Aug 2026· JHEP Reports· pp.
102019
· 0 citations· 25 references
Medicine
TL;DR
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.
Abstract
Background
&
Aims
Genetic testing for Lynch and BRCA1/2-associated hereditary cancer syndromes is recommended in colon or pancreatic cancer patients, but their association with hepatocellular carcinoma (HCC) risk is unknown. We evaluated associations between rare germline variants in DNA-repair genes and HCC risk across ancestrally diverse cohorts.
Methods
We analyzed whole exome (WES) and whole genome sequencing (WGS) data from 2,594 HCC cases and 290,547 cancer-free controls from diverse biobanks and cohorts: Penn Medicine BioBank, All of Us, Mayo Clinic, ESCALON, and the Million Veteran Program. Participants were classified into six population groups. We focused on six DNA-repair genes previously implicated in HCC: BRCA2, BRIP1, MSH6, PMS2, CHEK2, and FANCA. Gene-level burden analyses of rare predicted loss-of-function (pLoF) and damaging missense variants were performed in European and African populations, and across all six ancestry groups.
Results
In the European population, MSH6, a Lynch syndrome-associated gene, had the strongest association with HCC, with a 2.75-fold increased HCC risk at 1% minor-allele frequency (MAF) (OR= 2.75 [1.50, 5.04], P=0.001, FDR q=0.02), while PMS2, showed a nominally significant association at the same MAF threshold (OR=1.90 [1.08, 3.34], P=0.03, FDR q=0.09). Combined analysis across all populations strengthened the MSH6 finding (OR=2.53 [1.43, 4.49], P=0.001, FDR q=0.01) at a MAF of 0.1%. A significant BRCA2 association was also observed in the combined analysis at a MAF of 0.1% (OR=2.26 [1.39, 3.67], P=0.001, FDR q=0.01).
Conclusions
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. These findings may inform genetic risk stratification and surveillance strategies.
IMPACT AND IMPLICATIONS
Rare variants in MSH6 and BRCA2 genes are associated with 2.3 to 2.8-fold higher HCC risk. These findings may warrant further evaluation of liver cancer risk in individuals with MSH6-associated Lynch syndrome or BRCA2-associated hereditary cancer syndromes.
Suggestive evidence supporting associations between rare germline variants in eight hereditary cancer genes and lung cancer were obtained from two large independent datasets.
Sierra R. Broad, Jun Wei, Keri L. Denson et al.· Annals of Thoracic Surgery· 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
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
BACKGROUND
Hereditary cancer syndromes (HCSs) account for approximately 5-10% of all cancers and are frequently associated with pathogenic variants (PVs) in genes such as BRCA1 and BRCA2. Nevertheless, a substantial proportion of individuals with strong familial cancer aggregation remain genetically unexplained after standard multigene panel testing. Clinical exome sequencing (CES) may overcome this limitation by enabling a broader exploration of cancer susceptibility genes.
METHODS
This retrospective study included 500 high-risk patients who previously tested negative for BRCA1/2 PVs. All samples were analysed using next-generation sequencing technology. Initially, a 60-gene filtered panel recommended by the American Society of Clinical Oncology (ASCO) guidelines was applied, followed by a 102-gene filtered panel derived from CES to identify additional PVs or likely PVs (LPVs) beyond current diagnostic panels. Variant classification was performed according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, incorporating ClinGen and gene-specific expert curation recommendations when available.
RESULTS
Within the ASCO panel, PV/LPVs were identified in 9% of patients while 35% carried variants of uncertain significance. CES identified additional PVs/LPVs in 5% of patients in genes not currently included in ASCO-recommended surveillance panels, such as RAD50, BLM, WRN, PMS1 and FANCA. These variants may represent candidate susceptibility loci requiring further clinical and functional validation.
CONCLUSIONS
CES may provide additional exploratory genomic information in selected high-risk BRCA1/2-negative patients, particularly when standard panel testing is uninformative. Although many of the additional findings identified are not yet clinically actionable, CES represents a valuable resource for future reinterpretation as gene-disease evidence evolves. Overall, our findings support the use of CES as a second-tier exploratory approach in carefully selected high-risk cases, while emphasising the need for cautious interpretation and continued gene-disease curation.
Anastasia Dell'Elice, Claudia Palmarini, Federico Anaclerio et al.· Journal of Medical Genetics· 0 citations
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.
Chengguang Hu, Guang Yang, Han Xiong et al.· Human Mutation· 0 citations
Bladder cancer is the ninth most common cancer worldwide, caused by genetic and environmental risk factors. Here, we report the findings of a multi-population meta-analysis of genome-wide association studies, including 32,470 individuals with and 1,753,462 without bladder cancer. We identify 70 independent risk loci, of which 43 are novel. Using a 70-marker polygenic risk score (HR = 1.63 per standard deviation), we increase the area under the curve from 0.71 (baseline risk model) to 0.75. Integrative analyses reveal the enrichment of the associated variants within accessible chromatin regions, and of the prioritized genes within pathways for xenobiotic metabolism and smoking behavior. Specifically, we show that the 15q25.1 variant rs71581744-ACCCC/A co-localizes with tissue-specific CHRNA3 expression, modulates mRNA stability, and associates with risk of muscle-invasive bladder cancer among current smokers. Together, these findings substantially expand the known genetic architecture of bladder cancer risk and highlight the germline regulation of smoking behavior as a mechanism driving bladder cancer susceptibility. This study integrates genetic data from diverse populations to identify 70 loci linked to bladder cancer risk, including 43 novel, and uses experimental approaches to uncover how inherited variation influences this risk in the context of smoking.
L. Prokunina-Olsson, O. Flórez-Vargas, Michael G. Levin et al.· Nature Communications· 0 citations
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