Rare deleterious germline variants and risk of lung cancer
Abstract Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial role in the etiology of lung cancers (LC). Whole exome plus targeted sequencing of germline DNA was performed on 1045 LC cases and 885 controls in the discovery set. To unveil the inherited caus...
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Nature Portfolio
2021
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oai:doaj.org-article:3431e92f9faa47b7bce60db50d9cfdaf2021-12-02T14:18:09ZRare deleterious germline variants and risk of lung cancer10.1038/s41698-021-00146-72397-768Xhttps://doaj.org/article/3431e92f9faa47b7bce60db50d9cfdaf2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41698-021-00146-7https://doaj.org/toc/2397-768XAbstract Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial role in the etiology of lung cancers (LC). Whole exome plus targeted sequencing of germline DNA was performed on 1045 LC cases and 885 controls in the discovery set. To unveil the inherited causal variants, we focused on rare and predicted deleterious variants and small indels enriched in cases or controls. Promising candidates were further validated in a series of 26,803 LCs and 555,107 controls. During discovery, we identified 25 rare deleterious variants associated with LC susceptibility, including 13 reported in ClinVar. Of the five validated candidates, we discovered two pathogenic variants in known LC susceptibility loci, ATM p.V2716A (Odds Ratio [OR] 19.55, 95%CI 5.04–75.6) and MPZL2 p.I24M frameshift deletion (OR 3.88, 95%CI 1.71–8.8); and three in novel LC susceptibility genes, POMC c.*28delT at 3′ UTR (OR 4.33, 95%CI 2.03–9.24), STAU2 p.N364M frameshift deletion (OR 4.48, 95%CI 1.73–11.55), and MLNR p.Q334V frameshift deletion (OR 2.69, 95%CI 1.33–5.43). The potential cancer-promoting role of selected candidate genes and variants was further supported by endogenous DNA damage assays. Our analyses led to the identification of new rare deleterious variants with LC susceptibility. However, in-depth mechanistic studies are still needed to evaluate the pathogenic effects of these specific alleles.Yanhong LiuJun XiaJames McKaySpiridon TsavachidisXiangjun XiaoMargaret R. SpitzChao ChengJinyoung ByunWei HongYafang LiDakai ZhuZhuoyi SongSusan M. RosenbergMichael E. ScheurerFarrah KheradmandClaudio W. PikielnyChristine M. LuskAnn G. SchwartzIgnacio I. WistubaMichael H. ChoEdwin K. SilvermanJoan Bailey-WilsonSusan M. PinneyMarshall AndersonElena KupertColette GabaDiptasri MandalMing YouMariza de AndradePing YangTriantafillos LiloglouMichael P. A. DaviesJolanta LissowskaBeata SwiatkowskaDavid ZaridzeAnush MukeriaVladimir JanoutIvana HolcatovaDana MatesJelena StojsicGhislaine SceloPaul BrennanGeoffrey LiuJohn K. FieldRayjean J. HungDavid C. ChristianiChristopher I. AmosNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-12 (2021) |
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yanhong Liu Jun Xia James McKay Spiridon Tsavachidis Xiangjun Xiao Margaret R. Spitz Chao Cheng Jinyoung Byun Wei Hong Yafang Li Dakai Zhu Zhuoyi Song Susan M. Rosenberg Michael E. Scheurer Farrah Kheradmand Claudio W. Pikielny Christine M. Lusk Ann G. Schwartz Ignacio I. Wistuba Michael H. Cho Edwin K. Silverman Joan Bailey-Wilson Susan M. Pinney Marshall Anderson Elena Kupert Colette Gaba Diptasri Mandal Ming You Mariza de Andrade Ping Yang Triantafillos Liloglou Michael P. A. Davies Jolanta Lissowska Beata Swiatkowska David Zaridze Anush Mukeria Vladimir Janout Ivana Holcatova Dana Mates Jelena Stojsic Ghislaine Scelo Paul Brennan Geoffrey Liu John K. Field Rayjean J. Hung David C. Christiani Christopher I. Amos Rare deleterious germline variants and risk of lung cancer |
