Whole exome sequencing and machine learning germline analysis of individuals presenting with extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma
Background Tobacco is the main risk factor for developing lung cancer. Yet, while some heavy smokers develop lung cancer at a young age, other heavy smokers never develop it, even at an advanced age, suggesting a remarkable variability in the individual susceptibility to the carcinogenic effects of...
| Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | article |
| Publication Date: | 2024 |
| Country: | España |
| Institution: | Universidad de Navarra |
| Repository: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Language: | English |
| OAI Identifier: | oai:dadun.unav.edu:10171/111407 |
| Online Access: | https://hdl.handle.net/10171/111407 |
| Access Level: | Open access |
| Keyword: | Cancer risk Extreme phenotypes Whole exome sequencing Tobacco Lung adenocarcinoma |
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Whole exome sequencing and machine learning germline analysis of individuals presenting with extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma |
| title |
Whole exome sequencing and machine learning germline analysis of individuals presenting with extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma |
| spellingShingle |
Whole exome sequencing and machine learning germline analysis of individuals presenting with extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma Patiño-García, A. (Ana)|||/items/d68c74f1-df22-4e04-9b77-9cf48fd87b46 Cancer risk Extreme phenotypes Whole exome sequencing Tobacco Lung adenocarcinoma |
| title_short |
Whole exome sequencing and machine learning germline analysis of individuals presenting with extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma |
| title_full |
Whole exome sequencing and machine learning germline analysis of individuals presenting with extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma |
| title_fullStr |
Whole exome sequencing and machine learning germline analysis of individuals presenting with extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma |
| title_full_unstemmed |
Whole exome sequencing and machine learning germline analysis of individuals presenting with extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma |
| title_sort |
Whole exome sequencing and machine learning germline analysis of individuals presenting with extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma |
| dc.creator.none.fl_str_mv |
Patiño-García, A. (Ana)|||/items/d68c74f1-df22-4e04-9b77-9cf48fd87b46 Guruceaga-Martínez, E. (Elizabeth)|||/items/71d8df8b-4fab-4004-a38e-4057dddc85b2 Ocón-de-Miguel, M.M. (María del Mar)|||/items/55eb0fb0-0bc0-44f1-8925-d82b06764cb2 Sokoudjou, J.F. (Junior Fodop)|||/items/e2613050-7766-45a9-b02b-a23d9f355bd5 Villalonga-Zornoza, N. (Nicolás de)|||/items/e7827adb-1dfb-4025-92e6-15cea32a42bb Alkorta-Aranburu, G. (Gorka)|||/items/1b68902d-4b46-4598-959f-c3dfe99df2c8 Tamayo-Uria, I. (Ibon)|||/items/c12d0077-933b-40cd-b2ef-0532d694168f Gurpide-Ayarra, L.A. (Luis Alfonso)|||/items/0935e09d-b036-414b-ac0f-688dbfa94d7f Camps, C. (Carlos)|||/items/3f670e07-35ed-47eb-b769-ed71635a78dc Jantus-Lewintre, E. (Eloisa)|||/items/efd6c26d-c4fa-48fc-b7ba-040557d28e4a Navamuel-Andueza, M. (María)|||/items/e8e7be4d-3a77-4634-9f88-1914ef58ce58 Fernández-de-Sanmamed-Gutiérrez, M. (Miguel)|||/items/35ac602c-f0ff-4664-bbd2-506afc96db09 Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e Elgendy, M. (Mohamed)|||/items/4f21126e-5b25-439c-abda-48b8b4349ca2 Fusco, J.P. (Juan Pablo)|||/items/fe28f0c1-acce-4320-8bbe-04283c0e7f6f Zulueta, J. (Javier)|||/items/1979cb86-b86c-41b7-8494-1f00acb7eb1f Torres-Tajes, J.P. (Juan Pablo) de|||/items/b7010baa-6964-4f25-a3e0-7e5586fb3f4c Bastarrika-Alemañ, G. (Gorka)|||/items/70f0d5d9-0b96-4349-8554-ab3ba7158250 Seijo, L. (Luis)|||/items/abfac499-8cb5-4c80-9152-88309b94a9ae Pio, R. (Rubén)|||/items/d5c409b3-dbed-4f0c-8bad-94c31e0e5a95 Montuenga-Badia, L.M. (Luis M.)|||/items/4c999705-b2c9-45ac-ba13-3f18594ae596 Hernaez-Arrazola, M. (Mikel)|||/items/954a4ee7-b04c-4dc5-9bfc-7a48332c7e5a Perez-Gracia, J.L. (Jose Luis)|||/items/7be82c5d-4858-4e04-bd77-7ef5a883021b Ochoa-Álvarez, I. (Idoia)|||/items/6326dacc-419f-4156-a9c3-9e79cfcc6a3c |
