Melissa L. Bondy - US grants

This proposal describes a plan for a Preventive Oncology Academic Award and my personal development towards a multi-disciplinary approach to breast cancer prevention and control. Two projects are described, the first using data from the 1987 Texas Breast Cancer Screening Project, a state-wide mammography program, to validate or refine the risk model for breast cancer devised by Gail et al. (1990) that gives a numerical life-time breast cancer risk estimate. This validation follows-up a study of risk and use of the Gail model previously completed (Bondy et al.) which assigned risk scores to women who participated in the 1987 TBSP. During the award period, we will contact the 3,165 women identified as being at high risk to check the accuracy of their risk scores. We will mail a detailed risk factor questionnaire to gain additional information and identify women who have developed breast cancer since their participation in the TBSP. We will then conduct a nested case-control study with the newly detected breast cancer cases to validate the Gail model, or devise a refinement of it and calculate a new breast cancer risk determination model. If we can ascertain we have accurately determined degrees of risk or what factors are needed to determine risk, we can improve the general effectiveness of screening programs in identifying high risk individuals. The second project, a primary prevention effort, is a case-control study of breast cancer risk factors in Hispanic women. The study incorporates epidemiologic risk factor data with molecular genetic marker data to provide a better understanding of the etiology of breast cancer in Hispanic women. The study aims to identify modifiable risk factors for breast cancer where alteration would lead to a reduction in breast cancer morbidity and mortality. These two projects, though focusing on genetics, have broader applications and would lead to investigations of environmental and genetic interactions. This award will advance comparative ethnic research and the assessment of breast cancer risk in high risk populations. Research enabled by the award will broaden my understanding of the interactions of molecular genetic markers and epidemiologic risk factors related to the etiology of breast cancer and benefit the field of preventive oncology.

DESCRIPTION: (Adapted from Investigator's Abstract) There is substantial evidence that genetic events are associated with the etiology of brain tumors. The purpose of this study is to characterize the cancer risk in large number of kindreds of glioma patients using combined epidemiologic and statistical techniques and incorporating molecular genetic markers. The investigators will continue to accrue families to obtain a sufficiently large sample size to have precise estimates of the heritable component of gliomas. Several types of analyses will be performed on the data set. First, a descriptive analysis to detect overall cancer excess or excess of specific sites by computing Standardized Incidence Ratios (SIRs). The SIRs will determine whether excess cancer exists in first-degree relatives of glioma patients, by specific site, or by specific proband or relative characteristics. The next type of analysis is hypothesis testing using segregation analysis (with the computer program, Statistical Analysis for Genetic Epidemiology - SAGE) to determine the genetic model and parameter estimates that characterize the mode of inheritance of gliomas and identify specific kindreds showing evidence for a major gene to include in linkage analysis. Through linkage analysis the investigators will determine if mutations at distinct cancer predisposing loci are etiologically relevant, and inherited from an antecedent relative. The candidate gene analysis will be conducted by Dr. Peter O'Connell from The University of Texas Health Science Center at San Antonio. With a larger sample the investigators will be able to confirm their finding that patients with multifocal glioma, gliomas as a secondary malignancy, and a family history, constitute a genetically predisposed subgroup. This study will be the first comprehensive evaluation of familial aggregation in families of unselected glioma patients. In addition, they are collecting blood from each new patient and their specimen repository will be available to study future candidate genes to integrate with the family data.

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We propose a molecular epidemiologic cohort study of all newly diagnosed Stage IIA and IIB breast cancer patients who registered at The University of Texas M.D. Anderson Cancer Center (MDACC) between January 1, 1985 and December 31, 1999, and were residents of the state of Texas (N=2,875). This cohort is characterized by extensive long-term follow-up, and equal access to "best of care" practices. It offers us the opportunity to test hypotheses regarding the role of host genetic (i.e., such as gene polymorphisms in drug and radiation sensitivity, family history and ethnicity) and exposure factors (i.e., smoking, reproductive events, BMI, HRT, co-morbid conditions) in relation to tumor phenotype, as independent and interactive determinants of risk of recurrence, distant metastasis, contralateral breast cancer, second malignancies, and/or disease-free survival. In this population, we will examine a series of promising candidate host genetic markers and suspected environmental and lifestyle factors for their added value in clinical decision making when compared or combined with standard histopathological prognostic markers (e.g., lymph node status, tumor size, histological grade). In order to address our study hypotheses, we propose the following 4 specific aims: 1) To compile a comprehensive database of epidemiologic risk factors and clinical data (including treatment, pathology, and long-term follow-up) on all breast cancer patients seen exclusively at MDACC for Stage II disease. 2) To evaluate baseline epidemiologic profiles as independent and inter-related determinants of risk of recurrence, distant metastasis, contralateral breast cancer, new primary malignancies, and disease-free survival. These profiles will include comprehensive information on the use of tobacco, reproductive factors including ovarectomy and the use of HRT, body mass index (BMI), family history of cancer, age and ethnicity in relation to standard histopathology markers. 3) We will evaluate the interaction between these epidemiological factors and a) host and b) tumor molecular markers that show a relationship with disease prognosis and patient events. Specifically, in our sample set we will evaluate: the tumor specific expression of HER2-neu, Ki-67, ER, PR and p53, using standardized immunohistochemical analysis, as informative markers of tumor phenotype and patient performance. Inherited variability in genes that modulate host sensitivity to therapeutic agents, including the glutathione sulfotransferase (GSTpi, GSTM1, GSTT1); enzymes important in defending against chemical injury by catalyzing conjugation of reactive electrophilic molecules with glutathione, and an allele variant in the multi-drug resistance gene MDR-1 whose products, P- glycoprotein, is strongly linked with chemotherapeutic resistance. Our fourth aim is to construct statistical models to determine which marker or combination of markers and host factors (genetic and lifestyle) are better predictors of patient performance than the commonly used histopathologic methods.

