Comparative Whole Genome Sequencing to Identify Candidate Somatic Driver Mutations of Li-Fraumeni Syndrome Sarcomagenesis in Humans and Mice. J. Wong1,2, L. C. Strong1,2, G. Lozano1,3, L. L. Bachinski1, R. Krahe1,2,3 1) Genetics, MD Anderson Cancer Center, Houston, TX; 2) Human & Molecular Genetics Program, University of Texas-Houston Graduate School in Biomedical Sciences, Houston, TX; 3) Genes & Development Program, University of Texas-Houston Graduate School in Biomedical Sciences, Houston, TX.

   Li-Fraumeni Syndrome (LFS) is a rare, clinically heterogeneous, variably penetrant cancer susceptibility syndrome that has largely been attributed to germline mutations in the tumor suppressor gene TP53 (p53; >70% of all cases). The tumor spectrum for LFS is considerably broad, characterized by a high incidence of sarcomas considered a hallmark of LFS. p53 LFS carriers develop sarcomas at a wide range of ages and sites, suggesting that while the p53 mutation confers cancer predisposition, additional mutations are necessary for sarcomagenesis. To evaluate potential somatic drivers, we performed whole genome sequencing (WGS) across two sarcomas and matched (PBL) normal tissue from known p53 LFS carriers (M133T, R175H) to pinpoint recurrent acquired changes. However, driver identification is complicated by the acquisition of driver mutations along with numerous passenger events, which is potentially confounded by genome architecture. To distinguish drivers from passengers in human sarcomas, we performed comparative WGS on tumor and normal tissues from a humanized LFS mouse model with a germline p53+/R172H missense mutation (analogous to the human hot-spot TP53 R175H LFS mutation) that predisposes to a similarly broad tumor spectrum, including sarcomas. Two mouse sarcomas were evaluated against a pool of five normal mice for recurrent somatic changes. In several genes with known human orthologs, the mouse sarcomas had somatic variants predicted to have functional consequences and demonstrated roles in human cancers. Integration of human and mouse data revealed the PTEN pathway as a potential key cancer pathway shared between human and mouse sarcomas. Several genes, such as TRIM16 and PCDHB8, showed potential driver mutations across multiple samples. Our overall results indicate the utility of comparative WGS of human cancers and their mouse models for the identification of somatic driver mutations.

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