Retinoblastoma (RB) is typically associated with highly penetrant pathogenic sequence variants (PSVs) in the RB1 gene; however, some families exhibit low penetrance RB (LPRB). We aimed to determine the penetrance rate and identify genetic and clinical characteristics of LPRB. To that end two cohorts were analyzed: 250 genetically confirmed LPRB cases identified through systematic literature review and 78 classical germline RB (CGRB) from three international centers- Thailand, Korea, and Israel. Penetrance rate was estimated as the proportion of affected individuals among RB1 PSV carriers. Multivariate models assessed parent-of-origin effects and predictors of penetrance. PSVs were annotated with Combined Annotation Dependent Depletion (CADD) scores and mapped to pRB structural domains. LPRB penetrance ranged from 50% (125/250, non-age-adjusted, CI [43.8%-56.2%]) to 64% (125/196, age-adjusted, CI [56.8%-70.2%]). Paternal inheritance of RB1 PSV was associated with a significantly increased risk of LPRB in offspring (OR = 6.24; P < 0.0001). Clinically, LPRB were significantly more likely than CGRB to present with unilateral disease (OR = 9.3, P < 0.0001), diagnosed at an older age (13 Vs 6.5 months, P = 0.01), and affect males (OR = 2.4, P = 0.03). LPRB-associated PSVs showed lower CADD scores (OR = 1.5; P = 0.0008), indicating lower predicted pathogenicity, and were enriched in pRB's N- or C-terminal domains (OR = 3.2; P = 0.007), consistent with hypomorphic effects. In conclusion, LPRB shows a 50-64% penetrance rate, more likely to be paternally inherited, have unilateral presentation, and associated with hypomorphic RB1 PSVs in the terminal pRB regions. These findings support retitling 'low penetrance RB' to 'medium penetrance RB'.

BackgroundSERPINE1 has attracted considerable attention in tumor biology, but its clinical importance in head and neck squamous cell carcinoma (HNSCC) is not yet clear. We therefore examined whether SERPINE1 expression is related to survival in patients with HNSCC.MethodsWe searched three major databases (PubMed, EMBASE, and the Cochrane Library) and identified observational studies reporting survival outcomes in relation to SERPINE1 expression through November 11, 2024. From eligible reports we extracted data on progression-free survival (PFS), overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS), and calculated pooled hazard ratios (HRs) using random-effects models.ResultsEleven studies including 733 individuals with HNSCC met the inclusion criteria. Across these cohorts, higher SERPINE1 expression was consistently linked with shorter OS (HR 2.81, P = 0.003) and shorter DFS (HR 1.57, P = 0.004). In contrast, no clear associations were observed for PFS or DSS (P ≥ 0.05).ConclusionCurrent evidence suggests that increased SERPINE1 expression is associated with an unfavorable prognosis in HNSCC, particularly for OS and DFS. Larger prospective studies are needed to confirm these findings and to determine how SERPINE1 assessment might be incorporated into risk stratification and treatment planning for patients with HNSCC.

An increasing number of studies have shown that ferroptosis is related to the initiation and development of small cell lung cancer (SCLC). The systematic review aimed to summarize the characteristics of ferroptosis from its pathogenetic role to translational therapeutic implications in SCLC.

Pituitary neuroendocrine tumours (PitNETs) range from slow-growing to highly aggressive tumours; however, traditional prognostic markers often fail to predict clinical outcomes reliably. DNA methylation has recently emerged as a promising biomarker for assessing tumour behaviour. This systematic review evaluates its predictive value in PitNETs. To systematically assess the clinical applicability of DNA methylation profiles in predicting behaviour of PitNETs. Systematic review. A comprehensive search was conducted in Medline, Embase, Web of Science, and Cochrane CENTRAL on December 13, 2024, with an update on October 17, 2025. The search included studies on adult PitNET patients, specifically examining tumour behaviour in relation to DNA methylation. Excluded were studies that focused on cell-free DNA, investigated a single gene with no established relevance to tumour behaviour, or assessed tumour size only. Data were extracted from 20 eligible studies by four independent reviewers. The risk of bias was assessed using the QUIPS tool. Due to methodological differences across studies, the findings were summarised narratively. Twelve studies investigated tumour invasiveness, two examined tumour aggressiveness and five examined PitNET regrowth, recurrence and re-intervention. The majority of studies concentrated on non-functioning PitNETs and used Illumina arrays or PCR-based methods. These analyses identified several differentially methylated genes linked to invasiveness (e.g., PHYHD1, WNT4, STAT6, CDH1, CDH13), aggressive behaviour (e.g., AIP, PDCD1, LINE-1), and tumour regrowth (e.g., TERT, FAM90A1, ING2). DNA methylation profiling shows potential for predicting PitNET behaviour, but methodological inconsistencies limit its clinical application. Standardized methods and prospective validation are needed for clinical integration.

