Genetic Association Studies in Hepatocellular Carcinoma: Systematic Meta‐Analyses, a Comprehensive Field Synopsis, and Epidemiological Evidence

Meta-analysis/systematic review iScience Global genetic modifiers of fetal hemoglobin in sickle cell disease: Systematic review and meta-analysis

Association of germline ABCB1 and ERCC1 polymorphisms with CDK4/6 inhibitor-induced neutropenia in patients with breast cancer: a systematic review and meta-analysis

Background CDK4/6 inhibitors are standard-of-care for HR+/HER2− advanced breast cancer, but grade 3/4 neutropenia occurs in up to 60% of patients. Germline polymorphisms in ABCB1, encoding the P-glycoprotein efflux transporter, have been investigated as predictors of CDK4/6 inhibitor–induced neutropenia, with conflicting results across populations. No meta-analysis has previously pooled these findings. Methods PubMed, Scopus, and Web of Science were systematically searched. Studies reporting genotype-stratified grade 3/4 neutropenia in CDK4/6 inhibitor–treated patients were eligible. Four SNPs were analyzed: ABCB1 rs1128503, ABCB1 rs1045642, ERCC1 rs11615, and ERCC1 rs3212986. Odds ratios were pooled using Mantel-Haenszel weighting with random-effects (rs1128503, rs11615) or fixed-effect (rs1045642, rs3212986) models under dominant genetic models, stratified by ancestry. The protocol was registered in PROSPERO (CRD420261379298). Results Four studies (1,138 patients) were included. No SNP showed a significant overall association. However, significant ancestry-dependent heterogeneity was detected for two ABCB1 SNPs. For rs1045642, T-carrier status was significantly associated with increased neutropenia in European/Caucasian patients (pooled OR 1.62, 95% CI 1.05–2.52, p = 0.03, I2 = 0%) but decreased risk in East Asians (OR 0.31, 95% CI 0.13–0.74, p = 0.009; subgroup difference p = 0.0009). For rs1128503, a concordant European trend was observed (OR 1.87, 95% CI 0.87–4.00, p = 0.11) with reversed direction in North African/Middle Eastern patients (OR 0.33, 95% CI 0.12–0.92, p = 0.03; subgroup difference p = 0.02). For ERCC1 rs11615, the inclusion of Wang 2024 nullified the previously borderline European signal (pooled OR 0.99, 95% CI 0.42–2.33, p = 0.98, I2 = 75%), with subgroup differences no longer significant (p = 0.17). ERCC1 rs3212986 showed no association (OR 1.07, 95% CI 0.53–2.17, I2 = 0%). Conclusion These preliminary findings suggest that ABCB1 rs1045642 T-carrier status may be associated with CDK4/6 inhibitor–induced neutropenia in European/Caucasian patients, with a concordant trend for rs1128503 findings. Both associations appear ancestry-dependent, although the limited number of studies and single-study ancestry subgroups preclude definitive conclusions. ERCC1 rs11615, previously borderline in a single study, was not confirmed upon independent replication. Prospective validation in adequately powered, ancestry-stratified cohorts incorporating ABCB1 haplotype analysis and pharmacokinetic sampling is warranted. Systematic Review Registration identifier CRD420261379298.

MBOAT7 rs641738 TT genotype is associated with poorer survival in MASLD-related hepatocellular carcinoma

Introduction Genetic variants involved in lipid and glucose metabolism have been implicated in liver disease progression and hepatocellular carcinoma (HCC) development in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, their prognostic role in patients with established HCC remains unclear. We aimed to investigate the association between MASLD-related genetic variants and overall survival (OS) in patients with MASLD-related HCC. Methods We retrospectively evaluated 258 patients with MASLD-related HCC (median age: 73, 49–79 years; male sex: 86.8%); most patients had a diagnosis of early tumor (BCLC 0/A: n = 162; 62.8%). PNPLA3 rs738409, TM6SF2 rs58542926, MBOAT7 rs641738, GCKR rs780094, and HSD17B13 rs72613567 variants were genotyped. An independent cohort of viral-related HCC (n = 384) was analysed for exploratory comparison. Overall survival (OS) was evaluated using Kaplan-Meier analysis and multivariable Cox regression. Results Among the investigated gene variants, only the MBOAT7 rs641738 TT genotype was associated with reduced OS in patients with MASLD-related HCC compared to CC/CT carriers (19.8 vs. 32.2 months; p = 0.006). At multivariable analysis, MBOAT7 rs641738 TT genotype retained a nominal association with poorer OS after adjustment for age, sex, tumor burden, and metabolic cofactors (aHR = 1.61, 95% CI 1.05–2.46; p = 0.028). Conversely, OS did not differ according to MBOAT7 rs641738 genotype in the exploratory viral-related HCC comparison cohort (p = 0.449). Conclusions MBOAT7 rs641738 genotype was associated with poorer OS in patients with MASLD-related HCC. This finding was not observed in an exploratory viral-related HCC comparison cohort, but between-cohort differences limit etiological interpretation. These results should be considered hypothesis-generating and require external validation.

Multi-population GWAS meta-analysis identifies bladder cancer susceptibility loci and highlights genetic regulation of smoking-related risk

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.

PSCA rs2294008 C  T polymorphism contributes to gastric and bladder cancer risk

Association between the PNPLA3 I148M (rs738409) polymorphism and risk of metabolic dysfunction-associated steatotic liver disease: a meta-analysis (2015-2025).

BACKGROUND Metabolically-dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and is strongly influenced by genetic susceptibility. Among the identified genetic variants, the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 (I148M) polymorphism has been consistently associated with hepatic steatosis and disease progression. However, previous meta-analyses included fewer studies, limited ethnic diversity, and insufficient investigation of between-study heterogeneity. This study aimed to comprehensively evaluate the association between the PNPLA3 rs738409 polymorphism and MASLD susceptibility. METHODS A systematic literature search was conducted in PubMed, Embase, Scopus, Web of Science, and Google Scholar to identify eligible case-control studies published between 2015 and 2025. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under allelic, dominant, homozygous, heterozygous, and combined genotype models using random-effects meta-analysis. Between-study heterogeneity was assessed using the I² statistic, and ethnicity-based subgroup analyses were performed to investigate potential sources of heterogeneity. RESULTS Forty-one studies comprising 9,064 patients with MASLD and 10,894 controls were included. The G allele was significantly associated with increased susceptibility to MASLD (OR = 1.70, 95% CI: 1.49-1.93). Individuals carrying the GG genotype had approximately a twofold higher risk of MASLD (OR = 2.00, 95% CI: 1.65-2.42), whereas the CC genotype showed a protective association (OR = 0.51, 95% CI: 0.44-0.59). Significant associations were also observed for the CG genotype (OR = 1.22, 95% CI: 1.08-1.38) and the dominant model (CG + GG vs. CC) (OR = 2.64, 95% CI: 1.86-3.75). Although substantial between-study heterogeneity was observed (I² = 66%-96%), ethnicity-based subgroup analyses explained part of the variability while demonstrating consistent associations across major ethnic populations. CONCLUSIONS This updated meta-analysis confirms that the PNPLA3 rs738409 (I148M) polymorphism is a major genetic susceptibility factor for MASLD across diverse populations. Although ethnicity contributes to between-study heterogeneity, the association remains robust across populations. These findings support the incorporation of PNPLA3 into multifactorial risk assessment models and provide an updated evidence base for future precision medicine approaches in MASLD.