DESCRIPTION (provided by applicant): The outcome for patients with primary malignant brain tumors is poor. Radiotherapy and chemotherapy have improved the outcome, especially in the chemotherapy-sensitive group of tumors such as anaplastic astrocytoma and anaplastic oligodendroglioma. Yet it is not possible to identify the patients who will benefit from such treatments in advance. Inherited variability in metabolism of therapeutic agents is suggested to be responsible, in part for individual differences in response to cancer treatment. Overall purpose of the proposed study is to investigate the role of genetic polymorphisms in the glutathione s-transferase (GST) enzyme family in predicting survival in 305 patients with anaplastic astrocytoma, anaplastic oligodendroglioma and anaplastic oligoastrocytoma, treated at the University of Texas MD Anderson Cancer Center between 1994 and 2004. We hypothesize that patients with inherent low GST activity have reduced clearance of reactive agents of chemo- and radiotherapy and are more likely to have a better treatment effect at the tumor site. Further, we predict that individuals with low activity GST genotypes will have increased survival time when compared to those with inherently high GST activity. We will determine the frequencies of GSTM1, GSTT1, and GSTP1 polymorphisms in 350 cases by polymerase chain reaction and restriction fragment length polymorphisms. We will review medical records of the 350 patients and abstract information on outcome, treatment and clinically significant adverse events related to radiotherapy and, chemotherapy that required delaying or cessation of treatment. To assess if GST polymorphisms are associated with outcome in patients with primary malignant brain tumor we will perform Kaplan-Meier and Cox proportional hazard analyses. To explore whether metabolic polymorphisms of the GST enzyme family are correlated with occurrence of adverse effects secondary to chemotherapy we will use logistic regression, Kaplan-Meier and Cox proportional hazard analyses. Based on the results of the proposed study, in the future chemotherapy regimens can be tailored according to individual patient's metabolic enzyme profile. Thus, patients who can tolerate higher doses of chemotherapy can be treated more efficiently, suffering from less side effects and potentially may have a better outcome.

