNA-125a Reduces Proliferation and Invasion of Oral Squamous Cell Carcinoma Cells by Targeting Estrogen-related Receptor alpha IMPLICATIONS FOR CANCER THERAPEUTICS

Estrogen-related receptor (ESRRA) functions as a transcription factor and regulates the expression of several genes, such as WNT11 and OPN. Up-regulation of ESRRA has been reported in several cancers. However, the mechanism underlying its up-regulation is unclear. Furthermore, the reports regarding the role and regulation of ESRRA in oral squamous cell carcinoma (OSCC) are completely lacking. Here, we show that tumor suppressor miR-125a directly binds to the 3UTR of ESRRA and represses its expression. Overexpression of miR-125a in OSCC cells drastically reduced the level of ESRRA, decreased cell proliferation, and increased apoptosis. Conversely, the delivery of an miR-125a inhibitor to these cells drastically increased the level of ESRRA, increased cell proliferation, and decreased apoptosis. miR-125a-mediated down-regulation of ESRRA impaired anchorage-independent colony formation and invasion of OSCC cells. Reduced cell proliferation and increased apoptosis of OSCC cells were dependent on the presence of the 3UTR in ESRRA. The delivery of an miR-125a mimic to OSCC cells resulted in marked regression of xenografts in nude mice, whereas the delivery of an miR-125a inhibitor to OSCC cells resulted in a significant increase of xenografts and abrogated the tumor suppressor function of miR-125a. We observed an inverse correlation between the expression levels of miR-125a and ESRRA in OSCC samples. In summary, up-regulation of ESRRA due to down-regulation of miR-125a is not only a novel mechanism for its up-regulation in OSCC, but decreasing the level of ESRRA by using a synthetic miR-125a mimic may have an important role in therapeutic intervention of OSCC and other cancers.

A novel Monoclonal Antibody against Notch1 Targets Leukemia-associated Mutant Notch1 and Depletes Therapy Resistant Cancer Stem Cells in Solid Tumors

Higher Notch signaling is known to be associated with hematological and solid cancers. We developed a potential immunotherapeutic monoclonal antibody (MAb) specific for the Negative Regulatory Region of Notch1 (NRR). The MAb604.107 exhibited higher affinity for the ``Gain-offunction'' mutants of Notch1 NRR associated with T Acute lymphoblastic Leukemia (T-ALL). Modeling of the mutant NRR with 12 amino-acid insertion demonstrated ``opening'' resulting in exposure of the S2-cleavage site leading to activated Notch1 signaling. The MAb, at low concentrations (1-2 mu g/ml), inhibited elevated ligand-independent Notch1 signaling of NRR mutants, augmented effect of Thapsigargin, an inhibitor of mutant Notch1, but had no effect on the wild-type Notch1. The antibody decreased proliferation of the primary T-ALL cells and depleted leukemia initiating CD34/CD44 high population. At relatively high concentrations, (10-20 mu g/ml), the MAb affected Notch1 signaling in the breast and colon cancer cell lines. The Notch-high cells sorted from solid-tumor cell lines exhibited characteristics of cancer stem cells, which were inhibited by the MAb. The antibody also increased the sensitivity to Doxorubucinirubicin. Further, the MAb impeded the growth of xenografts from breast and colon cancer cells potentiated regression of the tumors along with Doxorubucin. Thus, this antibody is potential immunotherapeutic tool for different cancers.

Quercetin, a Natural Flavonoid Interacts with DNA, Arrests Cell Cycle and Causes Tumor Regression by Activating Mitochondrial Pathway of Apoptosis

Naturally occurring compounds are considered as attractive candidates for cancer treatment and prevention. Quercetin and ellagic acid are naturally occurring flavonoids abundantly seen in several fruits and vegetables. In the present study, we evaluate and compare antitumor efficacies of quercetin and ellagic acid in animal models and cancer cell lines in a comprehensive manner. We found that quercetin induced cytotoxicity in leukemic cells in a dose-dependent manner, while ellagic acid showed only limited toxicity. Besides leukemic cells, quercetin also induced cytotoxicity in breast cancer cells, however, its effect on normal cells was limited or none. Further, quercetin caused S phase arrest during cell cycle progression in tested cancer cells. Quercetin induced tumor regression in mice at a concentration 3-fold lower than ellagic acid. Importantly, administration of quercetin lead to -5 fold increase in the life span in tumor bearing mice compared to that of untreated controls. Further, we found that quercetin interacts with DNA directly, and could be one of the mechanisms for inducing apoptosis in both, cancer cell lines and tumor tissues by activating the intrinsic pathway. Thus, our data suggests that quercetin can be further explored for its potential to be used in cancer therapeutics and combination therapy.

