Abstract
Genome-wide association studies (GWAS) are an important tool for the characterization of the genetic architecture of cancer susceptibility, and a key step towards understanding the process of cancer development. Each susceptibility region explains only a small fraction of cancer risk, but the aggregation of those regions allows us to understand a significant part of the heritability, using polygenic risk scores. Renal cancer GWAS have detected 13 susceptibility regions, which explains 14% of the germline risk. Precision prevention will use polygenic risk scores to individualize strategies for screening and primary prevention. However, it is necessary to increase our knowledge of renal cancer susceptibility in order to create a meaningful polygenic risk score for this tumor. This proposal comprises three main complementary research plans. Therefore, for our first research plan, we will use a new GWAS with Brazilian samples to identify additional renal cancer susceptibility regions, as well as develop new strategies to transpose polygenic risk scores into different populations. Since risk regions are unique agnostic opportunities to identify new molecular oncogenic mechanisms, for research plan 2 a post-GWAS study will evaluate the deregulation of key tumor-specific pathways by risk variants. During his postdoc at NIH, the Principal Investigator developed a series of large-scale screening functional assays (ATAC-seq, Chip-seq, eQTL, Capture-HiC, and MPRA) to prioritize top functional variants in each renal cancer susceptibility region. Here, we will use a functional follow-up study to identify the molecular mechanism for renal cancer development in three regions: 12p12, 14q24, and 2q22. Finally, for research plan 3, we will use the modern approach of germline and somatic interaction to evaluate the impact of germline susceptibility on renal cancer prognosis and treatment outcome. In summary, we think this proposal is a unique opportunity to develop a translational genotype-molecular-phenotype study to generate and understand germline susceptibility, molecular mechanisms, and precision treatment for renal cancer. (AU)
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