Dataset Information

Genetic Analysis of Lung Cancer and the Germline Impact on Somatic Mutation Burden.

ABSTRACT:

Background

Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking behaviors and DNA repair genes, but further work is required to identify susceptibility variants.

Methods

To identify LC susceptibility loci, a family history-based genome-wide association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387 controls) was combined with a previous LC GWAS (29 266 patients, 56 450 controls) by meta-analysis. Colocalization was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic risk scores (PRS) were tested within an independent validation cohort (1 666 LC patients vs 6 664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumor resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided.

Results

The GWAx-GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1), and smoking propensity genes (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as subgenome-wide significant variants related to expression quantitative trait loci and/or smoking propensity, assisted in LC genetic risk prediction (odds ratio = 1.37, 95% confidence interval = 1.29 to 1.45; P < .001). Patients with higher genetic PRS loads of smoking-related variants tended to have higher mutation burdens in their lung tumors.

Conclusions

This study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development.

SUBMITTER: Gabriel AAG

PROVIDER: S-EPMC9360465 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Genetic Analysis of Lung Cancer and the Germline Impact on Somatic Mutation Burden.

Gabriel Aurélie A G AAG Atkins Joshua R JR Penha Ricardo C C RCC Smith-Byrne Karl K Gaborieau Valerie V Voegele Catherine C Abedi-Ardekani Behnoush B Milojevic Maja M Olaso Robert R Meyer Vincent V Boland Anne A Deleuze Jean François JF Zaridze David D Mukeriya Anush A Swiatkowska Beata B Janout Vladimir V Schejbalová Miriam M Mates Dana D Stojšić Jelena J Ognjanovic Miodrag M Witte John S JS Rashkin Sara R SR Kachuri Linda L Hung Rayjean J RJ Kar Siddhartha S Brennan Paul P Sertier Anne-Sophie AS Ferrari Anthony A Viari Alain A Johansson Mattias M Amos Christopher I CI Foll Matthieu M McKay James D JD

Journal of the National Cancer Institute 20220801 8

<h4>Background</h4>Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking behaviors and DNA repair genes, but further work is required to identify susceptibility variants.<h4>Methods</h4>To identify LC susceptibility loci, a family history-based genome-wide association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387 controls) was combined with a previous L ...[more]

PMID: 35511172

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Project description:BackgroundGermline mutations in numerous genes, particularly tumor suppressor genes, markedly heighten the risk of various cancers, including lung cancer, which is the leading cause of cancer-related deaths worldwide. Despite extensive research on well-known genes like BRCA1, BRCA2, and mismatch repair genes, many genetic factors contributing to cancer susceptibility remain unidentified.MethodsThis study reviewed sequencing data from 4,934 Chinese lung cancer patients. Matched white blood cell samples were sequenced using WES or gene panels to identify germline mutations. Analysis included statistical tests to compare patient demographics, clinical characteristics, and somatic mutation profiles.ResultsAmong the cohort, 89 patients carried pathogenic/likely pathogenic (P/LP) germline mutations in 20 known cancer susceptibility genes, with ATM, BRCA2, and CHEK2 being the most common. TP53 mutations were linked to early-onset lung cancer, while ATM mutations correlated with late-onset and higher PD-L1 expression, suggesting immunotherapy benefits. Germline mutations were more prevalent in younger patients and females. Somatic mutation profiles showed similarities in common mutations but differences in MTOR (p = 0.044) and MSH6 (p = 0.018) mutations in P/LP carriers. GO and KEGG analyses indicated distinct biological processes and pathways in patients with P/LP germline mutations. Gene exclusivity analysis revealed correlations and mutual exclusivity between specific germline and somatic mutations. Comparative analysis with the gnomAD database showed a higher prevalence of these mutations in lung cancer patients compared to the general and East Asian populations, suggesting an association with increased lung cancer risk in the Chinese cohort.ConclusionThis study underscores the prevalence of germline mutations in Chinese lung cancer patients, identifying significant associations with clinical characteristics and somatic mutation profiles. The findings highlight the importance of considering germline mutations in lung cancer treatment and the potential benefits of personalized therapy based on genetic susceptibility.

Project description:BackgroundAccumulating evidence indicates inherited risk in the aetiology of lung cancer, although smoking exposure is the major attributing factor. Family history is a simple substitute for inherited susceptibility. Previous studies have shown some possible yet conflicting links between family history of cancer and EGFR mutation in lung cancer. As EGFR-mutated lung cancer favours female, never-smoker, adenocarcinoma and Asians, it may be argued that there may be some underlying genetic modifiers responsible for the pathogenesis of EGFR mutation.MethodsWe searched four databases for all original articles on family history of malignancy and EGFR mutation status in lung cancer published up to July 2018. We performed a meta-analysis by using a random-effects model and odds ratio estimates. Heterogeneity and sensitivity were also investigated. Then we conducted a second literature research to curate case reports of familial lung cancers who studied both germline cancer predisposing genes and their somatic EGFR mutation status; and explored the possible links between cancer predisposing genes and EGFR mutation.ResultsEleven studies have been included in the meta-analysis. There is a significantly higher likelihood of EGFR mutation in lung cancer patients with family history of cancer than their counterparts without family history, preferentially in Asians (OR = 1.35[1.06-1.71], P = 0.01), those diagnosed with adenocarcinomas ((OR = 1.47[1.14-1.89], P = 0.003) and those with lung cancer-affected relatives (first and second-degree: OR = 1.53[1.18-1.99], P = 0.001; first-degree: OR = 1.76[1.36-2.28, P < 0.0001]). Familial lung cancers more likely have concurrent EGFR mutations along with mutations in their germline cancer predisposition genes including EGFR T790 M, BRCA2 and TP53. Certain mechanisms may contribute to the combination preferences between inherited mutations and somatic ones.ConclusionsPotential genetic modifiers may contribute to somatic EGFR mutation in lung cancer, although current data is limited. Further studies on this topic are needed, which may help to unveil lung carcinogenesis pathways. However, caution is warranted in data interpretation due to limited cases available for the current study.

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Dataset Information

Genetic Analysis of Lung Cancer and the Germline Impact on Somatic Mutation Burden.

Background

Methods

Results

Conclusions

Publications

Genetic Analysis of Lung Cancer and the Germline Impact on Somatic Mutation Burden.

Similar Datasets

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