Advanced bladder cancer patients show very variable responses to immune checkpoint inhibitors (ICIs) and effective strategies to predict response are still lacking. Here we integrate mutation and gene expression data from 707 advanced bladder cancer patients treated with anti-PD-1/anti-PD-L1 to build highly accurate predictive models. We find that, in addition to tumor mutational burden (TMB), enrichment in the APOBEC mutational signature, and the abundance of pro-inflammatory macrophages, are major factors associated with the response. Paradoxically, patients with high immune infiltration do not show an overall better response. We show that this can be explained by the activation of immune suppressive mechanisms in a large portion of these patients. In the case of non-immune-infiltrated cancer subtypes, we uncover specific variables likely to be involved in the response. Our findings provide information for advancing precision medicine in patients with advanced bladder cancer treated with immunotherapy.

Prognostic transcriptomic signatures for prostate cancer (PCa) often overlook the cellular origin of expression changes, an important consideration given the heterogeneity of the disorder. Current clinicopathological factors inadequately predict biochemical recurrence, a critical indicator guiding post-treatment strategies following radical prostatectomy. To address this, we conducted a meta-analysis of four large-scale PCa datasets and found 33 previously reported PCa-associated genes to be consistently up-regulated in prostate tumours. By analysing single-cell RNA-sequencing data, we found these genes predominantly as markers in epithelial cells. Subsequently, we applied 97 advanced machine-learning algorithms across five PCa cohorts and developed an 11-gene epithelial expression signature. This signature robustly predicted biochemical recurrence-free survival (BCRFS) and stratified patients into distinct risk categories, with high-risk patients showing worse survival and altered immune cell populations. The signature outperformed traditional clinical parameters in larger cohorts and was overall superior to published PCa signatures for BCRFS. By analysing peripheral blood data, four of our signature genes showed potential as biomarkers for radiation response in patients with localised cancer and effectively stratified castration-resistant patients for overall survival. In conclusion, this study developed a novel epithelial gene-expression signature that enhanced BCRFS prediction and enabled effective risk stratification compared to existing clinical- and gene-expression-derived prognostic tools. Furthermore, a set of genes from the signature demonstrated potential utility in peripheral blood, a tissue amenable to minimally invasive sampling in a primary care setting, offering significant prognostic value for PCa patients without requiring a tumour biopsy.

To assess the contribution of rare coding germline genetic variants to prostate cancer risk and severity, we perform here a meta-analysis of 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline whole exome or genome sequencing data, and one cohort with imputed array data. At the gene level, our case-control collapsing analysis confirms associations between rare damaging variants in four genes and increased prostate cancer risk: SAMHD1, BRCA2 and ATM at the study-wide significance level (P < 1×10-8), and CHEK2 at the suggestive threshold (P < 2.6×10-6). Our case-only analysis, reveals that rare damaging variants in AOX1 are associated with more aggressive disease (OR = 2.60 [1.75-3.83], P = 1.35×10-6), as well as confirming the role of BRCA2 in determining disease severity. At the single-variant level, our study reveals that a rare missense variant in TERT is associated with substantially reduced prostate cancer risk (OR = 0.13 [0.07-0.25], P = 4.67×10-10), and confirms rare non-synonymous variants in a further three genes associated with reduced risk (ANO7, SPDL1, AR) and in three with increased risk (HOXB13, CHEK2, BIK). Altogether, this work provides deeper insights into the genetic architecture and biological basis of prostate cancer risk and severity, with potential implications for clinical risk prediction and therapeutic strategies.

The vitamin D and its receptor the VDR have pleiotropic effects on different biological mechanisms, including skin cancers. The sun UV radiation has confirmed effects on both skin cancers and on VD/VDR pathways. We aim to investigate the role of the VDR and its interaction with specific environmental factors to develop skin cancers. We conducted meta-analyses of published association studies on the VDR gene polymorphisms FokI, BsmI, TaqI and AapI and skin cancers. Subgroup analyses were performed to investigate the impact of environmental factors on skin cancers. Meta-analysis showed that the VDR Fok I polymorphism was associated with melanoma risk (CT vs. CC + TT, P = 0.020), with CT genotype as a significant risk factor. We found also significant association for the VDR BsmI polymorphism (AG vs. GG model, P = 0.020), as AG genotype having a protective effect against melanoma. However the VDR TaqI and ApaI polymorphisms were not associated with melanoma in the overall analysis. Met-analysis of studies on non-melanoma cancers (NMSC) showed significant effects of FokI (TT vs. CT + TT, P = 0.002, CC vs. CT, P = 0.017 and CC vs. TT, P = 0.001), with TT genotype as a risk factor, whereas the CC genotype was protective against NMSC. The TaqI showed also significant association with NMSK (T vs. C contrast allele: P = 0.006 and TT vs. CT + CC, P = 0.011), with T allele and TT genotype as having protective roles. Stratification according to geographic localisation showed that the FokI CC genotype had protective effect in both North America (CC vs. CT + TT, P = 0.003) and North Europe (CC vs. CT + TT, P = 0.010). Stratification according to the study period revealed that the FokI CT genotype had a highly significant risk (CT vs. TT, P < 0.001) in the last decade 2011-2020. VDR FokI and BsmI polymorphisms showed significant associations with melanoma, whereas FokI and TaqI were significantly associated with NMSC. Subgroup analysis revealed that factors such as the geographic localisation and study period influenced the association between the VDR gene and the risk of skin cancers.

