IMPH Research in Cancer

Breast Cancer

Consortium Study to Identify Breast Cancer Susceptibility Loci 
Epidemiology of Molecular Risk Factors for Breast Cancer 
Genetic Factors for Breast Cancer: A Genome Wide Study 
Genome Sequencing to Identify Novel Genetic Factors for Breast Cancer Risk 
Genome-Wide Copy Number Variation and Breast Cancer Risk 
A Multi-Center Epidemiologic Study of Breast Cancer in African-American Women 
Shanghai Breast Cancer Survival Study (SBCSS) 
Shanghai Breast Cancer Study (SBCS) 
Vitamin D Status, Gene Polymorphism and Breast Cancer Progression/Prognosis

Colorectal Cancer

Dietary Calcium and Magnesium, Genetics, and Colorectal Adenoma 
Fatty Acid Desaturase Activity, Fish Oil and Colorectal Cancer Chemoprevention 
Genetic and Epigenetic Markers for Colorectal Adenoma Recurrence 
Inflammatory Biomarkers and Colorectal Cancer Risk 
Long-Chain Fatty Acids, Oxidative Stress and Colorectal Neoplasm Risk 
Personalized Prevention of Colorectal Cancer

Gastric Cancer

Helicobacter Pylori Blood Biomarker for Gastric Cancer Risk in East Asia 
Long-Term Follow-Up of Cohorts Previously Treated for H. Pylori Infection

Kidney Cancer

Molecularanalysis of Ethnic Variations in Wilms' Tumor

Lung Cancer

Exome Sequencing to Identify Novel Genetic Factors for Lung Cancer in Nonsmokers 
Immunobiomarkers for Screening and Early Detection of Lung Cancer 
Prognosis of Lung Cancer: Heredity or Environment? 
Regional Variation of FDG-PET Scans to Diagnose Lung Cancer

Urogenital Cancer

Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer 
Modifiable Risk Factors for Fatal Prostate Cancer: A Prospective Study in Asia 
The Quality of Care in Evaluating Patients Suspected of Having Bladder Cancer 
Shanghai Endometrial Cancer Study (SECS) 
Trends in Surveillance for Localized Prostate Cancer and Barriers to Its Use

Other/Non-Specific

Cancer Mortality Among Military Participants at US Nuclear Weapons Tests 
Cancer Risk Reduction and Diet: A Cohort Study of Women 
Parent-Child Communication About Cancer 
Shanghai Men's Health Study 
Telephone Counseling - Caregivers for Children with Cancer


Breast Cancer

Consortium Study to Identify Breast Cancer Susceptibility Loci

Breast cancer is the most common malignancy among women in the United States and many other parts of the world. Genetic factors play an important role in the etiology of breast cancer. Recent genome-wide association studies (GWAS) have identified multiple genetic susceptibility loci for breast cancer. However, these newly- identified genetic factors, along with high-penetrance susceptibility genes reported previously (such as the BRCA1 and BRCA2 genes), explain only a small fraction of genetic variation for breast cancer. In this application, we propose two novel projects that will significantly advance our understanding of the genetic basis for breast cancer and the methodology used for genetic epidemiologic research. The first project is a GWAS based on the newly-established Asia Breast Cancer Consortium and will include over 27,000 cases and controls recruited from 11 studies conducted among Asian women living in various parts of the world. Through analyzing GWA scan data from 3,500 cases and 3,500 controls, we will identify and evaluate the top 8,500 SNPs in an independent set of 3,500 cases and 3,500 controls and then validate approximately the top 100 SNPs in 6,700 cases and 6,700 controls. In the second project, we will sequence eight GWAS-mapped regions in 3,000 cases and 3,000 controls with the goal of identifying additional genetic risk variants, particularly low- frequency variants, for breast cancer in these regions. We will select up to 180 promising SNPs for replication in an independent set of 2,500 cases and 2,500 controls and then select the top 30 SNPs for further evaluation in another independent set of 2,500 cases and 2,500 controls. This is the only well-powered GWAS conducted in Asian women, and thus is the only existing GWAS capable of discovering genetic variants for breast cancer that are unlikely or more difficult to identify in other GWAS. The proposed sequencing project represents a new model for future genetic association studies. These two newly-proposed projects will be built upon several well- conducted, NCI-funded studies to generate substantial novel information that will help to not only understand breast cancer biology and genetics, but also to improve risk assessment models and identify high-risk women for cost-efficient prevention of breast cancer. Read more.

Funding Source: NIH/NCI 
PI: Wei Zheng

Epidemiology of Molecular Risk Factors for Breast Cancer

We propose to study molecular, genetic and histologic markers of breast cancer risk in women with benign breast disease. We will use a unique cohort of such women to pursue the following Specific Aims: 1. To determine the effects on breast cancer risk of the 6A polymorphism of the transforming growth factor beta type I receptor (T(3R-I). We will also study how expression levels of the TpR-l, and its principal substrate Smad2, affect breast cancer risk in women with proliferative breast lesions. 2. To evaluate the combined influence on breast cancer risk of benign breast lesions and 424 single nucleotide polymorphisms (SNPs) from 86 candidate genes involved in estrogen biosynthesis, function and oxidative metabolism. Cross-sectional analyses will also be performed that examine how specific genotypes are correlated with different types of benign breast disease. These studies will explore potential influences on breast cancer risk of ER-mediated cell proliferation or the generation of oxidative estrogen metabolites that may damage DNA. 3. To expand the size and length of follow-up of our study cohort. The research will be based on a large retrospective cohort study of women who underwent benign breast biopsy between 1954 and 1995. Paraffin-embedded tissue from the entry biopsy of these patients is available. By the end of this project we estimate that we will have observed 890 breast cancer cases during follow-up among the 11,547 members of this cohort. We will conduct a series of nested case- control studies on these women. The 890 breast cancer cases will be matched by race, age and year of their benign breast biopsy to 1780 controls (1:2 ratio). Genotyping will be performed using the Illumina GoldenGate assay while immunohistochemical methods will be used to identify abnormal protein expression. We will use supervised principal component analyses to assess the individual and combined effects of molecular, histologic and epidemiologic variables on breast cancer risk. A false discovery rate (FDR) approach will be used to identify promising findings that will be subject to validation in other data sets. This project takes advantage of an established cohort of women with biopsy-confirmed benign breast disease. Clinical, demographic, and histologic information, as well as genomic DNA is uniformly available. This project will permit the combination of modern methods in molecular biology, genetics, pathology and epidemiology to assess potentially powerful new markers of breast cancer progression and prognosis. We expect that it will lead to important advances in the prevention and treatment of this disease. Read more.