[unreadable] DESCRIPTION (provided by applicant): We propose an international multi-center multidisciplinary study to identify susceptibility genes in high-risk familial brain tumor pedigrees using the most sophisticated genetic analysis methods available. This research team is uniquely positioned to characterize genetic risk of familial brain tumors, and conduct important translational research studies that will enhance our understanding into the etiology of brain tumors. We define familial brain tumors as those pedigrees in which two or more relatives have been diagnosed with a glioma that is not associated with known genetic syndromes. From research that we and others have conducted support several important observations that familial aggregation of brain tumors exists, and recent linkage analyses shows that there is strong suggestive evidence for susceptibility genes in 6 separate regions on chromosomes 1p, 1q, 8p, 9p, 10p, and 15q with LOD Scores ranging from 1.07 to 3.35. Based on these observations, we hypothesize that there are specific discoverable genotypes that increase the risk of developing brain tumors. We will study high-risk familial pedigrees using newly developed but proven gene mapping techniques. We propose the following specific aims: Specific Aim 1: Establish a cohort of 400 high-risk pedigrees for genetic linkage analysis. We will screen and obtain epidemiologic data from approximately 17,08 glioma cases to identify a target of 400 families. We will establish a cohort of the first and second-degree relatives from these glioma cases, to obtain new knowledge about how cancer aggregates in glioma families. A cohort of multiplex extended pedigrees will be created from the 400 glioma families for genetic analysis. We will also acquire biospecimens (blood and tumor tissue), and risk factor data from relevant family members. This will be the largest collection of glioma families that will provide us sufficient power to identify susceptibility genes and eventually identify functional mutations for this heterogenous disease. Specific Aim 2: Identify candidate regions linked to familial brain tumors. To strengthen evidence of linkage to regions found in our preliminary analysis, and to identify additional regions linked to brain tumors, we will genotype informative glioma pedigrees identified in aim 1 using Affymetrix 10K GeneChip with markers spaced throughout the genome, and conduct a genome-wide multipoint linkage scan with these markers. All regions with a lod score of 1.05 will be taken forward for further analysis. Specific Aim 3: Fine map regions established in Aim 2 by genotyping selected SNPs from genome databases. We will attempt to further refine the regions identified in Aim 2 to less than 1 cM by using approximately 1,500 - 2,000 carefully selected SNPs. The prioritization of regions will be based on a combination of the strength of evidence for linkage from families of various ethnic backgrounds and the presence of obvious candidate genes. Through such efforts, this study will identify susceptibility genes that will provide a better understanding of the mechanisms of brain tumor etiology. This information has translational significance for brain tumor patients and their families, and will enable us to develop appropriate genetic screening and counseling approaches to reduce the incidence and mortality of this disease. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): No large-scale study within the United States has examined any aspect of the epidemiology of intracranial meningiomas, a lesion which accounts for up to 25% of all primary intracranial neoplasms. We propose to conduct a population-based case/control study of meningioma within the states of Connecticut, Massachusetts, North Carolina, and Texas as well as the San Francisco Bay area under the mechanism of an integrated R01 (Note that identical applications are submitted for all five sites). Cases will be selected using rapid case ascertainment and will include all male and female individuals diagnosed with a histologically confirmed intra-cranial meningioma between the ages of 20 and 79 years from 7/1/2006 through 6/30/2010 in the above listed regions. Control subjects will be identified via random-digit dial methods and matched to the cases by sex, ethnicity, geographic location, and five-year age category. Study subjects will be administered a telephone questionnaire to collect information on the two primary categories of risk, exposure to ionizing radiation and hormones as well as additional risk factors such as family history of meningioma and other tumors, cell-phone utilization, and head trauma as well as questions on outcome and quality of life. Parraffin-embedded tumor tissue blocks will be obtained for case subjects to allow for 1) a uniform histological review, and 2) immunohistochemical testing for estrogen, progesterone, androgen and MIB-1 receptors. Blood or buccal specimens will be collected from all study subjects for testing of DNA polymorphisms in DNA repair and cell cycle genes. This study represents the first concentrated effort to examine environmental and genetic risk factors for meningiomas.

This proposal builds upon the on-going multi-center family study entitled International Study of Familial Glioma (Gliogene - R01CA119215), and the funded Brain SPORE at University of California, San Francisco (UCSF) to explore genetic predictors of neurocognitive (NC) and clinical outcome. We will leverage these funded resources by using the existing infrastructures for recruiting glioma patients at The University of Texas . D. Anderson Cancer Center (UTMDACC) and UCSF. We will recruit from both sites a total of 800 patients between the ages of 18 and 70 years with newly diagnosed high-grade glioma (GBM). NC outcomes are shown to vary across patients and such variation may be partly due to genetic differences among patients that could potentially modulate treatment response, disease progression, and NC sequelae. We therefore propose a multidisciplinary integrative approach using a panel of biomarkers in patients receiving standardized treatment protocols to determine factors related to NC function, symptom burden and clinical outcomes (such as treatment toxicity and survival) all of which affect overall QOL. Hypothesis: Genetic polymorphisms in NC, metabolizing genes, DMA repair pathway, and inflammation genes alter the NC and clinical outcome of brain tumor patients and, in turn, impact their QOL. Specific Aim 1: To recruit approximately 100 newly diagnosed GBM patients per year from the neurooncology clinics at UTMDACC and UCSF. From these patients'DNA, we will genotype a panel of NC, metabolizing, DNA repair and inflammation genes. Specific Aim 2: To conduct NC evaluations on all patients treated and followed at each institution (200/year N=800 over 4 years) following the standardized testing established for a number of collaborative group and pharmaceutical company sponsored studies. Specific Aim 3: To integrate data derived from Aims 1 and 2 to determine if variants in the NC, metabolizing, DNA repair, and inflammation pathway genes alter overall QOL. Using the wealth of clinical information abstracted from medical records and data generated from this proposal, we will develop a Risk Prediction Model to determine which patients are more likely to develop NC dysfunction during their disease course and could therefore be targeted for personalized treatments that would potentially impact their QOL. Brain tumors cause progressive NC deficits similar to other neurodegenerative diseases, and these deficits frequently worsen because of treatment effects. Some patients even develop treatment related dementia that leads to death without evidence of tumor progression. Thus, the ability to determine markers that can identify those vulnerable patients would be of tremendous benefit and allow for alterations of primary treatment or neuroprotective therapies to reduce the risk of brain tumor therapy.

