American Association for Cancer Research
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Supplementary Data S3 from Multiple germline events contribute to cancer development in patients with Li-Fraumeni syndrome

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posted on 2023-04-03, 22:23 authored by Vallijah Subasri, Nicholas Light, Nisha Kanwar, Jack Brzezinski, Ping Luo, Jordan R Hansford, Elizabeth Cairney, Carol Portwine, Christine Elser, Jonathan L. Finlay, Kim E. Nichols, Noa Alon, Ledia Brunga, Jo Anson, Wendy Kohlmann, Kelvin C. de Andrade, Payal P. Khincha, Sharon A. Savage, Joshua D Schiffman, Rosanna Weksberg, Trevor J. Pugh, Anita Villani, Adam Shlien, Anna Goldenberg, David Malkin

1000G Variants



Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of individuals who fit the clinical definition of LFS harbour a pathogenic germline variant in the TP53 tumour suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers, approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumour detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of LFS patients (n=396) with variant (n=374) or wildtype TP53 (n=22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harboured a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the non-coding genome and methylome to identify inherited epimutations in genes including ASXL1, ETV6 and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in LFS patients with an AUROC of 0.725 [0.633-0.810].