Funding Source: NIH/NCI 
PI: William Dupont

Genetic Factors for Breast Cancer: A Genome Wide Study

Breast cancer is the most common malignancy among women in many parts of the world. Genetic factors play an important role in the etiology of breast cancer. However, to date, only a few breast cancer susceptibility genes have been identified, and they explain only a very small fraction of breast cancer cases in the general population. A large number of candidate-gene studies have been conducted over the past 10 years. These studies, however, are clearly inadequate to fully uncover the genetic basis of breast cancer. With recent significant advances in high-throughput genotyping technologies, it has become feasible to conduct genome-wide association (GWA) studies to systematically evaluate genetic risk factors for breast cancer. The multi-phase GWA study proposed in this application will be built upon the resources established in two large, on-going studies funded by NCI, the Shanghai Breast Cancer Study (R01 CA64277) a population-based case-control study, and the Shanghai Women's Health Study (RO1 CA70867) a population-based prospective cohort study. Approximately 8,000 breast cancer cases and controls will be included in this proposed study. In the first phase of the study, we will conduct a GWA scan in 1,000 cases and 1,000 controls using the Illumina HumanHap550 BeadChip. We will then select the 10,600 most promising SNPs for a validation study in an independent sample of 1500 cases and 1500 controls. All promising SNPs will be further validated using data from 1000 cases and 2000 controls selected from the prospective Shanghai Women's Health Study. The parent projects of this newly-proposed study have been exceptionally well-conducted with a strong methodology. The feasibility and utility of the proposed study have been clearly demonstrated in our pilot study. The study is unique and has many unique features that facilitate a rigorous evaluation of breast cancer genetic factors. The results from the study will be valuable in identifying high risk women for primary and secondary prevention of breast cancer. Read more.

Funding Source: NIH/NCI 
PI: Wei Zheng

Genome Sequencing to Identify Novel Genetic Factors for Breast Cancer Risk

Genetic factors play an important role in the etiology of both sporadic and familial breast cancer, a complex, multifactorial disease. Known genetic risk factors identified to date, including both rare high- penetrance genes and common low-penetrance variants, explain only about 28% of heritability for breast cancer. Recently emerged evidence strongly suggests that most of the heritable risk for breast cancer and other complex diseases may be due to a large number of low-frequency moderate-penetrance genes that are difficult to identify using conventional family-based linkage analyses and genome-wide association studies (GWAS). In this application, we propose a novel study to systematically search for the entire coding region in the human genome to identify new genetic susceptibility factors for breast cancer. This study will be built upon the resources we established in three NCI-funded large epidemiologic studies conducted among women in Shanghai, in which genomic DNA samples and comprehensive clinical and epidemiological data were collected from nearly 8,000 breast cancer cases and a large number of community controls. Specifically, we propose to sequence the whole exome for 600 genetically-enriched breast cancer cases and 600 controls (Stage 1). Using data from Stage 1 and those from the 1000 Genomes Project, we will select approximately 350 promising genes for replication through variant genotyping (Stage 2) in an independent set of cases and controls. Approximately 20 genes will be selected for Stage 3 replication from those that show promising association in Stage 2 but require additional evaluation to either confirm or reject the hypotheses. To our knowledge, this is the first large association study for breast cancer using whole exome sequencing. With strong methodology and the use of novel technology and study design, the proposed study will identify novel genes and pathways that will significantly improve our understanding of breast cancer genetics and biology. Newly identified genes, particularly those with a substantial effect size, could serve as targets for novel cancer treatment and be used for cancer screening and risk assessment. Read more.

Funding Source: NIH/NCI 
PI: Wei Zheng

Genome-Wide Copy Number Variation and Breast Cancer Risk

This is an expedited resubmission of a grant application, a genome-wide copy number variation study of breast cancer (R01CA137013). Breast cancer is the most common malignancy among women in the United States and many other parts of the world. Genetic factors play an important role in the etiology of breast cancer. Single nucleotide polymorphisms (SNPs) were thought to be the predominant form of genomic variation and were commonly used as genetic markers in genetic association studies. Over 100 candidate genes have been investigated in relation to breast cancer risk, however, only a few of them, have been replicated. Recently, genome wide association (GWA) studies have identified novel genetic risk factors for this common malignancy. However, it is unlikely that SNP markers could entirely explain genetic variation for breast cancer as other important genetic variations exist. Recently, large DNA fragment duplication and/or deletion, termed as copy number variation (CNV), has been shown to frequently occur in the human genome. CNVs account for more nucleotide variation than SNPs and they may be an unrecognized source of breast cancer genetic susceptibility. Strong associations between CNVs and human diseases are increasingly reported such as familial breast cancer, pancreatic cancer, prostate cancer, autism, etc. We propose to survey the entire human genome for CNVs associated with breast cancer. The multi-phase CNV GWA proposed in this application will be built upon the resources established in three large, on-going studies funded by NCI, a recently supported `Genome-wide association study for breast cancer (R01 CA124558), the Shanghai Breast Cancer Study (R01 CA64277) - a population-based case-control study, and the Shanghai Women's Health Study (RO1 CA70867) - a population-based prospective cohort study. In Phase I, we will conduct a genome wide CNV scan in 1,353 cases and 1,349 controls. We have recently completed Stage I genotyping for 1,353 cases and 1,349 controls by using Affymetrix 6.0 array as part of an existing SNP GWA study (RO1 CA124558). Intensity data from around one million SNPs and one million non-polymorphic probes included in the array for these 2,702 samples will be available for this proposed study to call CNVs. Associations of these CNVs with breast cancer risk will be investigated. In Phase II, the 500 most promising CNVs will be selected for validation in an independent sample of 1,500 cases and 1,500 controls. In Phase III, the most promising 30 CNVs will be further validated in 1,000 cases and 2,000 controls selected from the prospective SWHS. The parent projects of this newly-proposed study have been exceptionally well-conducted with a strong methodology. The study is unique and has many unique features that facilitate a rigorous evaluation of breast cancer genetic factors. The results from the study will be valuable in identifying high risk women for primary and secondary prevention of breast cancer. Because Phase I data and specimen collection are supported by the existing studies and the use of a multi-phase study design, this project will be very efficient. Read more.

Funding Source: NIH/NCI 
PI: Jirong Long

A Multi-Center Epidemiologic Study of Breast Cancer in African-American Women

Breast cancer, the most frequently diagnosed cancer among women, is the second leading cause of cancer death. Current breast cancer mortality rates in the United States, including Tennessee and South Carolina are considerably higher among African Americans than among Caucasians. Little is understood about the etiology of breast cancer nor do we know what factors might explain why African American women tend to be diagnosed with more aggressive disease than Caucasian women. Recent genome-wide association studies (GWAS) have opened opportunities to investigate breast cancer etiology. Approximately 20 susceptibility loci have been identified from the GWAS conducted among women of Chinese and European ancestry. Recent reports found breast cancer risk consistently increased among Caucasian and Chinese women with an increasing number of some of these loci. During the three years of this proposed project we anticipate an additional 15 to 20 susceptibility loci for breast cancer will be identified through GWAS, including our study conducted among Asian women. The relevance of these loci to African American women remains under-investigated, and data from our recent pilot investigation have showed that the majority of the initially-reported genetic risk variants identified in Caucasian and Chinese cannot be directly replicated among African Americans. The purpose of this proposed project is to investigate approximately 21 GWAS-identified loci to discover genetic risk variants relevant for African American women. In addition, we will establish a breast cancer risk assessment model that incorporates clinical and genetic factors to better identify high-risk African American women since the only existing breast cancer risk assessment model for African Americans does not include genetic markers. This full project will be supported by the Cancer Outreach Core. Read more.