SECTION N4: RESEARCH CORE - INTERVENTION STUDY PROJECT SUMMARY The proposed study will evaluate the efficacy of a theoretically- and empirically-based, culturally-tailored Motivation And Problem Solving (MAPS) inten/ention, conducted within a community-based participatory research (CBPR) framework(1-3) for reducing cancer risk related to smoking, poor diet, and physical inactivity. The entire study design and intervention approach builds on a large body of CBPR, outreach, and other research among Latinos by the investigators, all of which has led to the development of the proposed project (see the Preliminary Studies, Administrative Core, and Outreach Core for more detailed discussion of much of this work). High-risk MA individuals (i.e., smokers who are also ovenweight/obese; N = 400) will be recruited from the MA Cohort Study (>19,000 participants), will be followed for a period of 18 months, and will be randomly assigned to one of two groups: Health Education (HE) or MAPS. Participants do not need to be motivated to change their behavior. Assessments occur at Baseline and at 6,12, and 18 months after Baseline. All assessments occur in the participants' homes. Potential participants will be identified via data already collected in the MA Cohort Study. Potential participants will be contacted and screened for eligibility over the phone. A Baseline visit will be scheduled within at least two weeks. At the completion of the Baseline assessment, participants will be randomly assigned to HE or MAPS. Primary outcomes are smoking status, servings of fruits and vegetables, total calories, percent of calories from fat, and both self-reported and objective measures of physical activity (PA). HE is modeled to resemble a brief encounter with a lay health worker and includes brief counseling and self-help materials addressing the three risk behaviors, referrals to available resources, and a home-based exercise kit (e.g., pedometer, exercise ball, strength training cables). When and if a participant is ready to make a smoking cessation attempt, a 6-week supply of free nicotine patches will be provided. HE will occur a total of 3 times (Baseline, 6 months, and 12 months). MAPS will include HE plus 9 proactive, telephone counseling sessions over the 18 month period. The timing of the 9 counseling sessions in MAPS is flexible and determined jointly by the participant and the counselor. MAPS is a holistic, dynamic approach to facilitating behavior change based on a combination of motivational interviewing (Ml) (4,5) and social cognitive theory.(6-8) Moreover, MAPS incorporates key strategies from empirically-validated approaches such as the chronic care model and patient navigation that have been demonstrated to be effective across numerous diseases and conditions. (9-12) MAPS is designed for all individuals regardless of their readiness to change, and specifically targets motivation, agency/self-efficacy, and other key factors of particular relevance to underserved populations (e.g., stressors, family issues, financial resources). Because MAPS revolves around a wellness program that addresses numerous barriers and concerns that are prevalent among underserved populations, it is particularly appropriate for treating high-risk MA individuals. Motivational and social cognitive approaches have been used extensively in the treatment of smoking, diet, and PA. However, to the best of our knowledge, MAPS is among the first treatments to combine these approaches into a comprehensive, holistic intervention model built around the dynamic nature of motivation, target multiple cancer risk behaviors, and focus on high-risk, Spanish-speaking MA individuals.

DESCRIPTION (provided by applicant): The Texas regional Community Networks Program, Latinos Contra El Cancer, combines innovative research, extensive community outreach, and a multi-faceted training program, all conducted within a community-based participatory research (CBPR) context, to reduce cancer-related health disparities in Latinos, and to build a cadre of competitive health disparities researchers trained in CBPR in three regions of Texas (Houston, El Paso, the Lower Rio Grande Valley). This will be accomplished through the work of three distinct yet complementary cores (Outreach, Research, and Training) to integrate knowledge generation, community health education, and community and researcher capacity building within and across the three sites, building on existing research infrastructures, longstanding relationships, and novel communication systems. The overarching goals of each Core are described below. The goal of the proposed Outreach Program is to increase the use of evidence-based biomedical and behavioral procedures and interventions to reduce the cancer burden among Latinos in Texas. We will build on existing community partnerships, infrastructure, and programs to develop an Outreach Program that will accomplish this goal through capacity building with community partners and direct health promotion in Latino communities. The goal of the Research Core - Intervention Study is to develop and evaluate an innovative intervention approach for reducing cancer risk related to the three leading behavioral risk factors for cancer: smoking, poor diet, and physical inactivity. The project will focus on participants in a longitudinal study of cancer risk factors among Mexican Americans in Houston (Mexican American Cohort Study). The goal of the Research Core - Pilot Study is to utilize quantitative and qualitative methods to investigate the socio-demographic, acculturation, and psychosocial factors that influence Mexican Americans willingness to provide biologic specimens for biobanking. The goal of the mentored Training Program is to prepare a cadre of new and early stage investigators to conduct cancer disparities research in Latino communities, with a particular emphasis on building skills and capacity to conduct community-based participatory research.

