Universität zu Köln

de Biase, Maria Stella, Massip, Florian, Wei, Tzu-Ting, Giorgi, Federico M. ORCID: 0000-0002-7325-9908, Stark, Rory, Stone, Amanda, Gladwell, Amy, O’Reilly, Martin, Schütte, Daniel ORCID: 0000-0002-4746-537X, de Santiago, Ines, Meyer, Kerstin B. ORCID: 0000-0001-5906-1498, Markowetz, Florian, Ponder, Bruce A. J., Rintoul, Robert C. ORCID: 0000-0003-3875-3780 and Schwarz, Roland F. ORCID: 0000-0001-9155-4268 (2024). Smoking-associated gene expression alterations in nasal epithelium reveal immune impairment linked to lung cancer risk. Genome Medicine, 16 (1). pp. 1-19. Springer Nature. ISSN 1756-994X

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Abstract

[Artikel-Nr.: 54] Background: Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to modifiable lifestyle risk in the form of tobacco smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, 40% of which occur more than 15 years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk remain unclear. We thus set out to examine whether risk stratification in the clinic and in the general population can be improved upon by the addition of genetic data and to explore the mechanisms of the persisting risk in former smokers. Methods: We analysed transcriptomic data from accessible airway tissues of 487 subjects, including healthy volunteers and clinic patients of different smoking statuses. We developed a computational model to assess smoking-associated gene expression changes and their reversibility after smoking is stopped, comparing healthy subjects to clinic patients with and without lung cancer. Results: We find persistent smoking-associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune- and interferon-related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier. Conclusions: Our results provide initial evidence for germline-mediated personalized smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code de Biase, Maria Stella UNSPECIFIED UNSPECIFIED UNSPECIFIED Massip, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Wei, Tzu-Ting UNSPECIFIED UNSPECIFIED UNSPECIFIED Giorgi, Federico M. UNSPECIFIED https://orcid.org/0000-0002-7325-9908 UNSPECIFIED Stark, Rory UNSPECIFIED UNSPECIFIED UNSPECIFIED Stone, Amanda UNSPECIFIED UNSPECIFIED UNSPECIFIED Gladwell, Amy UNSPECIFIED UNSPECIFIED UNSPECIFIED O’Reilly, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Schütte, Daniel UNSPECIFIED https://orcid.org/0000-0002-4746-537X UNSPECIFIED de Santiago, Ines UNSPECIFIED UNSPECIFIED UNSPECIFIED Meyer, Kerstin B. UNSPECIFIED https://orcid.org/0000-0001-5906-1498 UNSPECIFIED Markowetz, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Ponder, Bruce A. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rintoul, Robert C. UNSPECIFIED https://orcid.org/0000-0003-3875-3780 UNSPECIFIED Schwarz, Roland F. UNSPECIFIED https://orcid.org/0000-0001-9155-4268 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-815331
Identification Number:	10.1186/s13073-024-01317-4
Journal or Publication Title:	Genome Medicine
Volume:	16
Number:	1
Page Range:	pp. 1-19
Number of Pages:	19
Date:	8 April 2024
Publisher:	Springer Nature
ISSN:	1756-994X
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Weitere > Centrum für integrierte Onkologie (CIO)
Subjects:	Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81533