Suggestive evidence supporting associations between rare germline variants in eight hereditary cancer genes and lung cancer were obtained from two large independent datasets.
Abstract
Background
Few germline susceptibility genes have been well established for lung cancer. We aimed to evaluate associations between germline variants in known hereditary cancer genes and lung cancer risk.
Methods
We analyzed subjects of European ancestry from two datasets: 2,272 LC cases and 185,510 controls from the UK Biobank, and 824 LC cases from Rush University Medical Center (RUSH) with 56,878 population controls from the Genome Aggregation Database (gnomAD). Rare pathogenic germline variants in 123 ClinGen-curated hereditary cancer genes were first tested for lung cancer risk in the UK Biobank using gene-based burden testing (robust SKAT-O). Genes with suggestive associations were further evaluated in the RUSH/gnomAD dataset. Meta-analysis of the two datasets was performed to estimate overall evidence and pooled odds ratios.
Results
Rare germline variants in ten genes showed nominally significant associations with lung cancer in the UK Biobank (p<0.05), and TP53 showed a borderline signal (p=0.11). These genes were tested in the RUSH/gnomAD dataset, and meta-analysis identified suggestive evidence supporting eight genes associated with increased lung cancer risk (p<0.05), including three previously reported lung cancer genes (ATM, BRCA2, TP53) and five novel genes (RB1, MET, CYLD, PDGFRA, CTNNA1). In the UK Biobank incident lung cancer cohort, aggregated rare pathogenic variants in these eight genes were significantly associated with lung cancer risk and earlier age at lung cancer diagnosis, independent and complementary to smoking history at recruitment.
Conclusions
Suggestive evidence supporting associations between rare germline variants in eight hereditary cancer genes and lung cancer were obtained from two large independent datasets.
Previous association studies between germline rare genetic variation and cancer risk have primarily examined a limited number of cancers in clinical samples, often with participants predominantly of European genetic ancestry. We conducted exome-wide rare variant association analyses across 70+ cancer types using data from more than 729,000 participants from the UK Biobank (UKB) and All of Us Research Program (AoU) cohorts. We used generalized linear mixed models to screen for cancer pleiotropic effects by conducting gene-based and single variant tests of predicted loss of function (pLoF) and missense variants and six groups of cancer defined by biological and etiological similarities. We then assessed significant genes for associations with 27 individual cancer types that had data for at least 500 cases. Of the 33 potential pleiotropic genes identified, 16 consistently showed significant associations across ≥ 3 individual cancer types. For example, the presence of at least one CHEK2 pLoF variant was associated with increased odds of diagnosis with 14 different cancers (OR range: 1.34 - 3.21). Similarly, the presence of at least one RTEL1 missense variant was associated with lower odds of diagnosis with 9 cancers (OR range: 0.67 - 0.88). Our results expand our knowledge about these loci and point to a larger impact on overall cancer risk than previously appreciated.
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Rare variants in MSH6 and BRCA2 are significantly associated with increased HCC risk, revealing a previously unconfirmed role for DNA repair genes in HCC susceptibility across ancestrally diverse populations and may inform genetic risk stratification and surveillance strategies.
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Introduction Genome‐wide association studies (GWAS) have identified over 200 germline risk loci for colorectal cancer (CRC), yet the causal variants and genes behind most GWAS signals remain unknown and the link between inherited risk and tumor outcome is largely unexplored. Connecting germline single nucleotide polymorphisms (SNPs) to gene expression through expression quantitative trait loci (eQTL) and to clinical outcome is needed to interpret this inherited risk. Methods We combined CRC GWAS summary data (73,149 cases and 112,467 controls of European ancestry) with GTEx v8 eQTL from colon sigmoid, colon transverse, small intestine terminal ileum, and whole blood, integrating causal transcriptome‐wide association study (cTWAS) with SuSiE fine‐mapping, Bayesian colocalization, MAGMA SNP‐to‐gene analysis, and AlphaGenome variant‐effect prediction. Prioritized proteins were assessed by western blot. Four experimentally selected regulatory variants were genotyped in HCT116, SW480, RKO, and NCM460 cells; genotype‐protein associations were tested across cell‐line means, and cis‐regulatory effects were assessed by allele‐specific expression (ASE) and reference‐versus‐alternate dual‐luciferase assays. Prognostic relevance was evaluated in TCGA colorectal tumors. Results cTWAS identified seven genes with posterior inclusion probability (PIP) > 0.50, and colocalization across 78 gene‐tissue pairs revealed 20 associations with PP.H4 > 0.80. Four genes showed convergent evidence: SMAD9 (PIP = 0.916, PP.H4 = 0.981), MAP3K2 (PIP = 0.762, PP.H4 = 0.827), FADS1 (PIP = 0.632, PP.H4 = 0.942), and ACTR1B (PIP = 0.566, PP.H4 = 0.994). All four proteins were reduced in CRC cells. Alt‐allele dosage was inversely associated with SMAD9 (Pearson r = −0.985, BH‐adjusted p = 0.029) and FADS1 protein abundance (r = −0.995, BH‐adjusted p = 0.020), but not with MAP3K2 or ACTR1B. Reporter and ASE assays detected the clearest allele‐specific effects at SMAD9 and FADS1, whereas MAP3K2 and ACTR1B were null in the tested systems. Lower SMAD9 expression was nominally associated with poorer survival (log − rank p = 0.022 to 0.050), but these associations did not survive Benjamini–Hochberg correction across 12 tests. Conclusions Integrating statistical genetics, regulatory prediction, and locus‐directed experiments prioritized SMAD9, MAP3K2, FADS1, and ACTR1B as CRC susceptibility genes. Functional evidence was strongest and most directionally coherent for SMAD9, demonstrated allele‐specific but context‐dependent regulation at FADS1, and placed experimental bounds on the proposed MAP3K2 and ACTR1B mechanisms.
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Germline PVs in NCCN-recommended DDR genes and the KLK3 I179T variant identify a subset of men at elevated risk of PCSM, including those with apparently localized disease.
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High-risk and early-onset PCa is associated with rare germline DDR alterations, and expanded germline testing in younger patients is supported and potential relevance for precision oncology approaches is suggested.
Rawaz Rizgar, Hassan, Abdulkarim Y Karim et al.· Galen medical journal· 0 citations
Simple Summary Breast cancer is one of the most common cancers among women, but its genetic causes remain poorly characterized in North African populations. In this study, we investigated germline genetic variants in 165 Tunisian breast cancer patients using targeted next-generation sequencing of a multigene cancer panel. We identified pathogenic or likely pathogenic variants (P/LPVs) in BRCA1 and BRCA2 genes in 19 patients (11.5%), with several recurrent variants and additional variants not previously reported in our Tunisian cohort. P/LPV carriers were more frequently younger at diagnosis and showed significant associations with family history and several clinical features. We also identified P/LPVs in other genes. In addition, 56 variants of uncertain significance (VUS) were detected, of which 7 were prioritized through computational analyses. Additional functional or segregation evidence should be collected to establish pathogenicity. Our findings expand the available genetic data on breast cancer in Tunisia and highlight the importance of population-specific genomic studies for improving variant interpretation and genetic counseling.
N. Ammous-Boukhris, Rania Abdelmaksoud-Dammak, W. Ben Kridis et al.· Cancers· 0 citations
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