Funding Source: NIH/NCI 
PI: Wei Zheng

Shanghai Breast Cancer Survival Study (SBCSS)

The Shanghai Breast Cancer Survival Study (SBCSS) is a population-based cohort study of 5,042 women who were diagnosed with primary breast cancer between age 25 and 74 years. Participants were identified from the population-based Shanghai Cancer Registry and recruited to the study approximately 6 months after cancer diagnosis between April 1, 2002 and December 31, 2006 (response rate: 80.1%). The study has completed multiple in-person interviews administered at 6, 18, 36, and 60 months after diagnosis, which collected information on cancer diagnosis, treatment, progression, lifestyle factors, and quality of life. The 10-year post-diagnosis survey is ongoing. Medical charts were abstracted to verify cancer diagnosis and initial treatments; tumor slides were collected. The vast majority of study participants (96%) provided DNA samples to the study. The SBCSS has published many high impact papers addressing the influences of lifestyle, psychosocial, and genetic factors on cancer outcomes and quality of life among survivors.

PI: Xiao Ou Shu

Shanghai Breast Cancer Study (SBCS)

The Shanghai Breast Cancer Study (SBCS) is a population-based, case-control study funded by NCI since 1996 to investigate lifestyle factors, genetic susceptibility, and other biomarkers associated with breast cancer risk and survival. Included in the study are approximately 3,500 breast cancer cases aged between 25 and 70 years and an equal number of community controls recruited among female residents of Shanghai, China. In addition to in-person interview data, biological samples were collected from study participants. The resources from the study have supported multiple research and training grants and provided opportunities for many graduate students and postdoctoral fellows to conduct research. To date, over 150 research papers have been published from the SBCS addressing a wide range of significant issues related to dietary, lifestyle, environmental, and genetic contributions to breast cancer risk and prognosis.. Read more.

Funding Source: NIH/NCI 
PI: Xiao Ou Shu

Vitamin D Status, Gene Polymorphism and Breast Cancer Progression/Prognosis

The association of vitamin D deficiency, or low levels of circulating vitamin D, with increased risk for cancers, including breast cancer (BC), has received extensive attention. Experimental studies have shown that vitamin D has many anti-cancer properties, including anti-proliferative, anti-angiogenic, pro-apoptotic, and immunomodulation effects. Less attention has been paid to the role of vitamin D deficiency on BC prognosis and survival outcomes. Studies have shown that circulating vitamin D and polymorphisms in genes regulating vitamin D metabolism and signaling are both associated with BC risk, however, we know less about associations with BC prognosis. A few studies have linked low circulating vitamin D levels with prognostic factors for BC outcome, such as advanced disease or metastasis. Only one study directly evaluated the association between vitamin D status and BC survival, and no study has investigated this association in relation to vitamin D polymorphisms. We propose to address these questions in a prospective cohort of Chinese women with BC and test three hypotheses: 1) Circulating vitamin D level will predict BC progression and prognosis (recurrence, metastasis, overall or disease-specific death) after cancer treatment; 2) Genetic polymorphisms in vitamin D metabolism and signaling pathway genes affect circulating vitamin D level and its bioavailability in BC survivors; and 3) Circulating vitamin D and vitamin D gene polymorphisms together affect BC progression and prognosis. The proposed study will use resources from the Shanghai Breast Cancer Survival Study (SBCSS) and the Shanghai Breast Cancer Genome-Wide Association Study (GWAS). We will include 2,073 women newly-diagnosed with invasive BC and aged 20-74 years at the time of diagnosis, who have both blood samples for assessing circulating 25(OH)D and genotype information. Information on cancer diagnosis and conventional treatment, breast cancer recurrence, and causes of death will be verified through medical chart reviews. We will evaluate the effect of circulating vitamin D level and its combined effect with polymorphisms in the vitamin D pathway genes on BC progression and prognosis using appropriate statistical methods and controlling for known prognostic factors. The Mendelian Randomization (MR) method will be used to re-assess this association. Breast cancer survivorship is recognized as a critical component of cancer- related public health programs. The proposed study aims to fill a gap in our knowledge by evaluating the associations of circulating vitamin D and vitamin D pathway gene polymorphisms with breast cancer prognosis. This study will expand our understanding of the role of "Vitamin D status" and related pathway gene polymorphisms in BC prognosis. The study results could potentially lead to the development of new preventive and therapeutic strategies that can be applied to BC patients. In addition, the research could help determine if chemoprevention clinical trials with vitamin D should be considered for BC patients at high-risk for disease progression. Read more.

Funding Source: NIH/NCI 
PI: Xiao Ou Shu


Colorectal Cancer

Dietary Calcium and Magnesium, Genetics, and Colorectal Adenoma

Results have been inconsistent on the protective effect of calcium and magensium intake on colorectal cancer and adenoma. We found very recently in the Tennessee Colorectal Polyp Study (TCPS; P50CA95103) that the associations between intake of calcium or magnesium and risk of colorectal adenoma and hyperplastic polyps may differ by the common Thr1482Ile polymorphism of the TRPM7 gene, a gene involved in calcium and magnesium re(absorption) and homeostasis. Our finding may partially explain the inconsistency in previous studies on calcium and magnesium. In addition, we found that the ratio of calcium to magnesium intake significantly interacted with the Thr1482Ile polymorphism in relation to both adenomatous and hyperplastic polyps. In response to PAR-07-377, we propose a clinical epidemiologic study, based on our promising data, to test several novel hypotheses regarding gene-nutrition interactions using data and biological samples collected as part of the TCPS, a large on-going molecular epidemiologic case-control study of colorectal adenoma. Specifically, we will 1) confirm our pilot finding in an independent set; and 2) conduct a two-phase study to evaluate the relationships between other polymorphisms in 14 candidate genes involved in magnesium and calcium (re)absorption, regulation and balance and risk of colorectal adenoma; and investigate whether the associations between intake of calcium and magnesium or the ratio of calcium to magnesium intake and risk of colorectal adenoma differs by the genotypes or haplotypes in the 14 genes. The first phase of the study will include 1200 cases and 2400 controls to comprehensively investigate promising polymorphisms and their interactions with nutrients. All promising variants will be re-evaluated in an independent set of 800 cases and 1600 controls to validate the identified associations or nutrient-gene interactions. The proposed two-phase study design will allow us to effectively address potential false positive findings (Type I error), one of the most serious concerns regarding association studies of low-penetrance genetic factors and will allow us to enhance the statistical power for evaluation of gene-gene and gene-nutrition interactions. The results from our study will help to identify people at a high risk of colorectal adenoma and to develop personalized strategies of dietary changes or nutritional fortication to prevent occurrence of colorectal adenoma, and, thus, colorectal cancer. In the general US population, 1 in 18 individuals will develop colorectal cancer over their lifetime and forty percent will die within five years of diagnosis, mainly due to diagnosis at a late stage. Therefore, development of primary preventive strategies for colorectal cancer is very critical. The results from our study will help to identify people at a high risk of colorectal adenoma and to develop personalized strategies to prevent occurrence of colorectal adenoma, and, thus, colorectal cancer through dietary changes or nutritional fortification. Read more.