DESCRIPTION (provided by applicant): Glioma comprises about 40% of all primary brain tumors accounting for as many as 26,000 U.S. and European deaths annually. Inherited susceptibility plays a role with 2-fold increased risk of glioma among first-degree relatives of glioma cases. We initiated a multi-center, international linkage study: Genetic Epidemiology of Glioma International Consortium in 2007 to address the role of inherited susceptibility. Since this study does not allow us currently to address the role of genetic susceptibility in sporadic cases, we propose this case- control study to address this gap. Members of the consortium have conducted genome wide association studies (GWAS) that will be the discovery phase (phase I). While of high value for discovery, we propose to recruit 6,000 newly diagnosed glioma cases and 6,000 age-gender-ethnicity-matched controls, and collect detailed epidemiologic data and biologic samples from the 13 participating Gliogene sites. We hypothesize that novel inherited variation influencing the susceptibility to glioma can be identified by high density SNP analysis, and propose the following specific aims: SA1: Identify common genetic variants contributing to the risk of glioma. We plan to conduct phases 2 and 3 of the 3 phase approach, specifically we will: (SA1a) Validate GWAS findings from the discovery sets, and replicate the top hits (~23,000 SNPs) with lowest p- values from the two phase GWA studies in a series of 2,000 cases and 2,000 controls (phase 2, validation). Validate the top hits from the test set (aim 1a). From stage 2, genes with SNPs displaying an association at pd10-4 (including the complete haplotype tagging - approximately 100 SNPs) will then be genotyped in a further series of 4,000 cases and 4,000 controls (stage 3, validation). SNPs significant at 10-7 or better will be considered in the final analyses. (SA1b). Using an a priori hypothesis that DNA repair in inflammation contribute to glioma risk, we will selectively interrogate DNA repair and inflammation pathway genes using data for select genes derived from the high-density array. We will conduct a hypothesis driven genetic association in DNA repair and in inflammation/immune function related genes with glioma risk using functional genomic and bioinformatic tools to interrogate available databases. (SA2): Evaluate gene-gene (G-G) and gene- environmental (G-E) interactions with strong biologic relevance to identify G-G and G-E interactions for glioma risk using machine-learning tools (MDR, FITF, and CART) in these exploratory analyses. There are no existing glioma case-control studies with sufficient numbers of biological samples and common epidemiologic data to conduct a comprehensive validation and replication study, or to address the issues of tumor heterogeneity as we will in this study.

DESCRIPTION (provided by applicant): Multidisciplinary training programs to prepare the next generation of pediatric cancer epidemiology and control researchers are urgently needed. We propose to establish a cross-institutional training program to address this underdeveloped area and provide future physician scientists the training opportunities required to develop their careers in pediatric oncology and childhood cancer epidemiologists. This training program will be under the umbrella of the Childhood Cancer Epidemiology and Prevention Center (CCEPC), a unique collaborative effort between Baylor College of Medicine/Texas Children's Hospital and The University of Texas MD Anderson Cancer Center (MDACC). The unique faculty strengths of these two neighbor institutions include pediatric oncology, molecular epidemiology, genomics, survivorship research, childhood obesity, statistics, and pharmacology, in the outstanding environment of the Texas Medical Center in Houston, provide the ideal setting for this training program. Our overall goal is to establish a multidisciplinary curriculum-driven training and career development program in Pediatric Cancer Epidemiology and Control (PCEC). We propose the following specific aims: 1. Recruit well qualified post-doctoral fellows (Ph.D.), and pediatric oncology clinical fellows (M.D. or M.D./Ph.D.) to receive specific mentored training (didactic and research experiences) in childhood cancer epidemiology and cancer prevention in a multi-disciplinary setting. We will also have a specific focus on recruiting quality minority applicants. 2. Develop a multidisciplinary curriculum that will provide a strong foundation in epidemiology, genetics, cancer biology, survivorship research, and cancer control. 3. Provide rich mentored research experiences for post-doctoral and clinical fellows. 4. Incorporate program evaluation and long-term tracking of trainees to assess efficacy of this training and career development program. 5. Provide career development mini-courses, seminars, and experiential activities for post-doctoral and clinical fellows to facilitate their transition from fellow to early-stage faculty member.

