Polycystic ovary syndrome (PCOS), the leading endocrine disorder in women of reproductive age, is highly heritable, yet its polygenic architecture remains poorly understood. Here we conducted a genome-wide association study on 12,419 Chinese women with PCOS and 34,235 controls, followed by a multi-ancestry meta-analysis with up to 13,773 European cases and 411,088 controls, identifying 94 independent loci, 73 of which were previously unreported. Despite different evolutionary pressures, Chinese and European ancestries showed substantial genetic overlap. Integrative functional analyses prioritized regulatory variants controlling gene activity in specific tissues, disease-causing genes including anti-Müllerian hormone (AMH), and biological pathways involving ligand-binding domain interactions and peroxisome proliferator-activated receptor gamma (PPARG) signaling. We identified granulosa cells as particularly important in PCOS development. Our genetics-driven drug discovery approach revealed multiple drug targets and repurposing opportunities, enabling personalized treatment strategies. These results enhance our understanding of the molecular basis of PCOS, paving the way for precision medicine.

Genomic heterogeneity in melanoma tumors remains a major obstacle to achieving durable responses with conventional and targeted therapies. In this study, we performed a genome-wide association study meta-analysis, integrated with proteome-wide Mendelian randomization and colocalization analyses, to identify potential therapeutic targets for cutaneous melanoma (CM). Analyzing data from 5527 CM cases and 645 797 controls, we uncovered seven novel genome-wide significant variants linked to CM risk. Additionally, genetically predicted protein levels revealed 15 proteins associated with CM susceptibility, among which ASIP, CD72, CCL11, LYZ, and CCL25 showed the strongest associations. Validation in independent cohorts further supported their potential as biomarkers. Notably, these protein-coding genes are predominantly expressed in macrophages, B cells, CD8 T cells, and malignant cells within CM tissue. Among them, CD72 and LYZ stand out as promising candidates for therapeutic repurposing. These findings enhance our understanding of CM-related genetic and protein biomarkers, providing a foundation for future therapeutic development.

The causal links between serum amino acids (AAs) and hepatobiliary neoplasms remain unclear. This study aimed to systematically investigate these associations using Mendelian randomization (MR). Summary-level data on 20 serum AAs were obtained from publicly available genome-wide association studies. Genome-wide association studies data on hepatobiliary neoplasms - including primary liver cancer (PLC), hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), gallbladder and extrahepatic bile duct carcinoma, secondary liver cancer, benign liver tumors, and benign tumors of the extrahepatic bile ducts - were derived from FinnGen and 2 UK Biobank-based studies. A meta-analysis was conducted to calculate pooled effect sizes. Inverse variance weighting was the primary method, supplemented by MR-Egger, weighted median, MR.RAPS, maximum likelihood, and MR-PRESSO methods for sensitive analyses. Higher serum methionine was associated with lower risks of PLC (OR = 0.84, 95% CI: 0.72-0.97, P = .021) and HCC (OR = 0.87, 95% CI: 0.80-0.94, P < .001), but not ICC. Alanine increased PLC risk (OR = 1.19, 95% CI: 1.00-1.42, P = .047), with no significant effect on HCC or ICC. No AAs were linked to gallbladder and extrahepatic bile duct carcinoma or secondary liver cancer. For benign tumors, aspartate (OR = 1.13, 95% CI: 1.01-1.26, P = .037), cysteine (OR = 0.72, 95% CI: 0.57-0.92, P = .008), and lysine (OR = 1.49, 95% CI: 1.15-1.93, P = .003) were significantly associated with benign liver tumors or benign tumors of the extrahepatic bile ducts. This study offers robust evidence of causal associations between specific serum AAs and hepatobiliary neoplasms, emphasizing their potential as biomarkers and modifiable targets for early intervention.

Chemoresistance is a significant issue in glioblastoma (GBM) treatment due to recurrence, poor survival and limited salvage options. Non-invasive biomarkers can identify early chemoresistance. These cohorts may benefit from initiating early chemotherapy or second-line drugs at an earlier timeline.

