Deep multi-region whole-genome sequencing reveals heterogeneity and gene-by-environment interactions in treatment-naive, metastatic lung cancer

Tracy L. Leong, Velimir Gayevskiy, Daniel P. Steinfort, Marc R. De Massy, Alvaro Gonzalez-Rajal, Kieren D. Marini, Emily Stone, Venessa Chin, Adrian Havryk, Marshall Plit, Louis B. Irving, Barton R. Jennings, Rachael A. McCloy, W. Samantha N. Jayasekara, Muhammad Alamgeer, Vishal Boolell, Andrew Field, Prudence A. Russell, Beena Kumar, Daniel J. Gough & 8 others Anette Szczepny, Vinod Ganju, Fernando J. Rossello, Jason E. Cain, Anthony T. Papenfuss, Marie Liesse Asselin-Labat, Mark J. Cowley, D. Neil Watkins

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Our understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early-stage surgical specimens. Here we used endoscopic sampling of paired primary and intrathoracic metastatic tumors from 11 lung cancer patients to map genomic heterogeneity inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain. Private mutation signatures, including patterns consistent with defects in homologous recombination, were highly variable both within and between patients. Irrespective of histotype, we observed a smaller than expected number of private mutations, suggesting that ancestral clones accumulated large mutation burdens immediately prior to metastasis. Single-region whole-genome sequencing of from 20 patients showed that tumors in ever-smokers with the strongest tobacco signatures were associated with germline variants in genes implicated in the repair of cigarette-induced DNA damage. Our results suggest that lung cancer precursors in ever-smokers accumulate large numbers of mutations prior to the formation of frank malignancy followed by rapid metastatic spread. In advanced lung cancer, germline variants in DNA repair genes may interact with the airway environment to influence the pattern of founder mutations, whereas similar interactions with the tumor microenvironment may play a role in the acquisition of mutations following metastasis.

Original languageEnglish
Pages (from-to)1661-1675
Number of pages15
JournalOncogene
Volume38
Issue number10
DOIs
Publication statusPublished - 7 Mar 2018

Cite this

Leong, Tracy L. ; Gayevskiy, Velimir ; Steinfort, Daniel P. ; De Massy, Marc R. ; Gonzalez-Rajal, Alvaro ; Marini, Kieren D. ; Stone, Emily ; Chin, Venessa ; Havryk, Adrian ; Plit, Marshall ; Irving, Louis B. ; Jennings, Barton R. ; McCloy, Rachael A. ; Jayasekara, W. Samantha N. ; Alamgeer, Muhammad ; Boolell, Vishal ; Field, Andrew ; Russell, Prudence A. ; Kumar, Beena ; Gough, Daniel J. ; Szczepny, Anette ; Ganju, Vinod ; Rossello, Fernando J. ; Cain, Jason E. ; Papenfuss, Anthony T. ; Asselin-Labat, Marie Liesse ; Cowley, Mark J. ; Watkins, D. Neil. / Deep multi-region whole-genome sequencing reveals heterogeneity and gene-by-environment interactions in treatment-naive, metastatic lung cancer. In: Oncogene. 2018 ; Vol. 38, No. 10. pp. 1661-1675.
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abstract = "Our understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early-stage surgical specimens. Here we used endoscopic sampling of paired primary and intrathoracic metastatic tumors from 11 lung cancer patients to map genomic heterogeneity inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain. Private mutation signatures, including patterns consistent with defects in homologous recombination, were highly variable both within and between patients. Irrespective of histotype, we observed a smaller than expected number of private mutations, suggesting that ancestral clones accumulated large mutation burdens immediately prior to metastasis. Single-region whole-genome sequencing of from 20 patients showed that tumors in ever-smokers with the strongest tobacco signatures were associated with germline variants in genes implicated in the repair of cigarette-induced DNA damage. Our results suggest that lung cancer precursors in ever-smokers accumulate large numbers of mutations prior to the formation of frank malignancy followed by rapid metastatic spread. In advanced lung cancer, germline variants in DNA repair genes may interact with the airway environment to influence the pattern of founder mutations, whereas similar interactions with the tumor microenvironment may play a role in the acquisition of mutations following metastasis.",
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Leong, TL, Gayevskiy, V, Steinfort, DP, De Massy, MR, Gonzalez-Rajal, A, Marini, KD, Stone, E, Chin, V, Havryk, A, Plit, M, Irving, LB, Jennings, BR, McCloy, RA, Jayasekara, WSN, Alamgeer, M, Boolell, V, Field, A, Russell, PA, Kumar, B, Gough, DJ, Szczepny, A, Ganju, V, Rossello, FJ, Cain, JE, Papenfuss, AT, Asselin-Labat, ML, Cowley, MJ & Watkins, DN 2018, 'Deep multi-region whole-genome sequencing reveals heterogeneity and gene-by-environment interactions in treatment-naive, metastatic lung cancer' Oncogene, vol. 38, no. 10, pp. 1661-1675. https://doi.org/10.1038/s41388-018-0536-1