DESCRIPTION (provided by applicant): Estrogen receptor-negative (ER-), early stage breast cancer (ESBC) patients show marked clinical heterogeneity with regard to outcomes. Further, there have been no major advances in improving prognostication or prediction over the last decade. We have completed an extensive analysis of copy number imbalances (CNI) in ER- ESBC and have developed the first practical, robust prognostic model applicable to ER-ESBC. The primary goal of this project is to validate, and if necessary, refine our prognostic CNI model for ER-/ESBC. Overall the project is complementary to the TCGA in that the follow-up for patients is much longer, a requirement for breast cancer studies, and the samples are solely from ESBC whereas many of the samples in the TCGA are from large, advanced tumors due to the study design. The overarching hypothesis of our study is that inclusion of information on somatic events or tumor 'genotype' will improve risk discrimination and prediction model calibration for individual ER-/ESBC patients for recurrence, distant metastasis, treatment response, and overall survival. Secondarily, we hypothesize that the pattern of somatic events in ER-/ESBC will differ by epidemiological factors (race/ethnicity, age of onset, screening behaviors) providing important public health information. Three specific aims encompass the validation and refinement of prognostic/predictive models based on somatic events for ER-/ESBC considering population structure. In aim 1, we will validate our current model as a fixed model in three independent sample sets for prognostication. In aim 2, we will take advantage of advanced methods for variable selection to evaluate whether or not we can improve model accuracy by considering interactions between somatic events and clinical factors. In aim 3, we will conduct comparative analyses of the models to assess overlap in information content, prognostic accuracy. We will explore the models for the ability to predict response to contemporary treatment with and without inclusion of HER2+ cancers including taxanes and HER2-targeted therapy. The primary translational goal of this project is to validate and refine our prognostic CNI model for ER-/ESBC to reflect current therapeutic protocols. A second translational goal is to assess the performance of our CNI prognostic model(s) in predicting treatment response. Importantly, we propose novel methods for variable selection that allow consideration of the joint effects of somatic events, epidemiologic factors, and treatment on patient outcomes that can be generalized to other marker discovery efforts.

ABSTRACT Flood waters from Hurricane Harvey (HH) damaged or destroyed more than 100,000 homes in the Houston area when over 50 inches of rain and flooding occurred. A dozen Superfund sites and several chemical/petroleum facilities were also involved in uncontrolled releases into the environment. Individuals and communities expressed environmental health concerns and reached out to us for assistance. In response, we formed a multi-institutional team with expertise relevant to NIEHS disaster research response (DR2) goals. With some institutional support we mobilized our team and developed study protocols, obtained IRB approvals with bi-lingual consents, and moved into the field within the 30-day window. We administered more than 150 health surveys, deployed equal number of wristbands, and collected more than 450 oral, nasal, and fecal biosamples, from individuals in 3 flooded communities. Based on our experience, we are confident that we can increase enrollment to 300 individuals complete with 6- and 12-month post-Harvey data. We hypothesize that individual- and neighborhood-level factors such as social support, access to resources, socioeconomic position (SEP), and proximity to point sources of contamination will affect health impact. We also hypothesize that personal environmental exposures to mold and chemicals will increase the health risks impacted by HH. We propose the following aims: Aim 1: To develop efficient methods for disaster epidemiology actions. We will conduct health assessments to identify the environmental health impact from HH at the individual and community level. Our overall goal is to develop and administer health risk assessments and exposure to flood waters in order to improve disaster research response (DR2) tools. These tools will be critical to optimize response rates, exposure measurements, and health assessments at 6 &12 months post-HH. Aim 2: To apply community-engaged research approaches to synthesize and disseminate findings and obtain resident feedback at 3 time points to inform study changes and provide the framework for the environmental health action plans for each neighborhood. These include recommendations for resource reallocation and tailored outreach programs to mitigate Harvey-related consequences. Aim 3: Evaluate the impact of Harvey-related exposures on short- and long-term health outcomes. Impact: Overall goal is to minimize the adverse environmental health effects of HH survivors and develop DR2 tools for improving rapid responses to other natural disasters in large urban centers.

