The genomic imprint of cancer therapies helps timing the formation of metastases

Abstract

A retrospective determination of the time of metastasis formation is essential for a better understanding of the evolution of oligometastatic cancer. This study was based on the hypothesis that genomic alterations induced by cancer therapies could be used to determine the temporal order of the treatment and the formation of metastases. We analysed the whole genome sequence of a primary tumour sample and three metastatic sites derived from autopsy samples from a young never‐smoker lung adenocarcinoma patient with an activating EGFR mutation. Mutation detection methods were refined to accurately detect and distinguish clonal and subclonal mutations. In comparison to a panel of samples from untreated smoker or never‐smoker patients, we showed that the mutagenic effect of cisplatin treatment could be specifically detected from the base substitution mutations. Metastases that arose before or after chemotherapeutic treatment could be distinguished based on the allele frequency of cisplatin‐induced dinucleotide mutations. In addition, genomic rearrangements and late amplification of the EGFR gene likely induced by afatinib treatment following the acquisition of a T790M gefitinib resistance mutation provided further evidence to tie the time of metastasis formation to treatment history. The established analysis pipeline for the detection of treatment‐derived mutations allows the drawing of tumour evolutionary paths based on genomic data, showing that metastases may be seeded well before they become detectable by clinical imaging.

Subclonal somatic copy number alterations emerge and dominate in recurrent osteosarcoma

“…A simple method for ascertaining whether a given metastasis arose before or after treatment with cisplatin or an alkylator is to find clonal SNVs attributed to the respective signature in a metastatic tumor sample 27 . When looking at the dominant clone in the first relapse sample for patients with recurrent disease (OSCE1-Clone D, OSCE4-Clone E/I, OSCE5-Clone C, OSCE6-Clone C/F/G, OSCE9-Clone C/G, OSCE10-Clone C/F), there was a cisplatin signature present in each of these respective clones/clades, indicating that the metastases arose after therapy (Fig.…”

A személyre szabott gyógyászat nyomában. DNS minták tulajdonságainak vizsgálata új generációs szekvenálási adatok alapján

“…Annak illusztrálására, hogy klinikailag milyen jelentősége lehet a kemoterápiás szerek mutagén hatásának részletes leírása, az MTA Enzimológiai Intézetének Genom Stabilitás Kutatócsoportjával végzett kutatásunk [166] során egy fiatal tüdődaganatos férfi többszörös metasztázisainak törzsfáját határoztuk meg a ciszplatin genomi lenyomatának ismeretében. A DT40 sejtvonal ciszplatin mutációs spektrumának meghatározása után nem sokkal a ciszplatin humán sejtvonalakra, illetve daganatsejtekre gyakorolt hatását is feltérképezték [167].…”

Cisplatin is more mutagenic than carboplatin or oxaliplatin at equitoxic concentrations

“…The mutagenicity of cisplatin has been investigated and reported using prokaryotic and eukaryotic reporter gene assays (reviewed by 31,32) and by whole genome sequencing of animals or cell lines (33)(34)(35)(36). The mutagenic footprint of platinum treatment was subsequently also found in the genomes of primary tumours (35,37,38) and metastases (39,40). In comparative studies, cisplatin and carboplatin were found to be similarly mutagenic in the Salmonella histidine reversion assay when a higher concentration of carboplatin was used (41), and cisplatin was found to be more mutagenic than oxaliplatin in the HPRT gene of mammalian cells at equimolar concentrations (42).…”