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- Lesseur, Corina, et al.
(author)
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Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers
- 2021
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In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:3
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Journal article (peer-reviewed)abstract
- Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.
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2. |
- Sun, Ryan, et al.
(author)
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Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer
- 2021
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In: Genetic Epidemiology. - : John Wiley & Sons. - 0741-0395 .- 1098-2272. ; 45:1, s. 99-114
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Journal article (peer-reviewed)abstract
- Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1 beta pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-kappa B signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.
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3. |
- Zhou, Wen, et al.
(author)
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Causal relationships between body mass index, smoking and lung cancer : Univariable and multivariable Mendelian randomization
- 2021
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In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 148:5, s. 1077-1086
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Journal article (peer-reviewed)abstract
- At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06,P= 2.70 x 10(-4)). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (ORMVMR= 1.28, 95% CI = 1.06-1.55,P-MVMR= .011), and an inverse effect on lung adenocarcinoma (ORMVMR= 0.86, 95% CI = 0.77-0.96,P-MVMR= .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (ORUVMR= 1.19, 95% CI = 1.01-1.40,P-UVMR= .036), but this effect disappeared after adjustment of smoking (ORMVMR= 1.02, 95% CI = 0.90-1.16,P-MVMR= .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.
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