Clinically relevant shifts in endogenous and exogenous mutational processes proximate to metastasis support local consolidative treatment in EGFR-driven non-small cell lung cancer
Abstract The progression of cancer—including the acquisition of therapeutic resistance and the fatal metastatic spread of therapy-resistant cell populations—is an evolutionary process that is challenging to monitor between sampling timepoints. Here we apply mutational signature analysis to clinically correlated cancer chronograms to detect and describe the shifting mutational processes caused by both endogenous (e.g. mutator mutation) and exogenous (e.g. therapeutic) factors between tumor sampling timepoints. In one patient, we find that cisplatin therapy can introduce mutations that increase the likelihood of genetic adaptation to subsequent targeted therapeutics. In another patient, we trace the emergence of known driver mutation CTNNB1 S37C to specific detection of defective mismatch repair associated mutational signature SBS3. Metastatic lineages were found to emerge from a single ancestral lineage arising during therapy—a finding that argues for the consideration of local consolidative therapy over other therapeutic approaches in EGFR-positive non-small cell lung cancer. Broadly, these results demonstrate the utility of phylogenetic analysis that incorporates clinical time course and mutational signature detection to inform clinical decision making and retrospective assessment of disease etiology..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 25. Mai Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Fisk, J. Nicholas [VerfasserIn] |
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| Links: |
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| doi: |
10.1101/2021.05.04.21256425 |
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| PPN (Katalog-ID): |
XBI020503466 |
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| 520 | |a Abstract The progression of cancer—including the acquisition of therapeutic resistance and the fatal metastatic spread of therapy-resistant cell populations—is an evolutionary process that is challenging to monitor between sampling timepoints. Here we apply mutational signature analysis to clinically correlated cancer chronograms to detect and describe the shifting mutational processes caused by both endogenous (e.g. mutator mutation) and exogenous (e.g. therapeutic) factors between tumor sampling timepoints. In one patient, we find that cisplatin therapy can introduce mutations that increase the likelihood of genetic adaptation to subsequent targeted therapeutics. In another patient, we trace the emergence of known driver mutation CTNNB1 S37C to specific detection of defective mismatch repair associated mutational signature SBS3. Metastatic lineages were found to emerge from a single ancestral lineage arising during therapy—a finding that argues for the consideration of local consolidative therapy over other therapeutic approaches in EGFR-positive non-small cell lung cancer. Broadly, these results demonstrate the utility of phylogenetic analysis that incorporates clinical time course and mutational signature detection to inform clinical decision making and retrospective assessment of disease etiology. | ||
| 700 | 1 | |a Mahal, Amandeep R. |e verfasserin |4 aut | |
| 700 | 1 | |a Dornburg, Alex |e verfasserin |4 aut | |
| 700 | 1 | |a Gaffney, Stephen G. |e verfasserin |4 aut | |
| 700 | 1 | |a Aneja, Sanjay |e verfasserin |4 aut | |
| 700 | 1 | |a Contessa, Joseph N. |e verfasserin |4 aut | |
| 700 | 1 | |a Rimm, David |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, James B. |e verfasserin |4 aut | |
| 700 | 1 | |a Townsend, Jeffrey P. |e verfasserin |4 aut | |
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