| author |
Patiño-García, A. (Ana)|||/items/d68c74f1-df22-4e04-9b77-9cf48fd87b46 |
| author_facet |
Patiño-García, A. (Ana)|||/items/d68c74f1-df22-4e04-9b77-9cf48fd87b46 Guruceaga-Martínez, E. (Elizabeth)|||/items/71d8df8b-4fab-4004-a38e-4057dddc85b2 Ocón-de-Miguel, M.M. (María del Mar)|||/items/55eb0fb0-0bc0-44f1-8925-d82b06764cb2 Sokoudjou, J.F. (Junior Fodop)|||/items/e2613050-7766-45a9-b02b-a23d9f355bd5 Villalonga-Zornoza, N. (Nicolás de)|||/items/e7827adb-1dfb-4025-92e6-15cea32a42bb Alkorta-Aranburu, G. (Gorka)|||/items/1b68902d-4b46-4598-959f-c3dfe99df2c8 Tamayo-Uria, I. (Ibon)|||/items/c12d0077-933b-40cd-b2ef-0532d694168f Gurpide-Ayarra, L.A. (Luis Alfonso)|||/items/0935e09d-b036-414b-ac0f-688dbfa94d7f Camps, C. (Carlos)|||/items/3f670e07-35ed-47eb-b769-ed71635a78dc Jantus-Lewintre, E. (Eloisa)|||/items/efd6c26d-c4fa-48fc-b7ba-040557d28e4a Navamuel-Andueza, M. (María)|||/items/e8e7be4d-3a77-4634-9f88-1914ef58ce58 Fernández-de-Sanmamed-Gutiérrez, M. (Miguel)|||/items/35ac602c-f0ff-4664-bbd2-506afc96db09 Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e Elgendy, M. (Mohamed)|||/items/4f21126e-5b25-439c-abda-48b8b4349ca2 Fusco, J.P. (Juan Pablo)|||/items/fe28f0c1-acce-4320-8bbe-04283c0e7f6f Zulueta, J. (Javier)|||/items/1979cb86-b86c-41b7-8494-1f00acb7eb1f Torres-Tajes, J.P. (Juan Pablo) de|||/items/b7010baa-6964-4f25-a3e0-7e5586fb3f4c Bastarrika-Alemañ, G. (Gorka)|||/items/70f0d5d9-0b96-4349-8554-ab3ba7158250 Seijo, L. (Luis)|||/items/abfac499-8cb5-4c80-9152-88309b94a9ae Pio, R. (Rubén)|||/items/d5c409b3-dbed-4f0c-8bad-94c31e0e5a95 Montuenga-Badia, L.M. (Luis M.)|||/items/4c999705-b2c9-45ac-ba13-3f18594ae596 Hernaez-Arrazola, M. (Mikel)|||/items/954a4ee7-b04c-4dc5-9bfc-7a48332c7e5a Perez-Gracia, J.L. (Jose Luis)|||/items/7be82c5d-4858-4e04-bd77-7ef5a883021b Ochoa-Álvarez, I. (Idoia)|||/items/6326dacc-419f-4156-a9c3-9e79cfcc6a3c |
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author |
| author2 |
Guruceaga-Martínez, E. (Elizabeth)|||/items/71d8df8b-4fab-4004-a38e-4057dddc85b2 Ocón-de-Miguel, M.M. (María del Mar)|||/items/55eb0fb0-0bc0-44f1-8925-d82b06764cb2 Sokoudjou, J.F. (Junior Fodop)|||/items/e2613050-7766-45a9-b02b-a23d9f355bd5 Villalonga-Zornoza, N. (Nicolás de)|||/items/e7827adb-1dfb-4025-92e6-15cea32a42bb Alkorta-Aranburu, G. (Gorka)|||/items/1b68902d-4b46-4598-959f-c3dfe99df2c8 Tamayo-Uria, I. (Ibon)|||/items/c12d0077-933b-40cd-b2ef-0532d694168f Gurpide-Ayarra, L.A. (Luis Alfonso)|||/items/0935e09d-b036-414b-ac0f-688dbfa94d7f Camps, C. (Carlos)|||/items/3f670e07-35ed-47eb-b769-ed71635a78dc Jantus-Lewintre, E. (Eloisa)|||/items/efd6c26d-c4fa-48fc-b7ba-040557d28e4a Navamuel-Andueza, M. (María)|||/items/e8e7be4d-3a77-4634-9f88-1914ef58ce58 Fernández-de-Sanmamed-Gutiérrez, M. (Miguel)|||/items/35ac602c-f0ff-4664-bbd2-506afc96db09 Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e Elgendy, M. (Mohamed)|||/items/4f21126e-5b25-439c-abda-48b8b4349ca2 Fusco, J.P. (Juan Pablo)|||/items/fe28f0c1-acce-4320-8bbe-04283c0e7f6f Zulueta, J. (Javier)|||/items/1979cb86-b86c-41b7-8494-1f00acb7eb1f Torres-Tajes, J.P. (Juan Pablo) de|||/items/b7010baa-6964-4f25-a3e0-7e5586fb3f4c Bastarrika-Alemañ, G. (Gorka)|||/items/70f0d5d9-0b96-4349-8554-ab3ba7158250 Seijo, L. (Luis)|||/items/abfac499-8cb5-4c80-9152-88309b94a9ae Pio, R. (Rubén)|||/items/d5c409b3-dbed-4f0c-8bad-94c31e0e5a95 Montuenga-Badia, L.M. (Luis M.)|||/items/4c999705-b2c9-45ac-ba13-3f18594ae596 Hernaez-Arrazola, M. (Mikel)|||/items/954a4ee7-b04c-4dc5-9bfc-7a48332c7e5a Perez-Gracia, J.L. (Jose Luis)|||/items/7be82c5d-4858-4e04-bd77-7ef5a883021b Ochoa-Álvarez, I. (Idoia)|||/items/6326dacc-419f-4156-a9c3-9e79cfcc6a3c |
