Protein-altering germline mutations implicate novel genes related to lung cancer development
Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for...
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| Vydáno v: | Nature communications Ročník 11; číslo 1; s. 2220 - 14 |
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| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
London
Nature Publishing Group UK
11.05.2020
Nature Publishing Group Nature Portfolio |
| Témata: | |
| ISSN: | 2041-1723, 2041-1723 |
| On-line přístup: | Získat plný text |
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| Abstract | Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an
ATM
L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82,
P
= 1.18 × 10
−15
) and replication (adjusted OR = 2.93,
P
= 2.22 × 10
−3
) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among
ATM
L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61,
P
= 7.98 × 10
−22
) and replication datasets (adjusted OR = 1.55,
P
= 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene,
KIAA0930
. Our findings implicate germline genetic variants in
ATM
with lung cancer susceptibility and suggest
KIAA0930
as a novel candidate gene for lung cancer risk.
In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk. |
|---|---|
| AbstractList | Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10
) and replication (adjusted OR = 2.93, P = 2.22 × 10
) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10
) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10−15) and replication (adjusted OR = 2.93, P = 2.22 × 10−3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10−22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk. Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10 −15 ) and replication (adjusted OR = 2.93, P = 2.22 × 10 −3 ) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10 −22 ) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930 . Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk. Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10 −15 ) and replication (adjusted OR = 2.93, P = 2.22 × 10 −3 ) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10 −22 ) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930 . Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio=8.82, P=1.18x10(-15)) and replication (adjusted OR=2.93, P=2.22x10(-3)) that is more pronounced in females (adjusted OR=6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR=2.61, P=7.98x10(-22)) and replication datasets (adjusted OR=1.55, P=0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk. Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10−15) and replication (adjusted OR = 2.93, P = 2.22 × 10−3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10−22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. © 2020, The Author(s). |
| ArticleNumber | 2220 |
| Author | McLaughlin, John Gorlova, Olga Shepherd, Frances Goodman, Gary E. Chen, Chu Hellmann, Matthew D. Swiatkowska, Beata Davies, Michael P. A. Andrew, Angeline S. Schabath, Matthew B. Shete, Sanjay Song, Lei Tsao, Ming-Sound Risch, Angela Srinivasan, Preethi Woll, Penella Fernandez-Tardon, Guillermo Gorlov, Ivan Ji, Xuemei Han, Younghun Saliba, Walid Stadler, Zsofia K. Leighl, Natasha Kiemeney, Lambertus FA Ognjanovic, Simona Berger, Michael F. Robson, Mark E. Mukherjee, Semanti Albanes, Demetrios Christiani, David C. Offit, Kenneth Wichmann, Erich Haura, Eric B. Xiao, Xiangjun Bolca, Ciprian Lazarus, Philip Solit, David B. Holcatova, Ivana Timens, Wim Haiman, Christopher Carreras-Torres, Robert Johansson, Mattias Stevens, Victoria Le Marchand, Loic Landi, Maria Teresa Bush, William S. Bickeböller, Heike Aldrich, Melinda C. Bandlamudi, Chaitanya Taylor, Fiona Bakke, Per Johansson, Mikael Butler, Lesley M. Heijden, Erik H. F. M. van der Janout, Vladimir Joubert, Philippe Byun, Jinyoung Mukeria, Anush Melander, Olle Trichopoulou, Antonia Kontic, Milic |
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Sklodowska-Curie Institute – Oncology Center – sequence: 80 givenname: Anush orcidid: 0000-0002-6847-9295 surname: Mukeria fullname: Mukeria, Anush organization: Department of Epidemiology and Prevention, Russian N.N.Blokhin Cancer Research Centre – sequence: 81 givenname: Simona surname: Ognjanovic fullname: Ognjanovic, Simona organization: International Organization for Cancer Prevention and Research – sequence: 82 givenname: Tadeusz M. surname: Orlowski fullname: Orlowski, Tadeusz M. organization: Department of Surgery, National Tuberculosis and Lung Diseases Research Institute – sequence: 83 givenname: Ghislaine surname: Scelo fullname: Scelo, Ghislaine organization: International Agency for Research on Cancer, World Health Organization – sequence: 84 givenname: Beata surname: Swiatkowska fullname: Swiatkowska, Beata organization: Nofer Institute of Occupational Medicine, Department of Environmental Epidemiology – sequence: 86 givenname: Per surname: Bakke fullname: Bakke, Per organization: Department of Clinical Science, University of Bergen – sequence: 88 givenname: Lesley M. surname: Butler fullname: Butler, Lesley M. organization: University of Pittsburgh Cancer Institute – sequence: 89 givenname: Kenneth surname: Offit fullname: Offit, Kenneth organization: Department of Medicine, Memorial Sloan Kettering Cancer Center – sequence: 90 givenname: Preethi surname: Srinivasan fullname: Srinivasan, Preethi organization: Department of Pathology, Memorial Sloan Kettering Cancer Center – sequence: 91 givenname: Chaitanya surname: Bandlamudi fullname: Bandlamudi, Chaitanya organization: Marie-Josée and Henry R. 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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32393777$$D View this record in MEDLINE/PubMed https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-174634$$DView record from Swedish Publication Index (Umeå universitet) |
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| CorporateAuthor | LUCC: Lunds universitets cancercentrum Övriga starka forskningsmiljöer Section V Patologi, Lund Pathology, Lund Kardiovaskulär forskning - hypertoni Department of Clinical Sciences, Lund Strategiska forskningsområden (SFO) Surgery LUCC: Lund University Cancer Centre Medicinska fakulteten Förbättrad diagnostik och prognostik vid lungcancer och metastaser till lunga Institutionen för kliniska vetenskaper, Lund Profile areas and other strong research environments Lunds universitet Department of Clinical Sciences, Malmö Lund University Improved diagnostics and prognostics of lung cancer and metastases to the lungs Sektion V Kirurgi Other Strong Research Environments EpiHealth: Epidemiology for Health EXODIAB: Excellence of Diabetes Research in Sweden Faculty of Medicine Strategic research areas (SRA) Profilområden och andra starka forskningsmiljöer Institutionen för kliniska vetenskaper, Malmö Cardiovascular Research - Hypertension |
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| SubjectTerms | 38 45/43 631/114 631/208 631/67 Adenocarcinoma Adenocarcinoma - genetics Aged Alleles Ataxia Telangiectasia Mutated Proteins - genetics Basic Medicine Databases, Genetic Female Gene expression Genetic diversity Genetic Predisposition to Disease Genetic variance Genotyping Techniques Germ-Line Mutation Health risk assessment Health risks Heterozygosity Heterozygote Humanities and Social Sciences Humans Jews - genetics Loss of heterozygosity Lung cancer Lung Neoplasms - genetics Male Medical and Health Sciences Medical Genetics and Genomics (including Gene Therapy) Medicin och hälsovetenskap Medicinsk genetik och genomik (Här ingår: Genterapi) Medicinska och farmaceutiska grundvetenskaper Middle Aged multidisciplinary Mutation Mutation, Missense Odds Ratio Oligonucleotide Array Sequence Analysis Pedigree Population genetics Replication Risk analysis Risk Factors RNA-Seq Science Science (multidisciplinary) Tumors White People - genetics |
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| Title | Protein-altering germline mutations implicate novel genes related to lung cancer development |
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