Funding Source: NIH/NCI 
PI: Qi Dai

Fatty Acid Desaturase Activity, Fish Oil and Colorectal Cancer Chemoprevention

Observational studies have suggested that the n-3 polyunsaturated fatty acids, eicosapentanoic acid and docosahexanoic acid, may reduce the risk of colorectal cancer. Our hypothesis is that individuals with lower activity of fatty acid desaturase-1(FADS1) will derive greater benefit from fish oil supplementation than individuals with higher FADS1 activity due to lower production of endogenous arachidonic acid. To test this hypothesis we will recruit 150 participants and conduct a 6-month double blind 3 X 2 factorial randomized controlled trial. Our first factor will be FADS1 genotype (GG, GT, and TT) and our second factor will be fish oil supplementation (fish oil versus placebo). Our specific aims include: 1) to determine the efficacy of fish oil supplements on rectal epithelial cell proliferation indexes and markers of rectal crypt apoptosis, and 2) to determine the effect of genetically-determined fatty acid desaturase 1 activity on fish oil supplementation for colorectal cancer chemoprevention. Read more.

Funding Source: NIH/NCI
PI: Harvey Murff

Genetic and Epigenetic Markers for Colorectal Adenoma Recurrence

Most colorectal cancers arise from adenomatous polyps, and a large proportion of adenoma patients develop new (metachronous) adenomas after their initial polypectomy. There is considerable controversy regarding an appropriate surveillance interval for adenoma patients after removal of their initial adenomas. We propose to conduct a follow-up study to evaluate both genetic susceptibility risk variants and tumor markers in relation to the risk of metachronous adenomas. The proposed study will be conducted in approximately 1,500 patients diagnosed with either multiple adenomas or a pathologically advanced adenoma. These patients have already been recruited in our previous studies. In addition to clinical and epidemiologic data, we have already obtained germline DNA samples, fresh-frozen polyp tissues, and formalin-fixed, paraffin-embedded (FFPE) from a large proportion of study participants. In this study, we propose to: 1) follow up with study participants to collect information related to follow-up exams and adenoma recurrence and to obtain FFPE blocks of initial adenomas from the remaining patients whose samples have not yet been collected 2) evaluate the association of genetic and epigenetic tumor markers with recurrent adenomas 3) evaluate the association of adenoma recurrence with GWAS-identified genetic variants 4) establish a risk-assessment model and evaluate the utility of genetic susceptibility and tumor markers alone and in combination with known predictors (such as pathologic features of initial adenomas) in predicting the risk of adenoma recurrence. This proposed study will provide critical information that is valuable to identify high-risk adenoma patients for intensive follow-up programs and chemoprevention. Read more.

Funding Source: NIH/NCI 
PI: Harvey Murff

Inflammatory Biomarkers and Colorectal Cancer Risk

This is a nested case-control study within the Shanghai Women’s Health Study, to evaluate the association of colorectal cancer (CRC) risk with measures of several key products of chronic inflammation and oxidative stress, and with related genetic markers. Urine samples collected at baseline were measured for PGE2 metabolite, F2-isoprostanes and its major metabolite using LC/GC MS-based methods. Baseline blood samples were measured for CRP, proinflammatory cytokines and their soluble receptors. Genomic DNA was assayed for polymorphisms in genes involved in redox balance and PGE2 production, metabolism and signaling. This study may contribute to further understanding the role of inflammation and oxidative stress in the etiology of CRC and to the development of new strategies for the assessment of CRC risk and prevention. Read more.

Funding Source: NIH/NCI
PI: Gong Yang

Long-Chain Fatty Acids, Oxidative Stress and Colorectal Neoplasm Risk

Chronic inflammation is contributors to colorectal carcinogenesis. Eicosapentanoic acid exhibits anti- inflammatory actions while arachidonic acid, an omega-6 polyunsaturated fatty acid, appears pro- inflammatory. Our overarching hypothesis is that individuals with increased dietary ratios of arachidonic acid to eicosapentanoic acid will have an increased risk of colorectal adenoma and that this increased risk is mediated through pro-inflammatory eicosanoids and increased oxidative stress. The specific aims of this research proposal are: 1) To test the hypothesis that a greater erythrocyte phospholipid membrane arachidonic acid to eicosapentanoic acid ratio is associated with an increased risk of colorectal adenomas; 2) To test the hypothesis that an increase in urinary levels of F2-isoprostanes is associated with an increase risk of colorectal adenomas and; 3) To test the hypothesis that a greater arachidonic acid to eicosapentanoic acid ratio is associated with increased levels of prostaglandin E2 and urinary F2-isoprostanes. Read more.

Funding Source: NIH/NCI 
PI: Harvey Murff

Personalized Prevention of Colorectal Cancer

The original version of this application was previously submitted as a R21 application and received a score of 184. To appropriately address the reviewers' suggestions, we are newly submitting this proposal as a R01 application. High calcium intake and magnesium may protect against colorectal cancer and adenoma, however, results have been inconsistent. Although the mean magnesium intake in the US population is similar to East Asian populations with traditionally low risks of colorectal cancer, the ratio of calcium to magnesium is much higher in the US. We reported recently that magnesium intake is related to a significantly reduced risk of adenoma and hyperplasic polyps. This association primarily appeared among those with a low ratio of calcium to magnesium intakes. We have found similar results for calcium intake. The TRPM7 gene is critically involved in calcium and magnesium (re)absorption and homeostasis. We found that the common Thr1482Ile TRPM7 polymorphism significantly interacted with the calcium/magnesium intake ratio in relation to both adenomatous and hyperplasic polyps. Participants who carried at least one 1482Ile allele and who consumed diets with a high calcium/magnesium ratio were at a higher risk of adenoma and hyperplasic polyps than were participants who did not carry the polymorphism. We propose to conduct an intervention trial of 240 participants to investigate the efficacy of modulating the dietary ratio of calcium to magnesium to change markers directly related to tumorigenesis, including apoptosis biomarkers (e.g. TUNEL and Bax), COX-2 (inflammation), Ki-67 (proliferation index), and TRPM7/TRPM6 in colorectal mucosa as well as total erythrocyte magnesium and urinary excretion of prostaglandin E2 metabolite (PGE-M) as primary endpoints. The progressive resistance to apoptosis is one hallmark for almost all cancer types. The apoptosis index is a strong predictor of future adenoma occurrence. The resistance to apoptosis is accompanied by an elevation in COX-2 expression during tumorigenesis. We found in a population-based cohort study that urinary levels of prostaglandin E2 metabolite (PGE-M) were associated with a substantially increased risk of colon and rectal cancers. Urinary level of PGE- M was also elevated among participants with large adenomas compared to those who had either no or small polyps. The primary aims of this study are to conduct a randomized placebo-controlled intervention trial to test whether reducing the calcium to magnesium intake ratio through supplementation of magnesium has effects on the above-mentioned biomarkers. Furthermore, we will examine whether the effect of modulating dietary intake ratio of calcium to magnesium may be more pronounced among those who carry the 1482Ile allele (GA or AA) compared those who do not carry the 1482Ile (GG). If findings from the study are promising, we will propose to conduct a large-scale clinical trial using recurrence of flat, depressed, and polypoid colorectal adenomas or colorectal cancer as clinical endpoints. The results from our study may ultimately help to develop personalized strategies to prevent the occurrence of colorectal adenoma, and, thus, colorectal cancer. Read more.