Metastatic castration-resistant prostate cancer (mCRPC) remains a clinically aggressive and lethal disease. Circulating tumor DNA (ctDNA), as a minimally invasive biomarker, has shown prognostic utility in several solid tumors. However, its clinical relevance in mCRPC has not been comprehensively elucidated.

Microsatellite instability (MSI), programmed death-ligand 1 (PD-L1) expression, and Epstein-Barr virus (EBV) positivity are emerging biomarkers in gastric cancer prognosis and treatment selection, particularly in immunotherapy. This review evaluates their prognostic significance through a systematic review and meta-analysis.

In proficient mismatch repair (pMMR) non metastatic rectal cancer, standard neoadjuvant chemoradiotherapy (nCRT) yields low pathological and clinical complete response rates. Early randomized trials suggest adding PD 1 inhibitors may increase response but randomized evidence has not been synthesized.

Somatic mutation testing in solid tumours represents a rapidly advancing field which increases opportunities for access to molecularly targeted therapeutics and clinical trials. This systematic review determined whether socio-demographic inequalities affect utilisation of novel somatic mutation testing.

Cerebral Cavernous Malformations (CCMs) are low-flow vascular lesions located within the central nervous system, with a reported prevalence in the general population of 0.16-0.5%. Patients with CCMs may remain asymptomatic or present new onset symptoms such as seizures or focal neurological deficits often related to the occurrence of intracerebral hemorrhage. CCM may appear sporadic or as part of familial forms linked to mutations in the CCM-gene cluster, affecting endothelial cell integrity and triggering molecular cascades, including the MEKK3/KLF2/4 signaling pathway. Recent studies have highlighted the roles of inflammatory, angiogenic, and coagulation pathways alongside the emerging evidence of a gut-brain axis influencing microbiome-driven TLR4 signaling. This systematic review aims to describe molecular biomarkers associated with CCM pathophysiology, emphasizing their potential use as diagnostic and prognostic tools. Circulating plasma biomarkers such as CRP, vitamin D, and interleukins may reflect ongoing inflammatory and endothelial processes, while some imaging biomarkers like Quantitative Susceptibility Mapping (QSM) have shown a correlation with iron deposition and vascular leakage. Leveraging both circulating and imaging biomarkers may improve the therapeutic decision-making process. Further studies are encouraged to validate these findings and to facilitate the development of personalized, evidence-based strategies for the management of CCM.

Adult-type gliomas are among the most prevalent and lethal primary central nervous system tumors, where prompt and accurate diagnosis is essential for maximizing survival prospects. Molecular classification, particularly the detection of isocitrate dehydrogenase (IDH) mutations and 1p/19q codeletions, has become crucial for accurate diagnosis and prognosis. Artificial intelligence (AI) has emerged as a promising adjunct in enhancing diagnostic accuracy using histopathological images. Existing reviews mostly focused on radiology rather than histopathology, and no comprehensive systematic review has specifically evaluated AI performance exclusively from histopathological images for detecting these two molecular markers.

Several genomic risk stratification tests are available to predict the risk of metastasis and mortality for prostate cancer patients at the time of diagnosis. However, the evidence supporting the clinical utility of genomic risk stratification tools is fragmented, posing challenges in assessing their real-world clinical impact and cost-effectiveness.

Human epidermal growth factor receptor 2 (HER2)-targeted therapies have been investigated for therapeutic benefit in RAS/BRAF wild-type/HER2+ metastatic colorectal cancer (mCRC). Unlike HER2+ breast and gastric cancer, there are no regulatory criteria for determining HER2 overexpression in patients with mCRC. This systematic literature review describes unmet needs for patients with HER2+ mCRC in relation to testing and treatment, highlights the importance of early HER2 testing at mCRC diagnosis, and discusses the evolving treatment landscape. We utilised PubMed and EMBASE databases up to November 2023 to identify journal articles and published congress abstracts relating to the HER2+ disease and treatment landscape, HER2 testing in mCRC, and HER2-targeted treatments in mCRC. Many studies have demonstrated the utility of immunohistochemistry, in situ hybridisation, and next-generation sequencing (tissue- and circulating tumour DNA-based) for detecting HER2 overexpression/amplification in mCRC and have attempted to establish consolidated criteria like those used for breast and gastric cancer. The value of HER2-targeted treatments in patients with HER2+ mCRC has been evidenced by clinical trials and meta-analyses, with strong evidence from MOUNTAINEER and DESTINY-CRC01 which supports the use of tucatinib + trastuzumab or trastuzumab deruxtecan, respectively, among this patient population. However, real-world analyses have confirmed that patients with HER2+ mCRC are not routinely tested for HER2 overexpression. Strong evidence and clinical guidelines support the value of HER2-targeted treatment among patients with HER2+ mCRC. There is a need for increased awareness and earlier uptake of HER2 testing among patients with mCRC to broaden treatment options and optimise outcomes for this patient population.

