Genomics of lung cancer: tumor evolution, heterogeneity and drug resistance

Ali Saber Hosseinabadi

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    In this thesis we studied genetic alterations in lung cancer associated with COPD, tumor progression and resistance to targeted therapy. We found no significant difference in the percentage of KRAS mutations in 325 lung cancer patients with or without COPD, whereas EGFR mutations were significantly more common in lung cancer patients without COPD. Mutation analysis of all protein-coding exons in three non-small cell lung and two small cell primary lung tumors with their corresponding metastases showed that only half of the mutations were shared between the tumors from different locations in the non-small cell lung cancer patients. In contrast, more than 95% of all mutations in small cell lung cancer patients were shared between the primary and metastatic tumors at different locations. Based on single cell whole genome sequencing of one of the two small cell lung cancer patients, we showed that two out of 83 examined cells of the primary tumor had chromosomal abnormalities that were consistent with the genomic aberrations in the liver metastasis. Finally, we examined three patients using paired-end RNA sequencing and focused on treatment-induced fusion genes as potential mechanisms of resistance to crizotinib. Only one of the four fusion genes could be potentially translated into protein and this fusion was identified in both pre- and post-treatment samples. In summary, we provide new insights into the genomic abnormalities of lung tumors in relation to COPD subtype and resistance to treatment.
    Originele taal-2English
    KwalificatieDoctor of Philosophy
    Toekennende instantie
    • Rijksuniversiteit Groningen
    Begeleider(s)/adviseur
    • van den Berg, Anke, Supervisor
    • Groen, Harry, Supervisor
    • Kok, Klaas, Co-supervisor
    • Hiltermann, Jeroen, Co-supervisor
    Datum van toekenning24-feb.-2016
    Plaats van publicatie[Groningen]
    Uitgever
    Gedrukte ISBN's978-90-367-8497-9
    Elektronische ISBN's978-90-367-8496-2
    StatusPublished - 2016

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