Breast cancer remains the most common cancer among women worldwide, and recurrence rates stay high despite current treatments, especially for those with negative estrogen receptor status, where therapies are less effective, and prognosis is worse. Identifying molecules with predictive value for therapy response and prognosis is therefore crucial. In this context, FOXA1 could serve as a potential biomarker to predict the progression of ER-negative tumors. A search was conducted to answer the question, "What is the prognostic value of FOXA1 expression in breast cancer, estrogen receptor negative?" using various databases. Controlled vocabulary and Boolean operators were employed. Only studies reporting overall survival and disease-free survival, defined as the time from evaluation to death or relapse, were included. We identified seven articles evaluating FOXA1 and its relationship with disease-free survival (DFS) or overall survival (OS) in patients with ER-negative breast cancer. Our data indicate that higher FOXA1 expression is associated with improved overall survival (HR = 0.61, CI = 0.45-0.83, p < 0.002) and better disease-free survival (HR = 0.69, CI = 0.51-0.93, p < 0.02). These findings suggest that FOXA1 is linked to a favorable prognosis in terms of overall survival and disease-free survival. Further studies are needed to assess the role of FOXA1 in response to chemotherapy. PROSPERO registration number: CRD42024453750.

Non-viral head and neck squamous cell carcinoma (HNSCC) has poor survival and high recurrence rates. Circulating tumor DNA (ctDNA) is a promising biomarker for understanding tumor biology, assessing treatment response, and monitoring disease progression. While extensively studied in virally mediated HNSCC, its role in non-viral HNSCC remains underexplored. This systematic review and meta-analysis consolidates evidence on the diagnostic, prognostic, and therapeutic value of ctDNA in non-viral HNSCC. A systematic search across Medline, PubMed, Embase, and the Cochrane Library identified 1,915 records, of which 47 were included. Data extraction followed PRISMA guidelines, with overall survival (OS), progression-free survival (PFS), and recurrence-free survival (RFS), pooled as hazard ratios (HRs) with 95% confidence intervals (CIs) using a fixed-effect model. Among 3,574 patients, the most common tumor sites were the oral cavity (35 %) and oropharynx (22 %), with the majority presenting with stage IVA/IVB disease (29 %). Pre-treatment ctDNA detection rates ranged from 50 % to 100 % (median: 83 %), while post-treatment detection rates varied between 28 % and 100 % (median: 48 %). ctDNA detected recurrence in 80 % of patients, with a median lead time of 4.6 months. ctDNA detection was significantly associated with worse OS (HR 10.26, 95 % CI 3.58-29.40; P < 0.0001). Residual ctDNA was strongly correlated with worse PFS (HR 7.32, 95 % CI 4.17-12.86; P < 0.00001) and RFS (HR 7.33, 95 % CI 2.75-19.58; P < 0.0001). ctDNA holds potential for improving diagnostic accuracy, monitoring progression, and predicting survival outcomes in non-viral HNSCC. However, further large-scale studies and standardized guidelines are needed for validation and clinical implementation.

Ph-like ALL is a high-risk subtype with diverse genomic alterations, including CRLF2 rearrangements, JAK2/EPOR mutations, and ABL-class fusions, which are targetable but underdiagnosed in low and middle-income countries (LMICs). This meta-analysis (78 studies, 15,201 patients, 42 countries) highlights disparities in detection and outcomes between high-income countries (HICs) and LMICs. HICs use comprehensive profiling (RNA-seq: 90-95% sensitivity), while LMICs rely on limited FISH/qPCR, detecting only 30-50% of cases due to cost barriers ($1200 vs. $15-42 for LMIC-adapted assays), infrastructure gaps, and delayed turnaround (4-6 weeks vs. < 7 days). CRLF2 rearrangements are found in 50-60% of cases in HMICs vs. 20-30% in LMICs (p < 0.001), while ABL-class fusions are missed in 75% of LMIC patients. Undiagnosed Ph-like ALL correlates with worse survival (5-year OS: 35-45% in LMICs vs. 60-65% in HICs) due to chemotherapy overuse instead of TKIs (e.g., dasatinib improves EFS by 30%). A tiered diagnostic approach, initial CRLF2 flow cytometry ($15, 80% sensitivity), confirmatory PHi-RACE PCR ($42, 95.2% sensitivity), and selective NGS referral could bridge 85% of the detection gap at 90% cost reduction. Cost-effective tools, subsidized NGS networks, workforce training, and WHO-endorsed guidelines could prevent 40-50% of relapses in LMICs.