Technology for Single Cell Protein Analysis in Immunology and Cancer Prognostics

The first chapter of this thesis deals with automating data gathering for single cell microfluidic tests. The programs developed saved significant amounts of time with no loss in accuracy. The technology from this chapter was applied to experiments in both Chapters 4 and 5.

The second chapter describes the use of statistical learning to prognose if an anti-angiogenic drug (Bevacizumab) would successfully treat a glioblastoma multiforme tumor. This was conducted by first measuring protein levels from 92 blood samples using the DNA-encoded antibody library platform. This allowed the measure of 35 different proteins per sample, with comparable sensitivity to ELISA. Two statistical learning models were developed in order to predict whether the treatment would succeed. The first, logistic regression, predicted with 85% accuracy and an AUC of 0.901 using a five protein panel. These five proteins were statistically significant predictors and gave insight into the mechanism behind anti-angiogenic success/failure. The second model, an ensemble model of logistic regression, kNN, and random forest, predicted with a slightly higher accuracy of 87%.

The third chapter details the development of a photocleavable conjugate that multiplexed cell surface detection in microfluidic devices. The method successfully detected streptavidin on coated beads with 92% positive predictive rate. Furthermore, chambers with 0, 1, 2, and 3+ beads were statistically distinguishable. The method was then used to detect CD3 on Jurkat T cells, yielding a positive predictive rate of 49% and false positive rate of 0%.

The fourth chapter talks about the use of measuring T cell polyfunctionality in order to predict whether a patient will succeed an adoptive T cells transfer therapy. In 15 patients, we measured 10 proteins from individual T cells (~300 cells per patient). The polyfunctional strength index was calculated, which was then correlated with the patient's progress free survival (PFS) time. 52 other parameters measured in the single cell test were correlated with the PFS. No statistical correlator has been determined, however, and more data is necessary to reach a conclusion.

Finally, the fifth chapter talks about the interactions between T cells and how that affects their protein secretion. It was observed that T cells in direct contact selectively enhance their protein secretion, in some cases by over 5 fold. This occurred for Granzyme B, Perforin, CCL4, TNFa, and IFNg. IL- 10 was shown to decrease slightly upon contact. This phenomenon held true for T cells from all patients tested (n=8). Using single cell data, the theoretical protein secretion frequency was calculated for two cells and then compared to the observed rate of secretion for both two cells not in contact, and two cells in contact. In over 90% of cases, the theoretical protein secretion rate matched that of two cells not in contact.

Estimating Dungeness crab (Cancer magister) abundance: crab pots and dive transects compared

Dungeness crabs (Cancer magister) were sampled with commercial pots and counted by scuba divers on benthic transects at eight sites near Glacier Bay, Alaska. Catch per unit of effort (CPUE) from pots was compared to the density estimates from dives to evaluate the bias and power of the two techniques. Yearly sampling was conducted in two seasons: April and September, from 1992 to 2000. Male CPUE estimates from pots were significantly lower in April than in the following September; a step-wise regression demonstrated that season accounted for more of the variation in male CPUE than did temperature. In both April and September, pot sampling was significantly biased against females. When females were categorized as ovigerous and nonovigerous, it was clear that ovigerous females accounted for the majority of the bias because pots were not biased against nonovigerous females. We compared the power of pots and dive transects in detecting trends in populations and found that pots had much higher power than dive transects. Despite their low power, the dive transects were very useful for detecting bias in our pot sampling and in identifying the optimal times of year to sample so that pot bias could be avoided.

The human papillomavirus and cancer: a multiphase study investigating preventative behaviours in young males