Survival for patients with multiple myeloma (MM) has improved but outcomes remain heterogeneous. Consistent diagnostic identification of high-risk disease is desirable to address unmet patient need. The aim was to investigate the consistency of association of co-occurrence of high-risk cytogenetic abnormalities (HRCAs) with prognosis in patients with newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM), and across a range of treatment modalities.

Recent studies suggest blood cells influence breast cancer, but no Mendelian randomization (MR) studies have confirmed a causal relationship between specific blood cell phenotypes and breast cancer. MR analysis of blood cell phenotypes used breast cancer data from Finngen R11, UKB, and open genome-wide association study databases. Meta-analyzed inverse variance weighted results were adjusted for multiple comparisons. The reverse relationship was also explored. MR and meta-analysis identified significant associations between specific blood cell phenotypes and breast cancer: neutrophil perturbation response (side fluorescence standard deviation of neutrophil 4 in response to alhydrogel perturbation): odds ratio (OR) = 0.967, P = .0009; neutrophil perturbation response (forward scatter median of neutrophil 4 in response to Pam3CSK4 perturbation): OR = 0.972, P = .031; white blood cell perturbation response (side scatter coefficient of variation of WBC 2 in response to nigericin perturbation): OR = 0.972, P = .031; white blood cell perturbation response (forward scatter coefficient of variation of WBC in response to Pam3CSK4 perturbation): OR = 1.042, P = 8.15 × 10-5. And there was no reverse result. Neutrophil perturbation response (side fluorescence standard deviation of neutrophil 4 in response to alhydrogel perturbation) and white blood cell perturbation response (side scatter coefficient of variation of WBC 2 in response to nigericin perturbation) are protective factors for breast cancer. Conversely, neutrophil perturbation response (forward scatter median of neutrophil 4 in response to Pam3CSK4 perturbation) and white blood cell perturbation response (forward scatter coefficient of variation of WBC in response to Pam3CSK4 perturbation) are risk factors for breast cancer.

Traditional B-cell mitogens often fail to promote effective cell division in vitro for mature B-cell neoplasms, hindering chromosome analysis. The combination of DSP30 and IL-2 (DSP30/IL-2) has been suggested as a better alternative. This review evaluates DSP30/IL-2 efficiency using a systematic review and meta-analysis of 20 studies. Studies comparing the successful culture rate (SCR) and/or abnormalities detection rate (ADR) of DSP30/IL-2 against traditional mitogens and/or fluorescence in situ hybridization (FISH) were included. Subgroup analyses were performed for cases of chronic lymphocytic leukemia (CCL) and other B-cell neoplasms (OBCN). The findings show no significant difference in SCR between DSP30/IL-2 and traditional mitogens, but DSP30/IL-2 significantly increases ADR. However, DSP30/IL-2's ADR is lower than that of FISH. Analyses by CLL and OBCN subgroups showed similar results. Overall, DSP30/IL-2 is a superior alternative for cytogenetic studies in mature B-cell neoplasms.

This network meta-analysis (NMA) aimed to identify the most effective first-line intervention (FLI) for advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), particularly in patients with varying brain metastasis (BM) status.

ETS-related gene (ERG) rearrangement and tensin homolog (PTEN) deletion are common molecular alterations in prostate cancer. Their prognostic significance for biochemical recurrence (BCR) after radical prostatectomy is not fully understood. This study aimed to conduct a systematic review and meta-analysis to assess the association between ERG and PTEN status and BCR risk.

