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Somatic Evolution in Li-Fraumeni Syndrome

In this study, we used ultradeep duplex sequencing (~15,000× depth) to measure somatic evolution in blood samples from a family of three individuals with Li-Fraumeni Syndrome (LFS) caused by an inherited TP53 pathogenic variant (p.R181H), and compared them to a cohort of unaffected controls using a set of genes related to Clonal Hematopoiesis of Indeterminate Potential (CHIP)/Acute Myeloid Leukemia (AML), as well as a mutagenesis panel designed to examine mutagenic processes. We found that individuals inheriting a single mutated copy of TP53 may experience less positive selection for subsequent TP53 mutations, as evidenced by a deficit of coding TP53 mutations, reduced dN/dS, and low predicted pathogenicity among the TP53 somatic mutations that do occur. However, the overall degree of mutagenesis in genomic regions without strong selection was higher in LFS patients. In addition, we investigated how LFS affects clonal evolution across multiple tissue contexts in one individual carrying p.R181H who succumbed to metastatic esophageal cancer.

The data available through dbGaP includes BAM files, MAF files (mutation data), and genomic MUT files (showing per-position depth of sequencing), from ultradeep duplex sequencing of multiple tissues from a LFS patient as well blood samples from family members and controls.