Deep multi-region whole-genome sequencing reveals heterogeneity and gene-by-environment interactions in treatment-naive, metastatic lung cancer. / Leong, Tracy L.; Gayevskiy, Velimir; Steinfort, Daniel P.; De Massy, Marc R.; Gonzalez-Rajal, Alvaro; Marini, Kieren D.; Stone, Emily; Chin, Venessa; Havryk, Adrian; Plit, Marshall; Irving, Louis B.; Jennings, Barton R.; McCloy, Rachael A.; Jayasekara, W. Samantha N.; Alamgeer, Muhammad; Boolell, Vishal; Field, Andrew; Russell, Prudence A.; Kumar, Beena; Gough, Daniel J.; Szczepny, Anette; Ganju, Vinod; Rossello, Fernando J.; Cain, Jason E.; Papenfuss, Anthony T.; Asselin-Labat, Marie Liesse; Cowley, Mark J.; Watkins, D. Neil.

In: Oncogene, Vol. 38, No. 10, 07.03.2018, p. 1661-1675.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Deep multi-region whole-genome sequencing reveals heterogeneity and gene-by-environment interactions in treatment-naive, metastatic lung cancer

AU - Leong, Tracy L.

AU - Gayevskiy, Velimir

AU - Steinfort, Daniel P.

AU - De Massy, Marc R.

AU - Gonzalez-Rajal, Alvaro

AU - Marini, Kieren D.

AU - Stone, Emily

AU - Chin, Venessa

AU - Havryk, Adrian

AU - Plit, Marshall

AU - Irving, Louis B.

AU - Jennings, Barton R.

AU - McCloy, Rachael A.

AU - Jayasekara, W. Samantha N.

AU - Alamgeer, Muhammad

AU - Boolell, Vishal

AU - Field, Andrew

AU - Russell, Prudence A.

AU - Kumar, Beena

AU - Gough, Daniel J.

AU - Szczepny, Anette

AU - Ganju, Vinod

AU - Rossello, Fernando J.

AU - Cain, Jason E.

AU - Papenfuss, Anthony T.

AU - Asselin-Labat, Marie Liesse

AU - Cowley, Mark J.

AU - Watkins, D. Neil

PY - 2018/3/7

Y1 - 2018/3/7

N2 - Our understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early-stage surgical specimens. Here we used endoscopic sampling of paired primary and intrathoracic metastatic tumors from 11 lung cancer patients to map genomic heterogeneity inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain. Private mutation signatures, including patterns consistent with defects in homologous recombination, were highly variable both within and between patients. Irrespective of histotype, we observed a smaller than expected number of private mutations, suggesting that ancestral clones accumulated large mutation burdens immediately prior to metastasis. Single-region whole-genome sequencing of from 20 patients showed that tumors in ever-smokers with the strongest tobacco signatures were associated with germline variants in genes implicated in the repair of cigarette-induced DNA damage. Our results suggest that lung cancer precursors in ever-smokers accumulate large numbers of mutations prior to the formation of frank malignancy followed by rapid metastatic spread. In advanced lung cancer, germline variants in DNA repair genes may interact with the airway environment to influence the pattern of founder mutations, whereas similar interactions with the tumor microenvironment may play a role in the acquisition of mutations following metastasis.

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