Genetic similarity of populations (or genetic ancestry) is associated with differences in somatic alterations in cancers. We meta-analyze two targeted panel sequencing cohorts with 275,605 samples from 14 cancer types. Here we find a recurrent depletion of TERT promoter mutations in patients of African and East Asian ancestry across multiple cancers. Several clinically actionable alterations, such as ERBB2 mutations in lung adenocarcinoma and MET mutations in papillary renal cell carcinoma, occur at a higher frequency in patients of non-European ancestry. Furthermore, in both cohorts, we show depletions in total driver alterations in non-European ancestries in multiple cancer types, potentially reflecting biases in current panel-based testing that prioritize established targets derived from predominantly patients of European ancestry. Our study highlights a need to increase population diversity in genomic studies to find new drivers and enhance precision oncology interventions for all populations.

Precision oncology, driven by next-generation sequencing (NGS), enables the use of matched targeted therapies (MTTs) tailored to tumour-specific genomic alterations. While benefits in early-stage cancer are well-established, the impact of MTTs in relapsed or metastatic settings remains unclear. This systematic review and meta-analysis (PROSPERO ID: CRD42023471466) evaluates the efficacy and safety of NGS-guided MTTs in patients with advanced solid and haematological tumours.

Breast cancer (BC) is one of the most common malignancies among women worldwide. Despite advances in early detection and treatment, prognosis remains highly variable. Molecular biomarkers, such as microRNAs (miRNAs), have emerged as promising tools to refine prognostic assessment. Among them, miR-21 is consistently overexpressed in solid tumors and implicated in key oncogenic pathways. This systematic review and meta-analysis aimed to clarify the prognostic significance of miR-21 in BC and explore its molecular mechanisms through bioinformatic analyses. A systematic search of PubMed, Scopus, and Web of Science up to April 2025 identified 18 eligible observational studies. Pooled analyses showed that high miR-21 expression was significantly associated with poorer overall survival (OS) (HR = 2.37, 95% CI: 1.42-3.98) and recurrence-related outcomes (DFS/RFS) (HR = 2.10, 95% CI: 1.32-3.34). Subgroup analyses confirmed robust associations across different cut-off definitions and revealed particularly strong effects in triple-negative BC (HR = 5.69) and mixed subtypes (HR = 2.55), but no significant association in HER2-positive BC. Bioinformatic analysis identified target genes such as PTEN, BCL2, STAT3, and MYC, involved in apoptosis regulation, proliferation, NF-κB signaling, and immune modulation. These findings provide consistent evidence that miR-21 is a promising minimally invasive prognostic biomarker in BC, particularly in aggressive subtypes, and support its integration into future multimodal prognostic models.

Polymorphisms in the XRCC3 gene, a key component of homologous recombination repair, have been studied for their potential role in thyroid cancer susceptibility. However, published findings remain inconsistent across populations and genetic variants. This meta-analysis aimed to clarify the associations between XRCC3 polymorphisms and thyroid cancer risk, with emphasis on variant- and ethnicity-specific effects.

Pancreatitis may be associated with the risk of developing pancreatic cancer (PC). Previous retrospective studies have shown that chronic pancreatitis (CP) may increase the risk of pancreatic cancer. However, the causal relationship between acute pancreatitis (AP) and pancreatic cancer remains unclear. We performed Mendelian randomization (MR) analysis to investigate the causal relationship between AP and PC and validate the effect of CP on PC identified in previous retrospective studies. Genome-wide association study data for AP, CP and PC were obtained from a public database. Inverse-variance weighting is the most important MR method for analyzing causality. Sensitivity analysis was used to evaluate the robustness of MR. Finally, a meta-analysis based on the inverse-variance weighting results was conducted to strengthen the robustness of the MR further. Four MR analyses were performed to investigate the effect of AP on PC. There was a result showing AP decreased the risk of PC (odds ratio [OR]: 0.773, 95% confidence interval [CI]: 0.612-0.975, P = .030), but other 3 results were not statistically significant (P > .05). The results of the meta-analysis revealed that AP did not increase the risk of PC (OR: 0.941, 95% CI: 0.861-1.029, P = .182). Three MR analyses were performed to validate the effect of CP on PC. There was a result showing CP increased the risk of PC (OR: 1.208, 95% CI: 1.037-1.406, P = .015), but the other 2 results were not statistically significant (P > .05). The results of the meta-analysis revealed CP increased the risk of PC (OR: 1.079, 95% CI: 1.011-1.152, P = .023). We confirmed that CP is associated with a greater risk of PC. However, there is no direct causal relationship between AP and PC. More clinical and experimental studies are needed to investigate the causal relationship.

