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Pancreatic cancer variant analysis of the All of Us cohort

我们所有人队列的胰腺癌变异分析

基本信息

批准号：
10660291
负责人：
Robert E. Lewis
金额：
$ 11.51万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10660291
关键词：
Acinar Cell Address Affect African African American Alcohol consumption Alcohols Black Populations Black race Characteristics Chemoresistance Classification Clinical Clinical Management Code Communities Data Data Set Databases Demographic Survey Development Disease Epigenetic Process Ethnic Origin Evaluation Exhibits Face Future Genes Genetic Transcription Genetic Variation Genomic Segment Goals Hispanic Hispanic Populations Impairment Incidence Inflammatory KRAS2 gene Latino Latino Population Latinx Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Malignant neoplasm of prostate Mass Spectrum Analysis Metabolic Minority Modeling Molecular Molecular Analysis Molecular Profiling Multivariate Analysis Mutation Oncogenes Outcome Pancreatic Ductal Adenocarcinoma Pathway interactions Patient Care Patient-Focused Outcomes Patients Polycomb Population Heterogeneity Prediction of Response to Therapy Proteins Proteome Proteomics Publishing Race Refractory Regulation Repressor Proteins Research Resistance Sampling Socioeconomic Status Therapeutic Time Transcript Tumor stage Untranslated RNA Validation Variant Work aggressive therapy black patient cBioPortal cancer subtypes cancer type cell dedifferentiation chemotherapy clinically relevant cohort differential expression ethnic health disparity experience experimental study genetic variant genome sequencing genome wide association study genomic variation health disparity improved in silico malignant breast neoplasm member molecular marker molecular subtypes new therapeutic target pancreatic cancer patients pancreatic tumorigenesis progenitor prognostic of survival racial and ethnic racial disparity racial diversity racial health disparity socioeconomics survival outcome targeted treatment treatment optimization treatment strategy tumor tumorigenesis whole genome

项目摘要

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is refractory to current treatment strategies due in part to adaptive mechanisms of chemoresistance. Racial health disparities also confound the treatment and care of these patients. Blacks have significantly higher incidence rates of PDAC and decreased survival times compared to Whites and Latino/Hispanics (L/H) even after socioeconomic status and tumor stages are controlled. Therefore, it is likely different racial groups exhibit unique molecular characteristics in PDAC tumors that contribute to these health disparities. The molecular characteristics that distinguish PDAC tumors between racial groups have the potential to identify novel therapeutic targets required to overcome the disparities. Indeed, delineating the underlying molecular basis for health disparities in lung, breast and prostate cancers has led to therapeutic advancements and improved patient outcomes. Similar breakthroughs for PDAC are possible and needed for this deadly disease, but this field of research has not yet been adequately explored. We identified 4 distinct subtypes of PDAC (Metabolic, Progenitor-like, Proliferative, and Inflammatory) that can be distinguished using multivariate analysis of quantitative mass spectrometry data. These PDAC subtypes are predictive of therapeutic response, but this has not yet been analyzed in a racially diverse population. We have examined the proteomes of primary PDAC tumors using quantitative mass spectrometry and identified unique protein signatures for Blacks, L/H, and Whites. In PDAC tumors from Black patients, we observed features consistent with the Inflammatory subtype of PDAC, which is characterized by an inflammatory microenvironment and resistance to chemotherapy. Therefore, it is possible that race influences subtype and Blacks could preferentially develop the more aggressive and treatment refractory Inflammatory subtype. However, the underlying genetic variants associated with PDAC subtype specification have not been examined. Toward this goal, our project will utilize the All of Us database to identify variants in a diverse cohort pancreatic cancer patients and evaluate specific gene sets associated with PDAC tumorigenesis, including alcohol responsive genes, and differentially expressed proteins in PDACs originating in Blacks. In addition, we will perform a discovery GWAS analysis to identify variants associated with PDAC development in the All of Us cohort and examine their predicted functional consequences in selected PDAC subtype specification genes. The successful completion of these aims outlined in this proposal has the potential to improve our understanding of the drivers of PDAC subtype specification, which could be developed to improve overall patient survival by optimizing treatment strategies.

项目总结