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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 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.

SUBMITTER: Liu Y 

PROVIDER: S-EPMC7887261 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Rare deleterious germline variants and risk of lung cancer.

Liu Yanhong Y   Xia Jun J   McKay James J   Tsavachidis Spiridon S   Xiao Xiangjun X   Spitz Margaret R MR   Cheng Chao C   Byun Jinyoung J   Hong Wei W   Li Yafang Y   Zhu Dakai D   Song Zhuoyi Z   Rosenberg Susan M SM   Scheurer Michael E ME   Kheradmand Farrah F   Pikielny Claudio W CW   Lusk Christine M CM   Schwartz Ann G AG   Wistuba Ignacio I II   Cho Michael H MH   Silverman Edwin K EK   Bailey-Wilson Joan J   Pinney Susan M SM   Anderson Marshall M   Kupert Elena E   Gaba Colette C   Mandal Diptasri D   You Ming M   de Andrade Mariza M   Yang Ping P   Liloglou Triantafillos T   Davies Michael P A MPA   Lissowska Jolanta J   Swiatkowska Beata B   Zaridze David D   Mukeria Anush A   Janout Vladimir V   Holcatova Ivana I   Mates Dana D   Stojsic Jelena J   Scelo Ghislaine G   Brennan Paul P   Liu Geoffrey G   Field John K JK   Hung Rayjean J RJ   Christiani David C DC   Amos Christopher I CI  

NPJ precision oncology 20210216 1


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. Du  ...[more]

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