| description |
Abstract Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial role in the etiology of lung cancers (LC). Whole exome plus targeted sequencing of germline DNA was performed on 1045 LC cases and 885 controls in the discovery set. To unveil the inherited causal variants, we focused on rare and predicted deleterious variants and small indels enriched in cases or controls. Promising candidates were further validated in a series of 26,803 LCs and 555,107 controls. During discovery, we identified 25 rare deleterious variants associated with LC susceptibility, including 13 reported in ClinVar. Of the five validated candidates, we discovered two pathogenic variants in known LC susceptibility loci, ATM p.V2716A (Odds Ratio [OR] 19.55, 95%CI 5.04–75.6) and MPZL2 p.I24M frameshift deletion (OR 3.88, 95%CI 1.71–8.8); and three in novel LC susceptibility genes, POMC c.*28delT at 3′ UTR (OR 4.33, 95%CI 2.03–9.24), STAU2 p.N364M frameshift deletion (OR 4.48, 95%CI 1.73–11.55), and MLNR p.Q334V frameshift deletion (OR 2.69, 95%CI 1.33–5.43). The potential cancer-promoting role of selected candidate genes and variants was further supported by endogenous DNA damage assays. Our analyses led to the identification of new rare deleterious variants with LC susceptibility. However, in-depth mechanistic studies are still needed to evaluate the pathogenic effects of these specific alleles. |
| format |
article |
| author |
Yanhong Liu Jun Xia James McKay Spiridon Tsavachidis Xiangjun Xiao Margaret R. Spitz Chao Cheng Jinyoung Byun Wei Hong Yafang Li Dakai Zhu Zhuoyi Song Susan M. Rosenberg Michael E. Scheurer Farrah Kheradmand Claudio W. Pikielny Christine M. Lusk Ann G. Schwartz Ignacio I. Wistuba Michael H. Cho Edwin K. Silverman Joan Bailey-Wilson Susan M. Pinney Marshall Anderson Elena Kupert Colette Gaba Diptasri Mandal Ming You Mariza de Andrade Ping Yang Triantafillos Liloglou Michael P. A. Davies Jolanta Lissowska Beata Swiatkowska David Zaridze Anush Mukeria Vladimir Janout Ivana Holcatova Dana Mates Jelena Stojsic Ghislaine Scelo Paul Brennan Geoffrey Liu John K. Field Rayjean J. Hung David C. Christiani Christopher I. Amos |
| author_facet |
Yanhong Liu Jun Xia James McKay Spiridon Tsavachidis Xiangjun Xiao Margaret R. Spitz Chao Cheng Jinyoung Byun Wei Hong Yafang Li Dakai Zhu Zhuoyi Song Susan M. Rosenberg Michael E. Scheurer Farrah Kheradmand Claudio W. Pikielny Christine M. Lusk Ann G. Schwartz Ignacio I. Wistuba Michael H. Cho Edwin K. Silverman Joan Bailey-Wilson Susan M. Pinney Marshall Anderson Elena Kupert Colette Gaba Diptasri Mandal Ming You Mariza de Andrade Ping Yang Triantafillos Liloglou Michael P. A. Davies Jolanta Lissowska Beata Swiatkowska David Zaridze Anush Mukeria Vladimir Janout Ivana Holcatova Dana Mates Jelena Stojsic Ghislaine Scelo Paul Brennan Geoffrey Liu John K. Field Rayjean J. Hung David C. Christiani Christopher I. Amos |
| author_sort |
Yanhong Liu |
| title |
Rare deleterious germline variants and risk of lung cancer |
| title_short |
Rare deleterious germline variants and risk of lung cancer |
| title_full |
Rare deleterious germline variants and risk of lung cancer |
| title_fullStr |
Rare deleterious germline variants and risk of lung cancer |
| title_full_unstemmed |
Rare deleterious germline variants and risk of lung cancer |
| title_sort |
rare deleterious germline variants and risk of lung cancer |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/3431e92f9faa47b7bce60db50d9cfdaf |
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