Mutational Changes in Solid Cancer Cells Induce DNA Damage Repair Deficiency in Hematopoietic Cells Leading to a Distinct Spectrum of Clonal Hematopoiesis Independent from Age-Related Clonal Hematopoiesis

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.5605-5605
• Main Authors: Leitner, Theo, Künstner, Axel, Kohl, Michael, Barmwater, Tobias, Ahmed, Helal Mohammed, Caliebe, Almuth, Dazert-Klebsattel, Eva, Fähnrich, Anke, Fliedner, Stephanie, Gebauer, Niklas, Spielmann, Malte, Kirfel, Jutta, Sailer, Verena-Wilbeth, Bastian, Lorenz, Von Bubnoff, Nikolas, Busch, Hauke, Khandanpour, Cyrus
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-184994

Clonal hematopoiesis (CH) is characterized by the acquisition of defined somatic mutations in hematopoietic stem cells (HSC). It is well known that CH contributes to the development of hematological malignancies but also increases the risk of developing non-malignant conditions such as cardiovascular, pulmonary, and inflammatory liver disease. However, less is known about the association between clonal hematopoiesis and solid cancer. Reports suggest that patients with solid cancer have a higher incidence of clonal hematopoiesis at an earlier age and an inferior prognosis. To investigate whether the presence of solid cancer itself can drive the development of clonal hematopoiesis, we analyzed 392 paired tumor and blood samples from patients with advanced cancer. In our cohort, all patients had evidence of clonal hematopoiesis based on a variant allele frequency (VAF) of at least 2%. With respect to a defined set of the 20 most frequently CH-associated genes, we discovered an increased CH rate of 23% of all patients (90 cases, median age of 61 years, defined by a VAF from 2% to 30%). The frequency of mutated genes differed greatly from published data from the general population and cancer patients, with the most common mutations being PABPC1 (39%), KMT2C (28%), RUNX1 (18%), and DNMT3A (10%). In addition, we observed a strong correlation between certain mutations in tumor samples and the frequency of CH. The mutational signature of CH was not mainly associated with a typical chemotherapy-dependent mutational signature, but with an impaired DNA repair capacity. For further investigation, we performed additional experiments in mice, which showed that the presence of malignant cells impairs DNA repair capacity in HSC through inflammatory changes in the stroma. In summary, we were able to show that patients with advanced or recurrent solid tumors have a significantly increased frequency of CH, which is not only the result of prior chemotherapy exposure but the result of diminished DNA repair capacity. This suggests a possible role of solid cancer in promoting the development of CH independent from chemotherapy exposure, which is supported by our additional murine experiments.