Copy number footprints of platinum-based anticancer therapies

Abstract

Recently, distinct mutational footprints observed in metastatic tumors, secondary malignancies and normal human tissues have been demonstrated to be caused by the exposure to several chemotherapeutic drugs. These characteristic mutations originate from specific lesions caused by these chemicals to the DNA of exposed cells. However, it is unknown whether the exposure to these chemotherapies leads to a specific footprint of larger chromosomal aberrations. Here, we address this question exploiting whole genome sequencing data of metastatic tumors obtained from patients exposed to different chemotherapeutic drugs. As a result, we discovered a specific copy number footprint across tumors from patients previously exposed to platinum-based therapies. This footprint is characterized by a significant increase in the number of chromosomal fragments of copy number 1–4 and size smaller than 10 Mb in exposed tumors with respect to their unexposed counterparts (median 14–387% greater across tumor types). The number of chromosomal fragments characteristic of the platinum-associated CN footprint increases significantly with the activity of the well known platinum-related footprint of single nucleotide variants across exposed tumors.

Whole genome mutational analysis for tumor-informed ctDNA based MRD surveillance, treatment monitoring and biological characterization of urothelial carcinoma

“…Whole-genome doubling (WGD) was identified in 51% of tumors (57/112) by separating tumors based on ploidy and the level of heterozygosity ( Supplementary Fig. S3a ) 21,22 . Tumors with WGD had a significantly higher number of SNVs ( p =0.013) and indels ( p =0.0004) and more TERT mutations ( p =0.02) when compared with near-diploid tumors.…”

“…5a). Whole-genome doubling (WGD) was identified in 51% of tumors (57/112) by separating tumors based on ploidy and the level of heterozygosity 20,21 (Extended Data Fig. 3a).…”

“…Whole genome doubling (WGD) status was determined by separating each sample based on ploidy and level of heterozygosity as previously described 20,21 , resulting in two separate clusters corresponding to near-diploid samples and samples with WGD.…”

Evaluating offspring Genomic and Epigenomic alterations after prenatal exposure to Cancer treatment In Pregnancy (GE-CIP): a multicentric observational study

“…Previous in vivo, ex vivo and clinical studies have shown that chemotherapeutic agents can cross the placental barrier (at passage rates that vary per drug). [11][12][13][14][15][16][17] Additionally, increasing evidence is showing that chemotherapy treatment can leave a genotoxic footprint, consisting of point mutations and/or larger chromosomal abnormalities [18][19][20][21] and induce long-lasting epigenetic changes, such as alterations in the DNA methylation profile [22][23][24] in cancer, and even non-cancerous cells, of directly exposed patients with cancer. Based on the above, it can be speculated that chemotherapeutic agents, administered during pregnancy, could target and damage the fetal DNA.…”