Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited cancer predisposition syndrome associated with germline mutations of the TP53 tumor suppressor gene. TP53 mutation carriers are susceptible to a wide range of cancers that occur at strikingly earlier age of onset than their sporadic counterparts. The lifetime cancer risk in TP53 mutation carriers is estimated to be ~73% for males and approaching 100% in females. Although improved survival outcomes have been demonstrated for carriers undergoing intense clinical surveillance, there is continued interest in identifying new environmental, genetic, and epigenetic risk factors that could improve our ability to predict disease onset and outcome. A number of studies have demonstrated age-associated DNA methylation (DNAm) changes at specific CG dinucleotides and that these changes can be combined into epigenetic age predictors to estimate chronological age. Deviation of chronological and predicted age have been associated with age-associated illnesses such as metabolic disease and cancer. For a given chronological age, older epigenetic age is presumed to indicate poorer health.

An epigenetic profile defining the DNA methylation age (DNAm age) of an individual has been suggested to be a biomarker of aging, and thus possibly providing a tool for assessment of health and mortality. Our goal was to test whether DNAm age could be a possible predictor of cancer risk in LFS patients. We applied the DNA age calculator ( (Horvath 2013) to DNA methylation profiles derived from lymphocytes extracted from 157 LFS patients' blood samples using the Illumina HumanMethylation450 BeadChip. While a correlation of DNAm age and actual age was observed in both ‘normal' and LFS patients, the latter showed significant deviations (differences between DNAm age and chronological age). Moreover, the extent of deviations seems selectively associated with two distinct age groups (0-5 years and 20-50 years). Remarkably, this bimodal DNAm age profile shows striking resemblance to the epidemiologically characterized age dependency of LFS cancers (Amadou, 2018). Individuals with germline mutant or germline wild-type TP53 and no cancer showed no epigenetic age acceleration whereas individuals who were carriers of mutant TP53 who developed cancer showed accelerated epigenetic aging. Our preliminary results suggest that DNAm age is a dynamic, real-time correlate of patient-specific cancer risk in LFS. Further, the age dependent deviations suggest that the cancer risk profiles derived from Horvath signatures are dynamic and reflect the changes in cancer risk throughout an individual's lifetime, and could be used as a predictor of cancer onset in TP53 mutation carriers.

Citation Format: Malgorzata Pienkowska, Nardin Samuel, Sanaa Choufani, Vallijah Subasri, Nish Patel, Rosanna Weksberg, Ran Kafri, David Malkin. Horvath clock as a predictor of cancer risk in LFS patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2114.