{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/385573"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/385573","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Somatic variation, carcinogenesis and cancer risk in the lung","abstract":"Somatic evolution is the driving force behind carcinogenesis, a principle recently underscored by discoveries in normal tissue. These discoveries have highlighted an underappreciated diversity of somatic mosaicism within every tissue and across individuals. Human tissue comprises thousands of macroscopically and microscopically sized cellular populations, each distinct in their genomic composition. The landscape of these clones, their competition, and their response to environmental influences shape the overall state of organs, eventually leading to loss of functionality and disease. Historically, cancer has been perceived as an evolutionary process involving the continuous acquisition of crucial alterations in a single cell, eventually resulting in its transformation into a cancer cell. However, observing the first changes that occur in normal cells during their progression to cancer and how exposures and risk factors alter mutation rates and clonal expansions has only recently become possible. In this thesis, we explore how evolution shapes the landscape of somatic mutations and clonal populations within an individual. Specifically, we use the lung and lung cancer as a primary example, given the exposure to environmental carcinogens, most notably tobacco, and the high prevalence of lung cancer. Chapter 1 provides the foundation for this work, introducing key concepts. Chapter 2 describes the materials and methods. In chapters 3 and 4, we conduct normal tissue sequencing studies, focusing on the two main compartments of the lung: the proximal airways and the alveoli. We combine the findings of a previously published study by Yoshida et al. with results from this work to shed light on seminal models of carcinogenesis, proposed half a century ago, but now testable with modern sequencing techniques. Chapter 5 provides an initial attempt at studying the clonal landscape at a population scale, focusing on non- and minimally invasive samples to characterise somatic variation in individuals with smoking exposure and distinct treatments. By contextualising these findings within concepts of carcinogenesis and clonal competition, we assess the scientific evidence supporting potential interventions and, most prominently, cancer risk prediction based on clonal landscapes. Notably, we also highlight the utility of this principle in breast tissue, provided as an appendix chapter. Overall, this thesis argues that studying somatic mutations in healthy populations offers valuable insights for predicting cancer risk and could facilitate early detection. Studying somatic evolution — the synergy between somatic mutation and clonal selection — will shape cancer research over the next decade, contributing to breakthroughs in cancer prevention.","abstract_html":"Somatic evolution is the driving force behind carcinogenesis, a principle recently underscored by discoveries in normal tissue. These discoveries have highlighted an underappreciated diversity of somatic mosaicism within every tissue and across individuals. Human tissue comprises thousands of macroscopically and microscopically sized cellular populations, each distinct in their genomic composition. The landscape of these clones, their competition, and their response to environmental influences shape the overall state of organs, eventually leading to loss of functionality and disease. Historically, cancer has been perceived as an evolutionary process involving the continuous acquisition of crucial alterations in a single cell, eventually resulting in its transformation into a cancer cell. However, observing the first changes that occur in normal cells during their progression to cancer and how exposures and risk factors alter mutation rates and clonal expansions has only recently become possible. In this thesis, we explore how evolution shapes the landscape of somatic mutations and clonal populations within an individual. Specifically, we use the lung and lung cancer as a primary example, given the exposure to environmental carcinogens, most notably tobacco, and the high prevalence of lung cancer. Chapter 1 provides the foundation for this work, introducing key concepts. Chapter 2 describes the materials and methods. In chapters 3 and 4, we conduct normal tissue sequencing studies, focusing on the two main compartments of the lung: the proximal airways and the alveoli. We combine the findings of a previously published study by Yoshida et al. with results from this work to shed light on seminal models of carcinogenesis, proposed half a century ago, but now testable with modern sequencing techniques. Chapter 5 provides an initial attempt at studying the clonal landscape at a population scale, focusing on non- and minimally invasive samples to characterise somatic variation in individuals with smoking exposure and distinct treatments. By contextualising these findings within concepts of carcinogenesis and clonal competition, we assess the scientific evidence supporting potential interventions and, most prominently, cancer risk prediction based on clonal landscapes. Notably, we also highlight the utility of this principle in breast tissue, provided as an appendix chapter. Overall, this thesis argues that studying somatic mutations in healthy populations offers valuable insights for predicting cancer risk and could facilitate early detection. Studying somatic evolution — the synergy between somatic mutation and clonal selection — will shape cancer research over the next decade, contributing to breakthroughs in cancer prevention.","abstract_has_math":false,"creators":["Przybilla, Moritz"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Martincorena, Iñigo","Campbell, Peter"],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-09-30","date_published":"2024-09-30","updated_at":"2026-07-22T22:24:24Z","subjects":["Cancer risk","Carcinogenesis","Lung cancer","Somatic evolution","Normal tissues"],"languages":[],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/8d326bbd-2a70-44b6-bac8-36925e65b1dc/download","http://purl.org/NET/rdflicense/allrightsreserved"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.119134","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Martincorena, Iñigo","Campbell, Peter"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["This thesis has been in part funded by CRUK grant funding in frame of the following project: Reinterpreting the ‘field of injury’ through understanding cellular level damage and dynamics and consequences for the Prediction, Prevention and Early Detection of lung cancer: ELIMINATE"]},{"key":"dc:creator","label":"Author","values":["Przybilla, Moritz"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2024-09-30"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/385573"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Cancer risk","Carcinogenesis","Lung cancer","Somatic evolution","Normal tissues"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/8d326bbd-2a70-44b6-bac8-36925e65b1dc/download","http://purl.org/NET/rdflicense/allrightsreserved"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2026-06-16"]},{"key":"dc:rights.embargotype","label":"Dc Rights Embargotype","values":["embargo"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.119134"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/cee145bd-34d8-437a-9a54-b7e7d2c2681c/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Somatic evolution is the driving force behind carcinogenesis, a principle recently underscored by discoveries in normal tissue. 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Chapter 5 provides an initial attempt at studying the clonal landscape at a population scale, focusing on non- and minimally invasive samples to characterise somatic variation in individuals with smoking exposure and distinct treatments. By contextualising these findings within concepts of carcinogenesis and clonal competition, we assess the scientific evidence supporting potential interventions and, most prominently, cancer risk prediction based on clonal landscapes. Notably, we also highlight the utility of this principle in breast tissue, provided as an appendix chapter. Overall, this thesis argues that studying somatic mutations in healthy populations offers valuable insights for predicting cancer risk and could facilitate early detection. 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Chapter 5 provides an initial attempt at studying the clonal landscape at a population scale, focusing on non- and minimally invasive samples to characterise somatic variation in individuals with smoking exposure and distinct treatments. By contextualising these findings within concepts of carcinogenesis and clonal competition, we assess the scientific evidence supporting potential interventions and, most prominently, cancer risk prediction based on clonal landscapes. Notably, we also highlight the utility of this principle in breast tissue, provided as an appendix chapter. Overall, this thesis argues that studying somatic mutations in healthy populations offers valuable insights for predicting cancer risk and could facilitate early detection. 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