TY - JOUR
T1 - Rare deleterious germline variants and risk of lung cancer
AU - Liu, Yanhong
AU - Xia, Jun
AU - McKay, James
AU - Tsavachidis, Spiridon
AU - Xiao, Xiangjun
AU - Spitz, Margaret R.
AU - Cheng, Chao
AU - Byun, Jinyoung
AU - Hong, Wei
AU - Li, Yafang
AU - Zhu, Dakai
AU - Song, Zhuoyi
AU - Rosenberg, Susan M.
AU - Scheurer, Michael E.
AU - Kheradmand, Farrah
AU - Pikielny, Claudio W.
AU - Lusk, Christine M.
AU - Schwartz, Ann G.
AU - Wistuba, Ignacio I.
AU - Cho, Michael H.
AU - Silverman, Edwin K.
AU - Bailey-Wilson, Joan
AU - Pinney, Susan M.
AU - Anderson, Marshall
AU - Kupert, Elena
AU - Gaba, Colette
AU - Mandal, Diptasri
AU - You, Ming
AU - de Andrade, Mariza
AU - Yang, Ping
AU - Liloglou, Triantafillos
AU - Davies, Michael P.A.
AU - Lissowska, Jolanta
AU - Swiatkowska, Beata
AU - Zaridze, David
AU - Mukeria, Anush
AU - Janout, Vladimir
AU - Holcatova, Ivana
AU - Mates, Dana
AU - Stojsic, Jelena
AU - Scelo, Ghislaine
AU - Brennan, Paul
AU - Liu, Geoffrey
AU - Field, John K.
AU - Hung, Rayjean J.
AU - Christiani, David C.
AU - Amos, Christopher I.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41698-021-00146-7
DO - 10.1038/s41698-021-00146-7
M3 - Article
AN - SCOPUS:85110190489
SN - 2397-768X
VL - 5
JO - npj Precision Oncology
JF - npj Precision Oncology
IS - 1
M1 - 12
ER -