R01CA262899

Multi-Ethnic High-Throughput Study to Identify Novel Non-HLA Genetic Contributors to Mortality after Blood and Marrow Transplantation - Project Summary

Blood and Marrow Transplant (BMT) is an effective cure for many life-threatening hematologic diseases. Survival after BMT has improved dramatically over the past two decades. However, up to 40% of patients still die within one year after HLA-matched unrelated donor allogeneic BMT.

This project will build upon our prior genome-wide (GWAS) and exome-wide association studies (EXWAS) involving approximately 2,900 patients named Determining the Influence of Susceptibility Conveying Variants Related to One-Year Mortality after BMT (DISCOVERY-BMT). Our GWAS identified several donor loci that significantly increased the recipient's risk of disease-related mortality (DRM). Additionally, donor-recipient genotype mismatches significantly increased the risk of transplant-related mortality (TRM) in European Americans (EAS). Our EXWAS discovered a rare nonsynonymous coding variant, where a donor-recipient genotype mismatch correlated with TRM. Furthermore, additional novel genes such as TEX38, OR51D1, and NT5E correlated with overall survival, TRM, and DRM.

The goal of this proposal is two-fold: to deepen our understanding of non-HLA genetic contributors to BMT mortality and to build clinical-genomic prognostic models to translate this understanding into clinical practice. The first goal will be fulfilled in two directions.

First, we will systematically survey both rare and common variants using whole-exome sequencing (WES) and meta-GWAS in EAS, as well as under-studied diverse populations, including African Americans, Asians, and Hispanics. Our prior EXWAS in EAS demonstrated the important roles played by rare coding variants in BMT mortality. However, only 2% of rare variants are in the exome array. Therefore, we will use WES to assay all exonic variants in 5,598 multi-ethnic donor-recipient pairs. Variants/genes that we identify as direct candidates for causality will undergo functional validation to investigate such relationships. In parallel, we will perform the largest meta-GWAS of BMT mortality to date. Through our collaborations, we have assembled all BMT GWAS data available in the US, including 8,576 donor-recipient pairs, of which 1,978 are minority pairs.

Second, we will interrogate WES and GWAS data to further reveal the biological networks contributing to BMT mortality. To meet the second goal, we will leverage our unique and powerful GWAS resource to develop prognostic models to predict patients' personalized mortality risk. This is the first study to use next-generation sequencing technology to analyze the contribution of non-HLA coding variants on post-BMT mortality. The GWAS data on 8,576 donor-recipient pairs, of which 5,598 pairs also have WES data, will make this the largest genetic study ever undertaken and provide a real opportunity to understand the genetics of BMT mortality across diverse populations. The prognostic models we develop will provide a valuable tool to help reduce BMT mortality and enhance donor-recipient matching in routine clinical practice.

Importantly, the data generated by this project will be shared publicly to serve as a resource for additional research to improve survivorship after BMT and enhance the public investment in this project.

Health Research

TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

Buffalo, New York 14263 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 227% from $954,265 to $3,120,296.