ABSTRACT Genetic susceptibility plays a significant role in glioma development. An individual with two or more first- and/or second-degree affected relatives has a two-fold increased risk of the disease. We were the first to suggest mutations in POT1 (Protection of Telomeres 1) as causative in familial glioma (FG). We have now established the presence of POT1 mutations in 5 different families, providing the strongest evidence of its role in glioma. However, we do not yet have direct functional evidence that loss of POT1 is causal in glioma leaving few options for carrier surveillance or potential treatment targets. We are currently able to explain the genetic basis of glioma in up to 12% of our families, using highly stringent criteria for calling a mutation deleterious and causal. In contrast, the majority of our families remain unexplained though several candidate genes have emerged as `suspects of interest (SOIs)'. We propose a data-driven, knowledge-based, computational approach to guide candidate gene selection for functional characterization. In order to further our efforts to explain the genetic basis of FG we propose two specific aims to: Identify new gene candidates that may cause FG through WGS (Aim 1). We will identify SNVs, small indels, and structural variants in both coding and noncoding regions of the genome, intensively annotate those variants using more than 50 data sources, and we will rank these variants using multiple criteria based on their likelihood to cause disease. In addition to the 270 FG cases (from 203 FG families) with sequence data already available, we will also sequence an additional 100 cases (from 100 families) already collected in our Glioma International Case-Control Study with a reported family history using Gliogene criteria, and 200 newly recruited cases (from 100 families) with a strong family history of glioma to enhance our discovery. ). We will molecularly characterize tumor samples when available to enable analysis of our cohort by tumor subtype. The second aim is to functionally validate SOIs to include: A) POT1 mutations identified in additional families and B) newly discovered FG susceptibility genes (SOIs) from Aim 1 using our novel experimental mouse stem cell spheres and mouse models of gliomagenesis.To determine the functional contributions of POT1 and novel mutations identified in our WGS studies, we will evaluate these genes in glioma mouse models using CRISPR gene editing technology. This study has the strong potential for delineating the genetic basis of glioma for genetic testing of high-risk families; success will offer insight on the underlying biology of glioma for future work on early detection and targeted treatment.

ABSTRACT Parent grant: Genetic susceptibility plays a significant role in glioma development. An individual with two or more first- and/or second-degree affected relatives has a two-fold increased risk of the disease. We were the first to suggest mutations in POT1 (Protection of Telomeres 1) as causative in familial glioma (FG). We have now established the presence of POT1 mutations in 5 different families, providing the strongest evidence of its role in glioma. However, we do not yet have direct functional evidence that loss of POT1 is causal in glioma leaving few options for carrier surveillance or potential treatment targets. We are currently able to explain the genetic basis of glioma in up to 12% of our families, using highly stringent criteria for calling a mutation deleterious and causal. In contrast, the majority of our families remain unexplained though several candidate genes have emerged as ?suspects of interest (SOIs)?. We propose a data-driven, knowledge-based, computational approach to guide candidate gene selection for functional characterization. In order to further our efforts to explain the genetic basis of FG we propose two specific aims to: Identify new gene candidates that may cause FG through WGS (Aim 1). We will identify SNVs, small indels, and structural variants in both coding and noncoding regions of the genome, intensively annotate those variants using more than 50 data sources, and we will rank these variants using multiple criteria based on their likelihood to cause disease. In addition to the 270 FG cases (from 203 FG families) with sequence data already available, we will also sequence an additional 100 cases (from 100 families) already collected in our Glioma International Case-Control Study with a reported family history using Gliogene criteria, and 200 newly recruited cases (from 100 families) with a strong family history of glioma to enhance our discovery, and 150 familial glioma tumor samples. The second aim is to functionally validate SOIs to include: A) POT1 mutations and B) newly discovered FG susceptibility genes (SOIs) from Aim 1 using a novel experimental mouse model of gliomagenesis. To determine the functional contributions of POT1 and novel mutations identified in our WGS studies, we will evaluate these genes in glioma mouse models using CRISPR gene editing technology. This study has the potential for future genetic testing in high-risk families, success will offer much needed insight on the underlying biology and etiology of glioma in both familial and sporadic cases. Supplement: The FDA?s expanded access program (EAP)?sometimes called ?compassionate use? for individual requests?is a potential option for patients with immediate, life-threatening conditions when no comparable or satisfactory options are available to gain access to experimental medicines outside of clinical trials. Yet we know little about how oncologists and patients navigate EAP requests, their understanding of federal policy, or how they manage informed consent after a request has been approved. There is no empirically-derived ethical guidance for oncologists considering experimental drugs as treatment options for their patients. We propose to develop and offer guidance to neuro-oncologists through a stepwise approach of empirical research and normative ethics. First, we will conduct individual, in-depth interviews through family-physician dyads, and ask about their experiences in discussing options of providing an experimental drug through compassionate use or expanded access. Family cohorts will include at least two living glioma cases, and will be identified through recruitment in the Discovery, Biology and Risk of Inherited Variants in Glioma (GLIOGENE) parent grant. Then, we will combine ethical principles and paradigmatic cases from the literature with the themes and cases derived from interviews to identify salient ethical areas of concern. Once identified, we will synthesize case scenarios and questions for normative discussion with investigators on the parent grant and three practicing neuro-oncologists. This exercise will be used to generate a set of clinically-relevant recommendations and decision tools for practitioners.