Funding Source: NIH/NCI 
PI: Qi Dai


Gastric Cancer

Helicobacter Pylori Blood Biomarker for Gastric Cancer Risk in East Asia

Gastric cancer is the second most deadly cancer in the world, and incidence and mortality rates are highest in East Asia. Infection with Helicobacter pylori, the strongest known risk factor for gastric cancer, is also endemic throughout East Asia, but only a small percentage of infected individuals ever develop gastric cancer. Due to the high level of genetic variation among H. pylori isolates, it may be possible to identify risk markers tht could classify H. pylori-infected individuals into high- and low-risk groups, presenting a unique opportunity for cost- effective disease prevention. This is especially significant because H. pylor eradication has been found to effectively reduce gastric cancer incidence. Currently, however, there is no known biomarker that is feasibly assessed that can estimate a substantially significant increase in risk for gastric cancer. Recently, we performed a pilot study nested in a prospective Chinese cohort to identify potential H. pylori blood biomarkers. Utilizing novel H. pylori multiplex serology, we found that increasing number of sero-positive results to six H. pylori proteins (Omp, HP0305, HyuA, HpaA, CagA, and VacA) may be a novel biomarker panel for gastric cancer risk. We have found that this biomarker panel is significantly stronger at discriminating risk than evidence of the CagA protein alone, resulting in those individuals with antibodies to all six indicated H. pylori proteins having a three- to five-fold increase in risk of distal gastric cancer. Replication of these results in other populations, particularly other high-rsk East Asian populations who may be colonized by similar Asian strains, would enhance the possibility of utilizing these H. pylori blood biomarkers for gastric cancer screening. Thus, we have assembled a consortium of eight prospective cohort studies in the high gastric cancer-incidence populations of China, Japan, and Korea, to determine if we can replicate this novel biomarker panel for gastric cancer risk. We aim to: assess the association of H. pylori protein antibody levels in pre-diagnostic blood samples with gastric cancer risk in 2,000 distal gastric cancer cases and 2,000 controls in East Asia; determine if host factors of inflammation or susceptibility to inflammation aid in assessing gastric cancer risk; and build a predictive model for gastric cancer risk in East Asia that includes H. pylori blood biomarkers and enables us to categorize individuals into high and low-risk groups for gastric cancer, and then validate this model among individuals with both cancer and precancerous lesions in a high-risk population. This project is proposed in direct response to PA-11-158: Biomarkers of Infection-Associated Cancers (R01), for which applicants were invited to investigate the association of H. pylori and gastric cancer "to identify subpopulations of exposed individuals who are likely to develop cancer." Should we ascertain and validate a risk prediction model that predicts increased risk in high-incidence populations, we will create the opportunity to substantially increase prevention of this deadly cancer through targeted prevention strategies among H. pylori-infected individuals at highest risk, while also reducing unnecessary antibiotic use among those at low risk. Read more.

Funding Source: NIH/NCI
PI: Meira Epplein

Long-Term Follow-Up of Cohorts Previously Treated for H. Pylori Infection

While Helicobacter pylori is now established as a pivotal factor in gastric carcinogenesis, its mechanisms of action and timing in the premalignant process are the subject of research. This project builds upon a recently completed 12-year randomized chemoprevention trial in a high-risk region of Colombia. A significantly greater regression of premalignant lesions was observed in study participants who were treated and were cleared of H. pylori infection. Upon completion of the trial, participants who had not been in the ant\-H.pylori treatment arm were offered standard triple therapy. Quarterly contact has been maintained with trial participants, and this project now proposes to evaluate the long-term effectiveness of anti-H.py/or/treatment in an adult population in which the community prevalence of infection is greater than 90%. A cohort of children has been followed-up for 6 years, String tests to culture H. pylori and stool samples to extract DNA are obtained periodically. The specific aims of the study are to: 1. Conduct endoscopy survey, gastric biopsies, and cultures at 18 and 20 years after intervention 2. Test biomarkers of progression of the precancerous process, mainly methylation of CpG islands 3. Genotype Helicobacter pylori at different ages and different stages in the precancerous process RELEVANCE (See instructions): This project provides information of the long term effects of treating patients with antibiotics to cure their infection with the bacterium Helicobacter pylori. The original treatment took place in 1992-1993. How effective the treatment was in preventing cancer development will be investigated. Read more.

Funding Source: NIH/NCI 
PI: Pelayo Correa


Kidney Cancer

Molecularanalysis of Ethnic Variations in Wilms' Tumor

This two-year study is uniquely designed to explore the biological basis for ethnic variations in the development and progression of the lethal childhood kidney cancer, Wilms' tumor. Several epidemiological studies have shown that children of black African ancestry carry the highest risk to develop Wilms' tumor when compared with all other ethnic groups regardless of country citizenship, which suggests an ethnic-specific biology in the development of this disease. North American children of black African ancestry have also been shown to have a lower survival despite similar enrollment in treatment protocols, which further implies a different tumor biology or responsiveness to therapy algorithms more than a disparity in access to adequate therapy. However, no analyses examining the molecular or genetic etiology for these different incidence rates among ethnically diverse Wilms' tumor patients have been reported. Given that diverse ethnic groups have unique genetic backgrounds and the potential for different pathways of drug therapy metabolism, the long-term objective of these studies is to identify novel targets for the development of ethnic-specific Wilms' tumor therapies. The short-term aim of these studies is first to assign a molecular signature to Wilms' tumor tissues that portend adverse outcomes between ethnic groups. Such an understanding of the unique biology between ethnic groups will lay the groundwork to reduce observed outcome disparities for Wilms' tumor in the future. These studies will involve an innovative approach to exploring the molecular basis for the disparate behavior of Wilms' tumor between Caucasian-American, black African-American and uniquely at-risk and less genetically diverse black Kenyan children. The three specific study aims are interwoven and will involve a multidisciplinary, multi-institutional collaboration, having secured the expertise and support of the Vanderbilt Institute for Global Health (VIGH). Taking advantage of the tremendous resources at the VIGH and expertise within the Mass Spectrometry Research Center at Vanderbilt, we will initially explore proteomic differences in the uniquely at- risk and underserved population of Wilms' tumor patients in Kenya. Results generated from Kenyan Wilms' tumor patients will be compared with specimens collected from African-American and Caucasian-American children, available through Vanderbilt and the Children's Oncology Group repositories. Primary Wilms' tumor tissue and pre-therapy urine will be analyzed using mass spectrometry (MALDI-TOF) to establish a molecular fingerprint of protein expression specific to ethnicity.

