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

• Published in: International journal of cancer Vol. 145; no. 3; pp. 694 - 704
• Main Authors: Németh, Eszter, Krzystanek, Marcin, Reiniger, Lilla, Ribli, Dezső, Pipek, Orsolya, Sztupinszki, Zsófia, Glasz, Tibor, Csabai, István, Moldvay, Judit, Szallasi, Zoltan, Szüts, Dávid
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.08.2019; Wiley Subscription Services, Inc
• Subjects: Adenocarcinoma; Adenocarcinoma of Lung - blood; Adenocarcinoma of Lung - drug therapy; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - pathology; afatinib; Algorithms; Autopsies; Autopsy; Cancer; Cancer therapies; Chemotherapy; Cisplatin; Cisplatin - administration & dosage; Cisplatin - adverse effects; EGFR amplification; EGFR T790M; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; Gefitinib; Gefitinib - administration & dosage; Gefitinib - adverse effects; Gene frequency; Gene Rearrangement; Genome-Wide Association Study; Genomes; Genomic Imprinting - drug effects; Humans; lung adenocarcinoma; Lung cancer; Lung Neoplasms - blood; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lungs; Medical research; Metastases; Metastasis; Models, Genetic; Mutagenesis - drug effects; mutagenic chemotherapy; Mutation; Neoplasm Metastasis; Nucleotide sequence; Patients; Protein Kinase Inhibitors - administration & dosage; Retrospective Studies; Tempering; Temporal variations; Tumors; tumour phylogeny; whole genome sequencing; whole genome sequencing; afatinib; tumour phylogeny; lung adenocarcinoma; cisplatin; EGFR T790M; EGFR amplification; mutagenic chemotherapy
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32159

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. What's new? Cancer treatment induces mutations either through direct DNA damage or through the evolutionary selection of resistance mutations. The authors exploited this effect to study temporal tumor phylogeny and the formation of metastases. Using whole‐genome sequences isolated from a patient with lung adenocarcinoma, they identify metastases that arose before or after onset of treatment with platinum and tyrosine kinase inhibitors, underscoring that metastases develop and need to be treated much earlier than they become clinically apparent.