Genomic and environmental drivers of HCC in Non-Hispanic Blacks: Nature and nurture

非西班牙裔黑人 HCC 的基因组和环境驱动因素：先天和后天

• 批准号: 10856546
• 负责人: Andrea D. Branch
• 金额: $ 36.04万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10856546
• 关键词: Address; Architecture; Area; Aristolochic Acids; Automobile Driving; Awareness; Black American; Black Populations; Black race; Cancer Etiology; Chronic Hepatitis C; Cirrhosis; Coal; Collaborations; Complex; DNA Damage; Data; Diagnosis; Disease Outcome; Disparity; Enrollment; Environmental Exposure; Environmental Pollutants; Environmental Risk Factor; Exposure to; Frequencies; Genes; Genetic; Genetic Risk; Genomics; Heavy Metals; Hepatotoxicity; High Prevalence; Histologic; Human; Immunogenomics; Immunophenotyping; Interferons; Intervention; Knowledge; Liver; Liver Cirrhosis; Liver diseases; Low Prevalence; Malignant Neoplasms; Malignant neoplasm of liver; Maps; Minority Groups; Molecular; Mutagens; Mutate; Mutation; Nature; Not Hispanic or Latino; Oncogenic; Oncology; Participant; Pathway interactions; Patients; Phenotype; Population Heterogeneity; Prevalence; Prevention; Prevention strategy; Primary carcinoma of the liver cells; Production; Prostatic Neoplasms; Provider; Research Personnel; Resistance; Risk; Risk Factors; Science; Single Nucleotide Polymorphism; Slide; Smoke; Special Population; Specimen; Study Subject; Susceptibility Gene; The Cancer Genome Atlas; Time; Toxin; Variant; biobank; black patient; cancer initiation; cancer predisposition; cancer risk; cohort; digital; exome sequencing; experience; innovation; insight; liver injury; mortality; multidisciplinary; neoplastic cell; nonalcoholic steatohepatitis; novel; people of color; polygenic risk score; risk variant; socioeconomics; synergism; tool; transcriptomics; treatment strategy; tumor; tumor progression; tumorigenesis; underserved minority

Genomicand environmental drivers of HCC in Non-Hispanic Blacks: Nature and nurture: Non-Hispanic Black Americans (Blacks) develop hepatocellular carcinoma (HCC) at about twice the rate of Whites and have far higher mortality. HCC has an atypical presentation in Blacks, with lower cirrhosis stage at the time of HCC diagnosis and more advanced and aggressive HCC. Blacks have higher exposure to environmental pollutants than Whites and these exposures are associated with liver damage. Although heavy metals and toxins are known to cause liver injury and cancer, they are often overlooked. This project addresses the need to understand the genomic and environmental factors causing the atypical presentation of HCC in Blacks so that effective prevention and treatment strategies can be implemented. It is responsive to RFA-CA- 23-023 in the topic area: Liver cancer in underserved minority populations. This innovative collaboration between experts in the Liver Cirrhosis Network and liver cancer researchers is expected to yield actionable mechanistic insights into environmental exposures, tumor immunophenotype, and genetic factors driving the atypical presentation of HCC in Blacks and may identify new targets for intervention and prevention. The study will also yield a polygenic risk score for cirrhosis for use among ancestrally diverse populations. The results will alert patients and providers to the fact that HCC risk is disproportionate to cirrhosis stage in Blacks, raising awareness of the threat and encouraging early enrollment in surveillance. This project will expand HCC tumor sequencing and transcriptomic data from Black patients over 4-fold. The Cancer Genome Atlas (TCGA) has only 17 HCCs from Blacks. Aim I: Hypothesis: Mutational signatures of toxic damage are more prevalent in HCCs of Blacks than in HCCs of Whites. We will perform whole exome sequencing on paired HCC/non-HCC specimens from Blacks and use our in-house pipeline to identify somatic single nucleotide variants (SNVs), to find known and novel mutational signatures, to define the tumor mutational burden, and to identify mutated genes. Aim II: Hypothesis: The HCC tumor cells and surrounding microenvironment in Blacks are primed for pro-tumor activity. We will perform global transcriptomic analysis on paired HCC/non-HCC specimens of Blacks to identify oncogenic drivers and computationally immunophenotype the microenvironment. Multiplexed IHC will be used to map the molecular findings onto the histological architecture of the patient's human liver specimens. Aim III: Hypothesis: Blacks with HCC have a lower prevalence of cirrhosis risk variants than Whites with HCC, but they have a high prevalence of cancer risk variants, including rare penetrant variants. We will compare the prevalence of cancer predisposition variants in Blacks with HCC vs. healthy controls, develop score cirrhosis a polygenic risk for cirrhosis, compare cirrhosis risk between Blacks and Whites with HCC, and explore genetic risks for in study subjects in the Liver Cirrhosis Network who develop HCC.

非西班牙裔黑人中HCC的基因组和环境驱动因素：自然与养育： 非西班牙裔黑人美国人（黑人）发育于肝细胞癌（HCC），大约是两倍 白人，死亡率更高。 HCC在黑人中具有非典型表现，肝硬化阶段较低 HCC诊断时间和更高级和更具侵略性的HCC。黑人接触更高 环境污染物比白人，这些暴露与肝损害有关。虽然很重 已知金属和毒素会引起肝损伤和癌症，它们常常被忽略。该项目解决 需要了解引起HCC非典型表现的基因组和环境因素的需求 黑人，以便可以实施有效的预防和治疗策略。它对RFA-CA-响应敏感 主题区域的23-023：服务不足的少数群体中的肝癌。这种创新的合作 肝肝硬化网络和肝癌研究人员的专家有望产生可行的机理 洞悉环境暴露，肿瘤免疫表型和驱动非典型的遗传因素 在黑人中介绍HCC，并可能确定用于干预和预防的新目标。这项研究也将 在祖先多样化的种群中使用肝硬化的多基因风险评分。结果将警报 患者和提供者的事实是，HCC风险与黑人的肝硬化阶段不成比例，提高了知名度 威胁和鼓励早期入学监视。该项目将扩大HCC肿瘤测序 来自黑人患者4倍以上的黑人患者的转录组数据。癌症基因组图集（TCGA）只有17个HCC 来自黑人。 目的I：假设：在黑人的HCC中，有毒损害的突变特征比HCC更为普遍 白人。我们将对来自黑人的配对HCC/非HCC标本进行整个外显子组测序，并使用 我们的内部管道识别躯体单核苷酸变体（SNV），以找到已知和新型突变 签名，定义肿瘤突变负担并鉴定突变的基因。 AIM II：假设：HCC肿瘤细胞和周围的黑色微环境被置于肿瘤 活动。我们将对黑人的配对HCC/非HCC标本进行全局转录组分析以识别 致癌驱动因素和计算免疫表型微环境。多路复用IHC将被使用 将分子发现映射到患者人肝标本的组织学结构上。 AIM III：假设：HCC的黑人的肝硬化风险变异的患病率低于HCC的白人， 但是它们具有癌症风险变异的较高流行率，包括罕见的渗透变体。我们将比较 HCC与健康对照的黑人中癌症易感变异的患病率，发展 分数 肝硬化 多基因风险 对于肝硬化，将黑人与白人之间的肝硬化风险与HCC进行比较，并探索遗传风险 在发展HCC的肝肝硬化网络中的研究对象中。