Abstract 847: Association of methylation-based stem cell divisions with lifetime cancer risk and cancer progression

Abstract Cancer initiation arises from the accumulation of somatic mutations acquired during stem cell mitotic events mediated by carcinogenic risk factors. On an ecological level, Tomasetti and Vogelstein (2015) demonstrated that lifetime risk of solid tumor cancer types were strongly correlated with total number of stem cell divisions estimated from tissue-specific cell lines. Recently, several mitotic clocks (MC) have been developed to estimate stem cell division rates (SCDR) based on whole-genome methylation arrays. Here, we compare estimated SCDR for several tissue types with tissue-specific cancer incidence and lifetime risk estimates. Furthermore, we assess the link between SCDR with cancer progression and survival. Array-based methylation data derived from normal adjacent tissue in TCGA was used to estimate SCDR for 15 cancer types. A Pearson correlation test was performed to assess the association between SCDR and cancer-specific incidence and lifetime risk for each cancer type overall and stratified by self-reported race (e.g. White and Black). SCDR was estimated in tumors from TCGA for 4 common cancers and subtypes: breast (BRCA), prostate (PRAD), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). A Spearman correlation test was used to identify potential trends between SCDR and pathological stage. Cox proportional hazard (PH) models adjusted for age at diagnosis and treatment status (e.g. surgery, radiation, etc.) were used to evaluate the association of time to death with SCDR terciles across different cancer stages. We observed a similar trend between SCDR and overall incidence (cor=0.61, p=0.01), aligning with earlier findings. Stratified-specific trends between cancer incidence and SCDR was consistent for both Black and White populations (cor=0.62 vs 0.66). Tumor analysis revealed a significant correlation between SCDR and pathological stage (e.g. stage 1, 2, and 3/4) for BRCA (p<0.001) and pathological stage (e.g. stage 2, 3 and 4) for PRAD (p<0.001), suggesting its potential as a marker of cancer progression. However, the correlation between LUAD, LUSC and pathological stage was insignificant. Based on Cox PH model, within stage III BRCA, SCDR significantly contributed to explaining variability in survival (p=0.04), emphasizing its potential prognostic value beyond cancer stage. Our study supports earlier findings applying methylation based SCDR estimates and shows that this association is consistent across racial groups. This implies that SCDR may act as a biological marker of a combination of various genetic and environmental risk factors underlying disease etiology. Further analyses will be extended to all cancers in TCGA. Lastly, we demonstrate that MC-based SCDR estimation has the potential to serve as a clinical tool to identify individuals at elevated risk of cancer initiation, track progression, and complement cancer stage for predicting survival. Citation Format: Yanning Wu, Cheryl Thompson, Fredrick Schumacher. Association of methylation-based stem cell divisions with lifetime cancer risk and cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 847.