Funding Source: NIH/NCI
PI: Harold Lovvorn


Lung Cancer

Exome Sequencing to Identify Novel Genetic Factors for Lung Cancer in Nonsmokers

We are conducting a whole-exome sequencing study to systematically search the entire coding region in the human genome to detect lung cancer susceptibility genes and variants. This study is built on the resources established in the Shanghai Women’s Health Study, Guangzhou Lung Cancer Study, and the Female Lung Cancer Consortium in Asia, all of which are conducted among East-Asian women. The specific aims of the study are as follows; all cases and controls are female never-smokers. Aim 1 is to sequence the whole exome of 600 NSCLC cases and 600 controls (Stage 1). Aim 2 is to validate variants in approximately 350 promising genes identified in Aim 1 in 2,500 NSCLC cases and 2,500 controls (Stage 2). Aim 3 is to validate approximately 15 genes from Stage 2 in an additional 2,500 NSCLC cases and 2,500 controls (Stage 3). To our knowledge, this is the first large association study of lung cancer conducted among never-smokers using whole-exome sequencing. Read more.

Funding Source: NIH/NCI
PI: Qiuyin Cai

Immunobiomarkers for Screening and Early Detection of Lung Cancer

We hypothesize that antibody profiles or signatures could be identified and used to distinguish lung cancer cases from controls at a very early stage by using a random peptide array. To test this hypothesis, we are conducting a nested case-control study within a prospective, population-based cohort study. The specific aims for the proposed study are: Aim 1: To conduct antibody profiling assays in 100 incident lung cancer cases and 100 matched controls using a novel, large, peptide array. Pre-diagnostic plasma samples will be used for the peptide array assays. Aim 2: To perform statistical analyses to identify antibody profiles or signatures that differ significantly between participants who subsequently develop lung cancer and participants who remain lung cancer free. The proposed study holds significant potential to develop a biomarker panel for lung cancer risk assessment and/or early diagnosis.

Funding Source: DOD
PI: Qiuyin Cai

Prognosis of Lung Cancer: Heredity or Environment?

This study seeks to find the reasons for poor survival after a lung cancer diagnosis, especially among people at greatest risk. Discovery of genes that affect lung cancer survival can identify new targets for drug treatments and lead to the development of important clinical tests to improve survival of lung cancer. Understanding the reasons for poor survival will lead to better quality of care and treatments for persons with lung cancer.

Funding Source: DOD
PI: Melinda Aldrich

Regional Variation of FDG-PET Scans to Diagnose Lung Cancer

Lung cancer kills over 160,000 people annually, more people than breast, prostate, kidney, colon, liver and skin cancer combined. More suspicious lung nodules are being found due to increased numbers of Computed Tomography (CT) scans being performed. F18-Fluorodeoxyglucose Positron Emission Tomography (FDG- PET) is approved by Centers for Medicare and Medicaid Services (CMS) for diagnosing suspicious lung nodules and is currently the most accurate non-invasive diagnostic tool available to clinicians. Lung cancer is typically metabolically active resulting in an FDG avid lesion seen on the PET scan. Active infections may also be metabolically active (FDG avid) resulting in false positive results. Retrospective single institution studies have demonstrated that infectious fungal lung diseases, such as histoplasmosis, reduce the specificity FDG- PET scans to diagnose lung cancer. Fungal lung disease is a soil based organism and common in the central Unites States. In regions of the country with high rates of fungal lung disease, false positive FDG-PET scans result in unnecessary lung operations being performed to diagnose lung cancer in 20 to 30 percent of cases. These operations have a 1-2% mortality rate. The ability to accurately and non-invasively diagnose lung cancer is limited by not knowing the circumstances and regions of the country that FDG-PET performs poorly. Understanding the regional variation of FDG-PET scan accuracy will aid cost-effectiveness studies, improve predictive models and help clinicians more accurately diagnose lung cancer. The American College of Surgeons Oncology Group (ACOSOG) Z4031 national cooperative study (5U10CA076001-11) was completed in 2006 and enrolled over 1000 patients with known or suspected lung cancer. The purpose of that study was to evaluate a serum blood test for lung cancer. Imaging reports and clinical data have been extracted into a database by trained reviewers for over 1000 patients and over 665 patients have FDG-PET scan results. The ACOSOG dataset provides an ideal source to examine the impact of FDG-PET. The purpose of our study is to test the hypothesis that regional accuracy of FDG-PET to diagnose lung cancer exists and determine if this test is useful in areas where there are high endemic rates of fungal lung disease. In aim 1 we will examine whether FDG-PET scan test characteristics in diagnosing lung cancer vary by institution and/or geographic region. This aim will determine the variation in specificity based on the enrolling institution and the relationship to the endemic histoplasmosis rate. In aim 2 we will use individual patient zip codes as a locator and examine whether false positive FDG-PET scans in the ACOSOG Z4031 study are increased in areas with endemic fungal disease compared to areas of with a low burden of fungal disease. The primary deliverable for aim 2 will use logistic regression to examine if an association exists between false positive FDG-PET scans to diagnose lung cancer and endemic histoplasmosis rates. Read more.

Funding Source: NIH/NCI 
PI: Eric Grogan


 Urogential Cancer

Genetic and Endocrine Pathways Linking Obesity with Prostate Cancer

The purpose of this study is to investigate the associations between obesity, prostate cancer, and high-grade prostatic intraepithelial neoplasia (PIN). Toward this goal, we developed a multi-centered rapid-recruitment protocol targeting men seeking a diagnostic prostate biopsy within any urology clinic in metro Nashville, TN.  Trained staff measure body size and body composition using bioelectric impedance analysis, collect pre-diagnosis blood and urine for biomarker and genetic analyses, administer a research lifestyle questionnaire, and perform medical chart review for clinical and pathology data.  Genetic and molecular markers of obesity are investigated toward prostate cancer and PIN risk. Read more.

Funding Source: NIH/NCI 
PI: Jay Fowke

Modifiable Risk Factors for Fatal Prostate Cancer: A Prospective Study in Asia

This analysis uses data from a consortium of 13 prospective cohort studies across Asia to investigate lifestyle risk factors for prostate cancer in regions where prostate cancer is relatively rare and there is substantially less screening. Read more.

Funding Source: NIH/NCI 
PI: Jay Fowke

The Quality of Care in Evaluating Patients Suspected of Having Bladder Cancer

The presence of blood in the urine, or "hematuria", may herald the presence of urologic malignancy such as bladder cancer or kidney cancer; benign urologic disease such as kidney stones (nephrolithiasis), urinary tract infection; or intrinsic renal disease, such as glomerulonephritis. The proper evaluation of patients with hematuria is essential to identify the 1 person in 10 who may have a life-threatening malignancy or other treatable condition. Chief among these conditions is bladder cancer (BC), because of its high incidence and lethality. Guidelines from the American Urological Associate (AUA) and the National Cancer Collaborative Network (NCCN) call for evaluation of persons presenting with suspicion for urothelial carcinoma using office cystoscopy (endoscopic evaluation of the bladder) to rule out BC and, in many instances, an imaging study of the kidneys and ureters to rule out other malignancies. There is some evidence of insufficient adherence to guidelines for surveillance of patients with BC, but there is a gap in the evidence with respect to the initial evaluation of those suspected of harboring BC. Delayed or incomplete evaluation indicates poor adherence to published guidelines, and could contribute to sub-optimal BC outcomes. In fact, one theory, which has yet to be tested, is that racial variation in adherence to evaluation guidelines could explain the racial paradox in BC: while BC is more common among Whites, African-American patients present with higher-stage disease, and have a higher likelihood of disease-specific mortality. We propose several approaches to determine the current quality of evaluation of patients with hematuria, to identify racial variation in the timely and complete evaluation of hematuria and to determine the underlying reasons for such variation. First, we will look broadly at the Medicare dataset to determine the frequency of use of cystoscopy and imaging for patients with hematuria, and investigate whether there are racial differences in their use on a national level. Second, we will use a well-characterized prospective cohort of over 86,000 economically disadvantaged and racially diverse persons in the Southeastern US (The Southern Community Cohort Study) in order to identify the factors that may underlie racial variation in the timely and complete workup of hematuria, such as socio-economic status, educational attainment, healthcare access indicators. The remaining unexplained variation may be amenable to educational interventions among primary care providers. The ultimate aim of the proposed study is to identify gaps in the quality of care for patients with hematuria, which will become targets in a planned interventional study through a multi-center quality collaborative in which we participate. Read more.

