Bergrún Ásbjörnsdóttir, Sigurgeir Ólafsson, Emilie C. H. Breekveldt, Monique E. van Leerdam, Pétur Snæbjörnsson and Kári Stefánsson
Introduction
Cancer genomes typically contain thousands of somatic mutations. Many anticancer treatments have mutagenic properties and treatment-induced mutational signatures, in cancer cells, have been reported. Epidemiological evidence also suggests that testicular cancer survivors, treated with platinum-based chemotherapy, are at increased risk of developing second primary colorectal cancer. Little is known about the impact of platinum-based chemotherapy on normal cells, but understanding the evolutionary forces within normal cells is important for comprehending the development of colorectal cancer.
Methods
We used laser capture microdissection (LCM) to isolate 100 normal colonic crypts from 15 patients who underwent cisplatin treatment, a platinum-based chemotherapy, for testicular cancer. Each crypt serves as a clonal unit, consisting of approximately 2000 cells. Subsequently, we performed whole-genome sequencing of the crypts to identify somatic mutations. Phylogenetic trees were then constructed.
Results
Patients have an excess of hundreds to thousands of somatic mutations compared to what is expected for their age. We quantified the number of mutations that result from each cycle of cisplatin chemotherapy. Additionally, mutational signatures were revealed; some, including known cisplatin signature (SBS35), were widespread and persistent, while others were found only in certain individuals or specific crypts. We do not see evidence of cisplatin increasing clonal spread within the colon.
Conclusions
Our study provides valuable insights into the relationship between exposure of cisplatin treatment and somatic mutagenesis in normal colorectal epithelial cells. Our findings suggest that cisplatin treatments are mutagenic, but we cannot conclude that cisplatin modifies the selection landscape and clonal spread within the colon.
