Association between CH mutation in TET2and solid cancer in elderly Asian women.
Authors: Ye Jiangfeng , Yim Willa , Wan Zi Yi , Goh Denise , Lim Zi Yi , Lim Xinru , Chong Li Yen , Ngo Nye Thane , Lim Tony Kiat Hon , Chua Melvin L.K. , Ho Roger , Tan Min-Han , Yeong Joe Poh Sheng 
Published: June 2024

10585

Background: Clonal hematopoiesis (CH), defined by the expansion of mutated hematopoietic cells due to somatic mutations acquired during aging, is associated with increased age and inflammatory conditions. CH serves as a predictor for the risks of cancer and cardiovascular events, highlighting the importance of early detection of genetic alterations for proactive intervention. As Asian societies are experiencing rapid aging alongside genetic and environmental variations distinct from Western cohorts, we aimed to evaluate the predictive significance of CH in solid cancer in an Asian cohort. Methods: We conducted a nested case-control study within Singapore Longitudinal Ageing Study 1 (SLAS1; NCT03405675). Chinese females (aged 55.0-83.9), comprising 31 patients with solid cancers (breast, lung, colon) who developed cancer during the follow-up, and 29 controls, were randomly selected from the SLAS1. SLAS1 is a community-based longitudinal aging cohort study. Subjects aged 55 years or older, capable of self-ambulation, were recruited between 2003 and 2005 (n=2804) and were followed up in 2005-2007, 2008-2009, and 2018-2020. We linked SLAS1 with records from the Singapore National Death Registry to identify subjects with cancers as cause of death during this period (median follow-up period 17 years). Buffy coat samples taken at baseline were sequenced using the 42-gene target HemeMark panel (Lucence, Singapore) with a reported 0.1% limit of detection. Chi-square test and t-test were performed to compare the frequency of CH variants and the mean number of mutations per person in the case and control group. We evaluated multiple variant allele frequency (VAF) thresholds on an exploratory basis (0.1% to 2%). The relationship between CH mutations and the likelihood of developing cancer was investigated through a logistic regression model, considering CH mutation defined at various cutoff points. Results: CH was found in 29.0% (9/31) of cases and 37.9% (11/29) of controls, with common mutated genes being TET2 (8/31, 25.8%), ASXL1 (4/31, 12.9%), and DNMT3A (2/31, 6.5%) in case group (VAF threshold=0.5%). Multi-gene CH did not predict cancer at any threshold (with the lowest P value of 0.5858 corresponding to VAF 0.5), Genes correlating with increased cancer risk included TET2 with adjusting for age, which was notably significant at thresholds of 0.3% and above (VAF 0.3%, adjusted OR=2.25, 95% CI: 1.14-4.47, p=0.0201; 0.5%, adjusted OR=4.12, 95% CI: 2.00-8.88, p=0.0002). Conclusions: CH determined through multi-genes was not associated with solid cancers, but TET2 mutations at 0.3-0.5% VAF thresholds were more prevalent in cancer cases, as compared to the current 2% threshold used for calling CHIP. The finding in this nested case-control study, conducted within a cohort with a 17-year follow-up, implies a potential association between TET2 mutation and solid cancer. Further study is warranted on a larger cohort.