Funding Source: NIH/NCI 
PI: Daniel Barocas

Shanghai Endometrial Cancer Study (SECS)

The Shanghai Endometrial Cancer Study is a population-based, case-control study of 1,204 endometrial cancer cases and 1,212 controls who were aged between 30 and 69 years and recruited between 1997 and 2003. The study recently recruited an additional 587 endometrial cancer patients. The major objectives of the study are to evaluate the role of and interactions between hormonal, dietary, and other lifestyle factors and genetic susceptibility in endometrial carcinogenesis. In addition to detailed dietary intake and other questionnaire-based information, the study also collected a blood or buccal cell sample and a urine sample from participants. The study has published multiple papers reporting novel findings on dietary risk/protective factors and genetic susceptibility factors. The SECS is one of the largest epidemiological studies of endometrial cancer and is a major contributor to the international Epidemiology of Endometrial Cancer Consortium. Read more.

Funding Source: NIH/NCI
PI: Xiao Ou Shu

Trends in Surveillance for Localized Prostate Cancer and Barriers to Its Use

Observation of localized prostate cancer is often a reasonable alternative to immediate definitive treatment because many prostate cancers are non-lethal and have a protracted natural history. Active surveillance (AS) is associated with nearly 100% disease-specific survival in the management of low-risk clinically localized prostate cancer in prospective cohort studies and has been promoted in recent years as a means of stemming over-treatment of low-risk disease. However, AS seems to be an underutilized strategy in the management of prostate cancer, perhaps in part because of its association with the passive observation strategy known as watchful waiting (WW), which was more commonly recommended in elderly and infirmed men in past decades. Whereas AS seeks to identify signs of disease progression and offers definitive therapy (radiation or surgery) if progression is found WW is designed to allow prostate cancer to progress, assuming that the patient is more likely to die of other causes, and only palliative intervention is offered for symptom relief. Observation of prostate cancer has gained wider acceptance in Europe and Canada than it has in the US, where utilization remains at 10% or less among low-risk patients. In order to expand the acceptance of and adherence to AS for management of low-risk clinically localized prostate cancer, it may be necessary to distinguish it from WW in common clinical practice and to identify patient-level factors and physician communication styles that impact the decision to select AS. We propose using data from two large, community-based prospective cohort studies of men with localized prostate cancer with similar study designs (Prostate Cancer Outcomes Study [PCOS] and Comparative Effectiveness Analysis of Surgery And Radiation [CEASAR]), to compare the use of surveillance between two eras (1990s for PCOS and 2010s for CEASAR). Our aim is to determine whether the evidence demonstrating that AS is a safe alternative to active treatment has led to an increase in its use among men with low-risk disease and to increased use among younger, healthier men across the two eras (suggesting a transition from WW to AS). Secondly, we will use the CEASAR baseline questionnaire to determine the extent to which physician communication style influences the selection of AS in favor of other currently available treatments. The results of the proposed study will provide the foundation for a planned study of AS utilization within the Urological Surgery Quality Collaborative, a multi-institutional group of 7 urology practices throughout the Mid- West, Mid-Atlantic and Southeastern United States. Using an established quality assessment, quality improvement model, we aim to assess prospectively the physician and patient level barriers to AS; then perform an educational intervention with physicians in an effort to increase use of AS in appropriate clinical scenarios; then reassess to evaluate the effectiveness of the intervention. Because prostate cancer is the most commonly diagnosed cancer among men, the potential public health impact of increasing AS use is enormous. Read more.

Funding Source: NIH/NCI 
PI: Daniel Barocas


 

Cancer Mortality Among Military Participants at US Nuclear Weapons Tests

The lifetime risk of cancer will be quantified among 125,000 United States atomic veterans who participated at one or more of the 230 aboveground atmospheric nuclear weapons tests at the Nevada Test Site or the Pacific Proving Ground between 1946 and 1958. Reliable estimates of radiation dose for individual atomic veterans will be made which were not possible in previous investigations. Advances in dose reconstruction methods will permit dose-response evaluations and risk quantification. New knowledge will be sought on specific cancer risks following protracted low-dose exposure to external and internal radiation, including the inhalation and ingestion of plutonium, uranium and radioactive fission products. Previous studies identified excesses of leukemia and several other cancers, but reliable estimates of radiation dose were not possible. The hypothesis to be tested is that chronic low-dose radiation exposure some 50 to 60 years ago can be linked to increases in leukemia and other diseases, including coronary heart disease. An additional 20 years of mortality data will enhance our ability to uncover any radiation-related risks among military personnel present at one or more of the seven atmospheric test series with the highest recorded exposures, i.e., CASTLE, GREENHOUSE, REDWING, UPSHOT- KNOTHOLE, PLUMBBOB, CROSSROADS and HARDTACK I. New developments in statistical methodologies will be applied to account for the uncertainty in the estimated radiation doses. Preliminary estimates indicate a broad range of doses from minimal (< 1 mSv or 0.10 rem) to over 900 mSv (or 90 rem). All causes of death will be evaluated, and radiation doses will be reconstructed for all veterans who died of leukemia and cancers of the thyroid, salivary gland, male breast, liver and bone, i.e., for cancers previously reported to be increased, as well as on a 1% random sample of the entire cohort. The focus will be on leukemia for which over 1,000 cases are estimated to have occurred. The proliferating use of CT x-ray as well as radionuclide imaging (e.g., PET scans) highlights the need for accurate estimates of lifetime radiation risk following chronic low-dose exposures for which cumulative population doses could be substantial. The evaluation of risks among persons with exposure to radioactive substances assumes greater importance as society debates expansion of nuclear energy and associated nuclear waste and the possibility of terrorist attacks with "dirty bombs." The proposed study thus provides a unique, timely and cost-effective opportunity to address important public health and societal issues, taking advantage of detailed radiation dose and veteran data already developed by the Department of Defense over the past 30 years. Finally, the proposed project is important to veterans and their families in providing a better understanding of the health risks associated with their prior military service. Public Health Relevance: Atomic veterans who participated in any of the 230 atmospheric nuclear weapons tests at the Nevada Test Site and the Pacific Proving Ground between 1946 and 1958 could have been exposed to various types of radiation including gamma rays, alpha particles and intakes of radioactive substances such as plutonium, uranium and fallout products. Results of this study will provide new knowledge on the lifetime risk of cancer following relatively low-dose exposures received gradually over time. Such information is helpful in understanding the very long-term consequences of radiation exposures and assumes greater importance today in light of the proliferating use of CT x-ray and radionuclide imaging, the possible expansion of nuclear power, and concerns over nuclear waste disposal and terrorist attacks with "dirty bombs." Read more.