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author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
Cancer risk Extreme phenotypes Whole exome sequencing Tobacco Lung adenocarcinoma |
| topic |
Cancer risk Extreme phenotypes Whole exome sequencing Tobacco Lung adenocarcinoma |
| description |
Background Tobacco is the main risk factor for developing lung cancer. Yet, while some heavy smokers develop lung cancer at a young age, other heavy smokers never develop it, even at an advanced age, suggesting a remarkable variability in the individual susceptibility to the carcinogenic effects of tobacco. We characterized the germline profile of subjects presenting these extreme phenotypes with Whole Exome Sequencing (WES) and Machine Learning (ML). Methods We sequenced germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age (extreme cases) or who did not develop lung cancer at an advanced age (extreme controls), selected from databases including over 6600 subjects. We selected individual coding genetic variants and variant-rich genes showing a significantly different distribution between extreme cases and controls. We validated the results from our discovery cohort, in which we analysed by WES extreme cases and controls presenting similar phenotypes. We developed ML models using both cohorts. Findings Mean age for extreme cases and controls was 50.7 and 79.1 years respectively, and mean tobacco consumption was 34.6 and 62.3 pack-years. We validated 16 individual variants and 33 variant-rich genes. The gene harbouring the most validated variants was HLA-A in extreme controls (4 variants in the discovery cohort, p = 3.46E-07; and 4 in the validation cohort, p = 1.67E-06). We trained ML models using as input the 16 individual variants in the discovery cohort and tested them on the validation cohort, obtaining an accuracy of 76.5% and an AUC-ROC of 83.6%. Functions of validated genes included candidate oncogenes, tumour-suppressors, DNA repair, HLA-mediated antigen presentation and regulation of proliferation, apoptosis, inflammation and immune response. Interpretation Individuals presenting extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma show different germline profiles. Our strategy may allow the identification of high-risk subjects and the development of new therapeutic approaches. |
| publishDate |
2024 |
| dc.date.none.fl_str_mv |
2024 2024-01-01 2024 2024-01-01 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/111407 |
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https://hdl.handle.net/10171/111407 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier |
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Elsevier |
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reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
| instname_str |
Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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| _version_ |
1869417460831092736 |
| spelling |