Background: The Human Papillomavirus (HPV) is one of the world’s most common sexually transmitted infections, and a causative factor of oropharyngeal, anal and penile cancers in males. Worldwide, an estimated 39,000 HPV-associated cancers occur each year in men. The highest rates of HPV infection are found in adults aged 18 to 28 years. Clinical evidence indicates that use of a condom in addition to obtaining the HPV vaccine provides the greatest protection from HPV infections. Aim: To explore young men’s attitudes, beliefs, and behavioural intention in relation to receiving the HPV vaccine and using a condom correctly and consistently. Collectively, both behaviours are linked to the prevention of HPV transmission and associated infections with HPV. Method: A multi- phase study, underpinned by the Theory of Planned Behaviour, involving a qualitative belief elicitation, pilot, and quantitative cross-sectional study was conducted. A belief elicitation (n=12) phase was used to generate items to include in a newly developed research instrument. Post pilot the research instrument was utilised in a cross sectional online survey to explore the attitudes, beliefs, and behavioural intention of young men (n= 359) with regard to receiving the HPV vaccine, and using a condom correctly and consistently. Data Collection: Data collection took place over a three month time frame. Male participants were recruited from a university in Southern Ireland via a student email system, as well as posting advertisements on numerous health, social and sports websites. Sample: Three hundred and fifty nine male participants aged 18- 28 years completed the online questionnaire. Data Analysis: Data were analysed using SPSS. Descriptive, correlational, multiple and hierarchical regression analysis were performed on the indirect and direct variables of the Theory of Planned Behaviour i.e. attitude, subjective norm, perceived behavioural control, and intention. Status variables were also included in descriptive analysis and hierarchical regressions. Findings are presented through text and graphical representation. Results: Alarming sexual health statistics identified that only 44.3% of participants always used a condom, and 78.6% never used a condom for oral sex. Furthermore, findings reveal that the constructs of the Theory of Planned Behaviour adequately measure male’s attitudes, beliefs and behavioural intention with regard to both behaviours. The Theory of Planned Behaviour has assisted in identifying how social pressures play an influential role in relation to males receiving the HPV vaccine. Attitudes presented as the most significant predictor of male’s intentions to use a condom correctly and consistently. Intention to perform both behaviours was identified as moderate to high. Conclusion: This study has contributed to the field of HPV research, as it is the first piece of research to explore preventative HPV behaviours i.e. receiving the HPV vaccine, and condom use, amongst young males, utilising the Theory of Planned Behaviour. A deeper understanding of young male’s attitudes, beliefs, and behavioural intention on this topic has been achieved. Additionally, a new robust research instrument has been constructed. Findings from this study will undoubtedly help in the implementation of the HPV vaccine in Ireland, as well as influence health promotion campaigns aimed at young males, addressing the topic of condom use.

Baseline health-related quality-of-life data as prognostic factors in a phase III multicentre study of women with metastatic breast cancer.

The potential value of baseline health-related quality-of-life (HRQOL) and clinical factors in predicting prognosis was examined using data from an international randomised phase III trial which compared doxorubicin and paclitaxel with doxorubicin and cylophosphamide as first line chemotherapy in 275 women with metastatic breast cancer. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the related breast module (QLQ-BR23) were used to assess baseline HRQOL data. The Cox proportional-hazards regression model was used for both univariate and multivariate analyses of survival. In the univariate analyses, performance status (P<0.001) and number of sites involved (P=0.001) were the most important clinical prognostic factors. The HRQOL variables at baseline most strongly associated with longer survival were better appetite, physical and role functioning, as well as less fatigue (P<0.001). The final multivariate model retained performance status (P<0.001) and appetite loss (P=0.005) as the variables best predicting survival. Substantial loss of appetite was the only independent HRQOL factor predicting poor survival and was strongly correlated (/r/>0.5) with fatigue, role and physical functioning. In addition to known clinical factors, appetite loss appears to be a significant prognostic factor for survival in women with metastatic breast cancer. However, the mechanism underlying this association remains to be precisely defined in future studies.

Associations between Intake of Folate, Methionine, and Vitamins B-12, B-6 and Prostate Cancer Risk in American Veterans.

Prostate cancer (PC) is the second leading cause of cancer death in men. Recent reports suggest that excess of nutrients involved in the one-carbon metabolism pathway increases PC risk; however, empirical data are lacking. Veteran American men (272 controls and 144 PC cases) who attended the Durham Veteran American Medical Center between 2004-2009 were enrolled into a case-control study. Intake of folate, vitamin B12, B6, and methionine were measured using a food frequency questionnaire. Regression models were used to evaluate the association among one-carbon cycle nutrients, MTHFR genetic variants, and prostate cancer. Higher dietary methionine intake was associated with PC risk (OR = 2.1; 95%CI 1.1-3.9) The risk was most pronounced in men with Gleason sum <7 (OR = 2.75; 95%CI 1.32- 5.73). The association of higher methionine intake and PC risk was only apparent in men who carried at least one MTHFR A1298C allele (OR = 6.7; 95%CI = 1.6-27.8), compared to MTHFR A1298A noncarrier men (OR = 0.9; 95%CI = 0.24-3.92) (p-interaction = 0.045). There was no evidence for associations between B vitamins (folate, B12, and B6) and PC risk. Our results suggest that carrying the MTHFR A1298C variants modifies the association between high methionine intake and PC risk. Larger studies are required to validate these findings.