Funding Source: NIH/NCI
PI: John Boice

Cancer Risk Reduction and Diet: A Cohort Study of Women

The Shanghai Women's Health Study (SWHS, R01 CA70867) is a population-based cohort study of approximately 75,000 Chinese women who were recruited between 1997 and 2000 and have been followed through multiple in-person follow-up surveys and record linkages. Over the years, data and biological samples collected in the SWHS have been used to evaluate many important etiologic hypotheses and support multiple studies, including several NCI-sponsored cohort consortium projects. In this renewal application, we request continued support for this unique cohort study to evaluate a new set of hypotheses and confirm, with a larger sample size and improved exposure assessments, some of the promising associations identified during the current grant period. We will continue to analyze survey data to evaluate dietary and other lifestyle factors in relation to cancer risk with a specific focus on evaluating dietary protective factors, such as regular consumption of soyfood, tea, and ginseng. With additional follow-up of the SWHS, we will have, for the first time, adequate statistical power to investigate less common cancers, such as cancers of the ovary, corpus uteri, and pancreas, as well as subtypes of common cancers. Using a case-cohort study design, we propose to investigate urinary prostaglandin E2 metabolite (PGE-M), as well as telomere length and mitochondrial DNA copy number measured in peripheral white blood cells in relation to the risk of cancer, and further identify lifestyle determinants for urinary PGE-M and blood cell telomere length. Finally, we will evaluate the utility of validated genetic markers in assessing an individual's risk for breast cancer. The renewal of this cohort study will enable continued follow-up of this cohort for five more years and provide adequate numbers of cancer cases for investigating the hypotheses proposed in this application and for future studies. Because of its size, setting, and inventory of biological specimens and epidemiologic/clinical data, the SWHS provides an exceptional opportunity to address many significant hypotheses that cannot be adequately investigated in any other existing cohort studies. The results from this study will have significant implications for the primary and secondary prevention of common cancers in both Western and Asian women. Read more.

Funding Source: NIH/NCI 
PI: Wei Zheng

Parent-Child Communication About Cancer

This is a competing renewal application to conduct theoretically-driven research to determine the course and predictors of mental health, social, and physical health outcomes in a cohort of children with cancer and their parents. We have been following a sample of 258 children (ages 5 to 17-years at entry into the study) from near the time of their cancer diagnosis over the first year after their diagnosis with a very high retention rate. By the end of this grant period we will have collected 3 waves of data including observations, interviews and questionnaires and we now propose to collect 2 additional waves of data, including direct observations of parent-child interactions, up to 5 years after diagnosis. Child and their parents completed measures about sources of cancer-related stress, how they cope with cancer, standardized indicators of distress and mental health problems, and they participated in video recorded observations. We propose to extend this work to examine the transition off treatment and into survivorship. Our aims are: 1) To examine continuity and change in parent-child communication about cancer; 2) To identify early predictors of later mental and physical health outcomes for children with cancer and their parents; and 3) To examine reciprocal relationships between parent and child coping, mental and physical health. To meet these aims, we propose to collect 2 additional waves of interview, observational and multi-agent questionnaire data spaced 12 months apart. The project is designed to identify risk and protective factors and processes that can be used to establish a theory-driven model of coping and adaptation to childhood cancer and to identify targets for the future early preventive psychosocial interventions with children with cancer and their parents. Read more.

Funding Source: NIH/NCI 
PI: Bruce Compas

Shanghai Men's Health Study

The Shanghai Men’s Health Study (SMHS), funded by NCI since 2001, is a population-based cohort study of 61,482 men aged between 35 and 75 years and recruited from 2002 to 2006. At baseline, detailed information on dietary intakes, personal habits, occupational history, medical history, and other lifestyle factors was collected, and anthropometrics were measured. Blood or buccal cell, and  urine samples were collected from 89% of participants. The cohort has been followed through multiple in-person surveys to update exposure information and through record linkages with the population-based Shanghai Cancer Registry and Shanghai Vital Statistics Registry to obtain information on cancer occurrence and survival status. Over the years, SMHS data and biological samples have been used to evaluate many important etiologic hypotheses addressing the contributions of environmental, dietary, lifestyle, and genetic exposures to the development of cancer and other chronic diseases. The cohort supports multiple studies, including over 25 consortium projects. Read more.

Funding Source: NIH/NCI 
PI: Xiao Ou Shu

Telephone Counseling - Caregivers for Children with Cancer

The rate of survival for childhood cancer continues to improve and now approaches 80%. Coincident with this survival are adverse long-term health-related outcomes for survivors and their family members. Throughout the cancer care continuum, from time of diagnosis through long-term survivorship, children and their families are confronted with multiple and pervasive stressors, including uncertainty about the chance of survival, treatment- related adverse health effects, disruption in daily activities and disruption of the parental role function. This may result in clinically significant global distress, depression, posttraumatic stress (PTS) and reduced self-efficacy. Therefore, providing psychosocial services to parents of children with cancer is necessary. Yet, feasible and theory-based psychosocial intervention studies are extremely limited, particularly at the completion of the child's cancer treatment, a time known to be anxiety-provoking and often characterized by feelings of abandonment and uncertainty about the future. Barriers to participation in face-to-face interventions at the treating institution include the considerable distance that many families live from the institution, difficulty leaving children, households or jobs and potential for sensory and interpersonal experiences at the treating institution to trigger symptoms of anxiety and PTS. In response to these concerns, we are proposing to extend the reach of essential psychosocial counseling services to primary caregivers of children with cancer by designing and implementing a small-scale feasibility pilot of an innovative and highly translatable telephone-based psychosocial intervention. This intervention will be implemented during the transition from primary active oncology treatment to follow-up care, reflecting a neglected area of research. Specifically, we propose to design and then test the feasibility of a two-group randomized trial of a psychosocial telephone counseling program for primary caregivers of children who have completed cancer therapy in the previous year, consisting of an attention control condition (educational materials and outcalls with no counseling) and an experimental condition (telephone counseling plus the educational materials). We will evaluate the proposed telephone counseling intervention for feasibility, satisfaction and perceived helpfulness. The primary endpoints will include psychosocial distress and benefit finding. Furthermore, we will assess and explore the plausible intervention mechanisms and pathways that may explain and elucidate intervention efficacy (mediator variables). The main theory-based mediator variables that will be tested include secondary appraisal (coping self-efficacy) and coping effort. Lastly, based on the preliminary data obtained from this study, we will seek funding to design and implement a larger randomized clinical efficacy trial, whose ultimate goal will be to develop a highly effective and exportable telephone counseling intervention for primary caregivers of children with cancer that could be become an integral component of care given to pediatric oncology patients. Read more.

Funding Source: NIH/NCI 
PI: Debra Friedman