Whole exome sequencing and machine learning germline analysis of individuals presenting with extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinomaPatiño-García, A. (Ana)|||/items/d68c74f1-df22-4e04-9b77-9cf48fd87b46Guruceaga-Martínez, E. (Elizabeth)|||/items/71d8df8b-4fab-4004-a38e-4057dddc85b2Ocón-de-Miguel, M.M. (María del Mar)|||/items/55eb0fb0-0bc0-44f1-8925-d82b06764cb2Sokoudjou, J.F. (Junior Fodop)|||/items/e2613050-7766-45a9-b02b-a23d9f355bd5Villalonga-Zornoza, N. (Nicolás de)|||/items/e7827adb-1dfb-4025-92e6-15cea32a42bbAlkorta-Aranburu, G. (Gorka)|||/items/1b68902d-4b46-4598-959f-c3dfe99df2c8Tamayo-Uria, I. (Ibon)|||/items/c12d0077-933b-40cd-b2ef-0532d694168fGurpide-Ayarra, L.A. (Luis Alfonso)|||/items/0935e09d-b036-414b-ac0f-688dbfa94d7fCamps, C. (Carlos)|||/items/3f670e07-35ed-47eb-b769-ed71635a78dcJantus-Lewintre, E. (Eloisa)|||/items/efd6c26d-c4fa-48fc-b7ba-040557d28e4aNavamuel-Andueza, M. (María)|||/items/e8e7be4d-3a77-4634-9f88-1914ef58ce58Fernández-de-Sanmamed-Gutiérrez, M. (Miguel)|||/items/35ac602c-f0ff-4664-bbd2-506afc96db09Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4eElgendy, M. (Mohamed)|||/items/4f21126e-5b25-439c-abda-48b8b4349ca2Fusco, J.P. (Juan Pablo)|||/items/fe28f0c1-acce-4320-8bbe-04283c0e7f6fZulueta, J. (Javier)|||/items/1979cb86-b86c-41b7-8494-1f00acb7eb1fTorres-Tajes, J.P. (Juan Pablo) de|||/items/b7010baa-6964-4f25-a3e0-7e5586fb3f4cBastarrika-Alemañ, G. (Gorka)|||/items/70f0d5d9-0b96-4349-8554-ab3ba7158250Seijo, L. (Luis)|||/items/abfac499-8cb5-4c80-9152-88309b94a9aePio, R. (Rubén)|||/items/d5c409b3-dbed-4f0c-8bad-94c31e0e5a95Montuenga-Badia, L.M. (Luis M.)|||/items/4c999705-b2c9-45ac-ba13-3f18594ae596Hernaez-Arrazola, M. (Mikel)|||/items/954a4ee7-b04c-4dc5-9bfc-7a48332c7e5aPerez-Gracia, J.L. (Jose Luis)|||/items/7be82c5d-4858-4e04-bd77-7ef5a883021bOchoa-Álvarez, I. (Idoia)|||/items/6326dacc-419f-4156-a9c3-9e79cfcc6a3cCancer riskExtreme phenotypesWhole exome sequencingTobaccoLung adenocarcinomaBackground Tobacco is the main risk factor for developing lung cancer. Yet, while some heavy smokers develop lung cancer at a young age, other heavy smokers never develop it, even at an advanced age, suggesting a remarkable variability in the individual susceptibility to the carcinogenic effects of tobacco. We characterized the germline profile of subjects presenting these extreme phenotypes with Whole Exome Sequencing (WES) and Machine Learning (ML). Methods We sequenced germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age (extreme cases) or who did not develop lung cancer at an advanced age (extreme controls), selected from databases including over 6600 subjects. We selected individual coding genetic variants and variant-rich genes showing a significantly different distribution between extreme cases and controls. We validated the results from our discovery cohort, in which we analysed by WES extreme cases and controls presenting similar phenotypes. We developed ML models using both cohorts. Findings Mean age for extreme cases and controls was 50.7 and 79.1 years respectively, and mean tobacco consumption was 34.6 and 62.3 pack-years. We validated 16 individual variants and 33 variant-rich genes. The gene harbouring the most validated variants was HLA-A in extreme controls (4 variants in the discovery cohort, p = 3.46E-07; and 4 in the validation cohort, p = 1.67E-06). We trained ML models using as input the 16 individual variants in the discovery cohort and tested them on the validation cohort, obtaining an accuracy of 76.5% and an AUC-ROC of 83.6%. Functions of validated genes included candidate oncogenes, tumour-suppressors, DNA repair, HLA-mediated antigen presentation and regulation of proliferation, apoptosis, inflammation and immune response. Interpretation Individuals presenting extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma show different germline profiles. Our strategy may allow the identification of high-risk subjects and the development of new therapeutic approaches.ElsevierDadun. Depósito Académico Digital Universidad de Navarra20242024-01-0120242024-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/111407reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/1114072026-06-21T12:47:57Z |
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15,198674 |