To evaluate cysteine dioxygenase 1 (CDO1) gene promoter methylation in circulating tumor DNA as a biomarker for the early diagnosis of lung cancer.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with a substantial risk of recurrence even in early-stage non-small cell lung cancer (NSCLC) after curative surgery. Circulating tumor DNA (ctDNA)-based detection of minimal residual disease (MRD) has emerged as a promising tool for identifying patients at increased risk of relapse. However, the predictive effectiveness of ctDNA remains uncertain because of variability in study designs, detection strategies, and statistical power.

There are meta-analyses about the correlation between non-coding RNA and the prognosis of gastric cancer, which are focus on a single or a particular type of non-coding RNA. This study aims to verify the correlation between various non-coding RNAs and the prognosis of gastric cancer through meta-analysis.

The BRAFV600E mutation is one of the most common genetic alterations in papillary thyroid cancer (PTC) and is widely recognized as a factor of poor prognosis. Radioactive iodine (RAI) therapy is recommended after thyroidectomy for patients with high-risk level PTC or distant metastatic PTC. However, the association between BRAFV600E mutation and RAI refractoriness remains controversial and requires additional investigation. This meta-analysis was conducted to evaluate the impact of BRAFV600E mutation on the curative effect of RAI therapy.

The introduction of the term pituitary neuroendocrine tumor (PitNET) to replace pituitary adenoma has sparked a versatile debate among experts. The controversy surrounding this nomenclature change includes the question of whether these tumors' biological identity truly corresponds to neuroendocrine tumors. In this meta-analysis, DNA methylation data were interrogated to clarify whether the old or new nomenclature more accurately reflects the epigenome of these tumors. Publicly available DNA methylation data of 100 NETs, 100 PitNETs/adenomas, and 100 adenomas of various origins and lineages were compiled from 18 different publications. Epigenomic signatures characteristic of NETs and adenomas were defined and compared to those of PitNETs/adenomas. Promoter CpG methylation levels were investigated for hallmarks of cellular differentiation. Comparative DNA methylation analyses demonstrated that all 100 PitNETs/adenomas aligned more closely with NETs than with adenomas. Focusing on promoter-associated CpGs moreover confirmed robust epigenomic features associated with neuroendocrine differentiation in PitNETs/adenomas. These findings indicate that PitNETs/adenomas resemble NETs rather than adenomas on the epigenomic level and support PitNET as the biologically more accurate term. Of note, appropriately addressing the broad spectrum of clinical behaviors in these tumors remains a critical issue in the current pituitary tumor classification framework and nomenclature.

Many women carry male cells of presumed fetal origin-so-called male-origin microchimerism (MOM) in their circulation and tissues. The association between MOM and cancer risk remains unclear. We aim to evaluate the effect of MOM on cancer risk among postpartum women.

Non-small cell lung cancer (NSCLC), as one of the most commonly diagnosed cancers globally, requires expedited identification of new drug targets. We conducted proteome-wide MR using genetic data for 4,853 plasma proteins. Summary-level data on lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) were extracted from GWAS meta-analyses (11,273 and 7,426 cases, respectively) and FinnGen cohort (1,590 and 1,510 cases, respectively). We genetically identified eight proteins with a causal role in the etiology of NSCLC. Lower levels of five proteins (CDH17, CXADR, FAM3D, POGLUT3, SFTPB) and higher levels of two proteins (CEACAM5, KLK1) were linked to increased LUAD risk, while higher CD14 levels were associated with elevated LUSC risk. Two proteins, POGLUT3 and SFTPB were validated through Bayesian colocalization. One protein SFTPB was identified using SMR and HEIDI tests. Bidirectional MR found no reverse causality. The primary findings were validated through scRNA-seq, GeneMANIA, GO analysis, druggability assessments and PheWAS analysis. These protein-coding genes are primarily expressed in epithelial cells, macrophages, monocytes, and endothelial cells. Furthermore, CEACAM5, KLK1, and CD14 correspond to existing drugs. These proteins may deepen our comprehension of the etiology and could serve as appealing novel biomarkers and drug targets for NSCLC management.

Immune checkpoint inhibitors targeting PD-L1 or PD-1 as monotherapy or combined with CTLA-4 inhibitors or chemotherapy (or both) are the standard of care for patients with advanced non-small-cell lung cancer (NSCLC). However, it remains unclear which patients benefit from the addition of CTLA-4 inhibitors. We aimed to evaluate whether dual checkpoint blockade with CTLA-4 and PD-L1 or PD-1 inhibitors provides similar efficacy to PD-L1 or PD-1 inhibitor monotherapy, or whether these strategies produce distinct outcomes across NSCLC subpopulations.