ABSTRACT Despite considerable molecular heterogeneity, all diffuse gliomas are incurable at present, signaling an urgent need for improved understanding of glioma biology. Even with recent advances, functional and clinically relevant correlations between somatic and germline genetics in glioma remain virtually nonexistent. In particular, the extent to which any or all glioma risk alleles drive the development of somatically designated glioma subclasses is largely unknown. This proposal builds on our extensive collaborative experience with the germline characterization of glioma, and leverages an existing repository of sporadic glioma patients accrued from two of the nation's largest cancer centers (MD Anderson (MDA) and Memorial Sloan Kettering (MSK)). These resources ideally position us to examine the interaction of germline and somatic genetics in glioma evolution. Most existing large-scale profiling efforts, including those of the Cancer Genome Atlas (TCGA), lack extensive information on disease treatment and progression along with genome-wide germline polymorphism data. We propose to molecularly profile 1,350 cases from a set of over 2,000 glioma patients treated at our institutions with: 1) readily available tumor tissue; 2) stored germline DNA; and 3) detailed clinical data including treatment information, disease progression, and survival. Importantly, we have already obtained high- density germline single nucleotide polymorphism (SNP) data for these patients using the Illumina OncoArray platform. We now propose to conduct focused and comprehensive molecular profiling on tumor tissue ascertained from this patient cohort to correlate both glioma subclass and patterns of somatic alterations with germline risk alleles and clinical outcome measures. Our overall hypothesis is that glioma susceptibility alleles will correlate with distinct sets of somatic alterations and predict disease evolution and outcomes both between and within molecularly designated glioma subclasses. We propose the following specific aims: Aim 1. Determine the spectrum of germline susceptibility alleles associated with molecularly and clinically distinct glioma subclasses. Aim 2. Refine risk stratification by correlating germline susceptibility alleles with specific somatic alterations within individual glioma subclasses. Our findings should lead to significant innovation in how gliomas are conceptualized, from the perspectives for both molecular pathogenesis and patient management. Robust associations between germline genetics, molecular subclass, and somatic alterations will provide novel insights into how distinct tumor subtypes arise in specific patient populations and even point toward strategies for therapeutic development by identifying early-stage, pre-transformative sequences of molecular events. Moreover, these data could also enable targeted surveillance and early detection in at-risk populations, a management strategy that remains strikingly underexplored for glioma patients and, accordingly, has the potential to be paradigm-shifting.

CANCER PREVENTION AND POPULATION SCIENCES (CPPS) PROGRAM PROJECT SUMMARY The mission of the Cancer Prevention and Population Sciences (CPPS) Program is to conduct exceptional translational research in cancer prevention and control. CPPS achieves this goal by promoting and facilitating innovative, multi-disciplinary scientific interactions focused on reducing cancer incidence, morbidity and mortality, and improving cancer outcomes. CPPS membership is comprised of nationally and internationally recognized scientists with expertise that spans the cancer continuum. The setting of CPPS' research priorities includes promoting scientific inquiry directed at addressing the cancer prevention and control needs of the people and communities of the Houston, Texas Metropolitan Statistical Area (MSA), our catchment area (CA). This includes special emphasis to facilitate the conduct of research that addresses the cancer health disparities specific to our CA. Following extensive strategic planning and exceptional targeted recruitments, we have focused and expanded our research efforts to reflect our expertise and the urgent needs of our CA into 3 Specific Aims as foundational to CPPS research. Aim 1 (Cancer Etiology and Primary Prevention) encompasses our scientific breadth and depth in the genetic and environmental causes of childhood and adult cancers and aims to advance risk assessment and guide primary prevention efforts. Aim 2 (Secondary Prevention and Cancer Outcomes Research) combines our outstanding secondary prevention and outcomes research to advance early detection, predictive, prognostic, behavioral, and surgical measures of cancer outcomes. Included are innovative behavioral interventions to reduce the negative consequences of cancer in our CA via individual, family, and community engagement. CPPS is also the programmatic home for national experts in quantitative methods and risk modeling (Aim 3). Their work integrates biomedical data and computational models to enable precision-based cancer prevention and improve cancer outcomes. CPPS has 35 Research and 14 Clinical members representing multiple scientific disciplines. Many of our members have research interests spanning 2, or even all 3 Specific Aims. CPPS members have been successful in obtaining independent funding to support their research: 100% of our Research members have peer-reviewed cancer-related research grants or contracts, resulting in a research portfolio (annual direct) totaling $17.5 million, of which $16.2 million is peer reviewed, $4.0 million is from NCI, and $9.6 million from other peer reviewed funding with $7.1 of that from CPRIT. During the current funding period, CPPS Program members published 1208 papers, of which 26% were intra-programmatic, 21% were inter-programmatic, and 40% were inter-institutional. About 37% of the publications are in journals with an impact factor above 5, and 13% are above 10. Our leaders are nationally and internationally recognized, and our members strive to train the next generation of cancer prevention researchers.