肝细胞癌的遗传遗传学-猫眼课题宝

肝细胞癌的遗传遗传学

批准号：

10632953

负责人：

Kirk J Wangensteen

金额：

$51.03万

依托单位：

MAYO CLINIC ROCHESTER

依托单位国家：

美国

项目类别：

财政年份：

2022

资助国家：

美国

项目状态：

未结题

起止时间：

2022-07-01 至 2027-06-30

来源：

https://reporter.nih.gov/project-details/10632953

关键词：

Address Age Age of Onset Alcohol consumption Alcohols American Animal Model BRCA2 gene CHEK2 gene Chronic Cirrhosis Clinical Confidence Intervals DNA Damage DNA Repair DNA Repair Gene DNA Sequence Alteration Data Defect Demographic Factors Development Diagnosis Enrollment Environmental Risk Factor Exposure to FANCD2 protein Family Family Cancer History Family history of Family member Fanconi Anemia Complementation Group A Protein Fatty Liver Fibrinogen First Degree Relative Gene Expression Gene Mutation Genes Genetic Genetic Models Germ-Line Mutation Goals Hepatitis B Hepatitis C Hereditary Malignant Neoplasm Hereditary Neoplastic Syndromes Histologic Individual Inherited Institution Investigation Link Liver neoplasms Loss of Heterozygosity MSH6 gene Malignant Neoplasms Malignant neoplasm of liver Medical Genetics Medical center Mutation Odds Ratio Oncogenes Outcome PMS2 gene Pathogenesis Pathogenicity Patient Care Patients Persons Pharmacotherapy Pilot Projects Play Population Population Control Predisposition Primary carcinoma of the liver cells Proteins Race Recording of previous events Risk Risk Factors Role Sampling Shapes Stains Test Result Testing Time Toxic Environmental Substances Tumor Tissue Venous blood sampling Virus Diseases base cancer risk cancer type carcinogenesis case control clinical center early onset exome sequencing fatty liver disease gene function gene panel gene repair genetic association genetic testing genomic locus high risk homologous recombination inhibitor liver cancer model loss of function medical schools mortality patient subsets personalized medicine precision drugs prospective recruit repaired research clinical testing response targeted treatment treatment strategy tumor

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PROJECT SUMMARY Hepatocellular Carcinoma (HCC) is a devastating and prevalent cancer of the liver with high rates of mortality. Major risk factors include chronic viral infection (hepatitis B or C), fatty liver disease, alcohol use, and exposure to environmental toxins. An independent risk factor is a family history of HCC in a first degree relative, which raises the risk by more than 2.5-fold. However, despite evidence of familial risk, few links to hereditary cancer syndromes have been identified. It is also not clear whether inherited gene mutations play a pathogenic role in HCC development, or whether they could be used to guide treatment. We have pioneered an investigation into inherited (i.e. germline) genetic factors associated with HCC. We have prospectively enrolled 220 patients with HCC from our medical center for clinical-grade genetic testing. We have recorded the details of their personal and family cancer history, risk factors, and outcomes. In our pilot analysis, we found a surprisingly high rate of pathogenic germline mutations in cancer-associated genes in patients with HCC, including numerous mutations in DNA damage response genes required for homologous repair (HR-DDR). In Aim 1, we will conduct a genetic association study that is powered to detect clinically meaningful germline mutations linked to HCC, and we will examine whether hereditary cancer syndromes are more common in persons who developed early onset HCC or have a family history of cancer. In Aim 2, we will explore the mechanism of HCC arising from defects in HR- DDR genes, and determine the implications for targeted therapies. These unique studies of the hereditary genetics of HCC have the potential to personalize therapies for the subset of patients with hereditary cancer syndromes. We have assembled a team of experts in HCC, hereditary genetics, and animal models to complete this investigation. This study has the potential to shape the care of patients with HCC in the US and worldwide.

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