The p53 protein is a tumor-suppressing transcription factor that is critical in tumorigenesis. While TP53 mutations are rare in differentiated thyroid cancer (DTC), they are significantly more common in anaplastic thyroid cancer (ATC). This study presents original results and a meta-analysis reevaluating the prognostic value of TP53 mutations in thyroid cancer, including surrogate markers such as immunohistochemical p53 expression and serum p53-Abs levels. TP53 mutations were analyzed using SSSP and direct sequencing in a DTC group (15 patients), an ATC group (3 patients), and a control group (25 patients). The immunohistochemical p53 expression was assessed in tissue samples. A meta-analysis of 14 eligible studies identified through the PubMed, Scopus, Google Scholar, and Cochrane databases was conducted. Our results showed TP53 mutations in all ATC cases, 6.67% of DTC cases (1 out of 15), and none in the control group. Immunohistochemical p53 overexpression was observed in 4 out of 15 DTC (26.67%) and all ATC cases but absent in controls. A meta-analysis confirmed that TP53 mutations are significantly more frequent in ATC than controls (OR 8.95; 95% CI: 1.36-58.70; p = 0.02) but not in DTC vs. controls (OR 1.87; 95% CI: 0.53-6.58; p = 0.33). p53 overexpression was significantly higher in both DTC and ATC vs. controls (OR 7.99; 95% CI: 5.11-12.51; p < 0.01 and OR 64.37; 95% CI: 27.28-151.89; p < 0.01, respectively). The serum p53-Abs positivity was also elevated in patients with PTC vs. controls (OR 2.07; 95% CI: 1.24-3.47; p < 0.01). TP53 mutations are frequent events in the pathogenesis of ATC. In DTC, further prospective studies are needed to determine the prognostic value of TP53 mutations and related surrogate markers (immunohistochemical p53 expression, p53-Abs positivity).

This meta-analysis aims to systematically evaluate the associations of four specific Single Nucleotide Polymorphisms (SNPs)-rs712829, rs712830, rs11568315, and rs884225-located in the promoter, intronic, and 3' untranslated regions (3'UTR) of the EGFR gene, with lung cancer risk.

To investigate the diagnostic value of high-resolution melting (HRM) analysis for oncology-associated epidermal growth factor receptor (EGFR) gene mutations.

Neoadjuvant immunotherapy (NIT) has been endorsed by clinical guidelines for the management of DNA mismatch repair deficiency/microsatellite instability-high (dMMR/MSI-H) locally advanced rectal cancer (LARC). Nonetheless, the therapeutic efficacy of NIT in mismatch repair-proficient/microsatellite stable (pMMR/MSS) non-metastatic rectal cancer (RC) remain pending matters. Therefore, a meta-analysis was carried out to assess the efficacy and safety of NIT in patients with non-metastatic pMMR/MSS RC.

This study aimed to investigate the diagnostic test accuracy of MRI-based radiomics studies for predicting EGFR mutation in brain metastasis originating from lung cancer.

We conducted a multiancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry, 58,236 African ancestry, 23,546 Hispanic/Latino and 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (P ≤ 5 × 10-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n = 95,768). Meta-analyzing discovery and replication (n = 392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino and 8.6% to 15.3% for Asian ancestry and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, offering potential to personalize prostate cancer screening.

To explore the potential influence of Sjogren's syndrome (SS) on thyroid cancer (TC).

The combination of genetic and environmental factors may contribute to the carcinogenesis of HNC. Despite the reported associations between xeroderma pigmentosum group D (XPD) polymorphisms and HNC, the results have been inconsistent, with different studies reporting varying results. Therefore, our aim is to assess the association of three XPD polymorphisms (rs13181, rs1799793, and rs238406) in a comprehensive meta-analysis.

Small nucleolar RNA host gene (SNHG) family were reported involved in various biological processes and may be used as a promising prognostic marker in esophageal cancer (EC). A meta-analysis was performed to investigate the relationship between SNHG expression and prognosis of EC in this study.

Understanding the BRAF alterations preoperatively could remarkably assist in predicting tumor behavior, which leads to a more precise prognostication and management strategy. Recent advances in artificial intelligence (AI) have resulted in effective predictive models. Therefore, for the first time, this study aimed to review the performance of machine learning and deep learning models in predicting the BRAF alterations in low-grade gliomas (LGGs)using imaging data.

The selective estrogen receptor modulator tamoxifen is a mainstay of endocrine breast cancer therapy. However, the clinical response rates of tamoxifen are inferior to those of aromatase inhibitors, which may be partially explained by variable drug exposure due to the pharmacogenetics of the drug-metabolizing enzyme cytochrome P450 (CYP) 2D6. Clinical trials investigating the association between CYP2D6 impairment and tamoxifen outcomes have yielded conflicting results. The results of a comprehensive meta-analysis of 33 single-center tamoxifen trials reported here address this inconsistency by adjusting for two biases that may affect the validity of previous association studies: allele coverage of CYP2D6 genotyping and loss of heterozygosity of the CYP2D6 locus in tumor-derived DNA. After adjustment for bias, meta-analyses show significantly reduced study heterogeneity and a higher risk of recurrence or death in patients with impaired CYP2D6 metabolism compared with those with normal activity. These data may support the use of pharmacogenetics-guided tamoxifen therapy to improve outcomes in patients with CYP2D6-compromised breast cancer. Prospective studies should be considered. See related article by MacLehose et al., p. 224.