Melanoma, colorectal cancer (CRC), and hepatocellular cancer (HCC) overexpress the PD-1/PD-L1 pathway to evade the immune response. Immune Checkpoint Inhibitors (ICIs) suppress this mechanism but lack specificity, leading to immune-related adverse events (irAEs). Small-interfering RNA (siRNA) offers precise gene suppression but requires a protective delivery vector. Attenuated Salmonella, with tumor-targeting and immunomodulatory properties, is a promising carrier.

Glioblastoma (GBM) is an aggressive tumor with limited therapeutic options. Zika virus (ZIKV) has demonstrated activity against GBM; however, the cellular pathways behind this interaction remain unclear. We systematically reviewed open-access primary studies assessing differentially expressed genes (DEGs) in GBM models infected with wild-type or engineered ZIKV using transcriptomic approaches (inclusion criteria); reviews, restricted-access studies, commentaries, preprints, abstracts, and articles lacking data or not meeting these conditions were excluded (PROSPERO CRD420251077092). We performed a pathway analysis of reported DEGs. PubMed and Google Scholar were searched up to 5 March 2025; 139 records were identified and 5 met the eligibility criteria. Risk of bias was evaluated using an adapted ToxRTool for in vitro experiments and the SYRCLE RoB tool for in vivo models. Altogether, 4360 genes were reported as upregulated and 2072 as downregulated; 12 genes (DNAJB9, SESN2, PMAIP1, PPP1R15A, KLF4, ATF3, IFNB1, IFNL1, ANKRD33B, ZC3HAV1, OASL, and CCL5) were consistently upregulated, none were consistently downregulated. Pathway analysis of the studies providing complete DEG lists identified 23 commonly enriched pathways mostly related to interferon signaling. These findings may help guide future research in this field; nevertheless, methodological heterogeneity limits comparability, reinforcing the need for standardized protocols. Funding: ITpS, CNPq, and FAPEMIG.

Almost half of patients with triple-negative breast cancer (TNBC) develop brain metastasis (TNBCBM), a marker of poor prognosis. TNBC is a more aggressive breast cancer subtype which lacks ER, PR, and HER2 expression, and thus, exploring predictive biomarkers is crucial to improving TNBCBM outcomes through targeted therapy. To curate these biomarkers, peer-reviewed publications from 2010 to 2025 were extracted from PubMed, Scopus, Embase, Cochrane, and Web of Science if they evaluated clinicopathological biomarkers of TNBCBM. A total of 130 studies (60 clinical and 70 pre-clinical) were included. Publications most often featured transcriptomic studies, growth factor receptors, and immune microenvironment markers with 37, 19, and 17 studies identified, respectively. While TNBC aggressiveness has been linked to metastasis, advancing stage, and poor prognosis, several studies focused on utilizing circulating protein and transcriptomic biomarkers for early detection. While few pathways appeared specifically for TNBCBM, investigating these biomarkers further may allow for improved risk stratification, clinical trial design, patient selection, and therapeutic development. Identification of the most promising biomarkers will pave the way for improved prognosis of the most lethal complications of TNBC.

Triple-negative breast cancer (TNBC) is characterized by marked clinical and molecular heterogeneity, which underlies the limited success of currently available targeted therapies and results in most patients relying on cytotoxic chemotherapy. This therapeutic gap underscores the pressing need for novel therapeutic approaches, in which non-coding RNAs (ncRNAs) have emerged as promising candidates. In this systematic review, 35 pre-clinical studies published between 2020 and 2025 were analyzed to evaluate the therapeutic potential of targeting ncRNAs in TNBC, including miRNAs, lncRNAs, and circRNAs. The original articles employed in vivo tumor models to assess the therapeutic response of ncRNA expression modulation, using miRNA mimics, antagomiRs, ASOs, shRNAs, and siRNAs integrated into advanced targeted delivery systems, such as nanoparticles and exosomes. According to the selected studies, 28 specific ncRNAs were identified as actionable molecular targets. Modulation of these molecules consistently resulted in tumor growth suppression, metastasis inhibition, and restoration of sensitivity to standard chemotherapeutic agents. Collectively, the pre-clinical evidence presented in these studies positions ncRNA-based therapies as innovative, promising, and potentially effective strategies for advancing TNBC treatment.

Gliomas are intracranial tumors characterized by limited diagnostics and treatment approaches. Blood-circulating miRNAs represent a regulatory class of molecules that change their expression under pathological conditions and can relatively easily be detected. The present study evaluates the diagnostic potential of blood-circulating miRNAs in glioma. All grades of gliomas are included in the analysis. The articles were retrieved from the PubMed, Web of Science and Scopus databases up to October 2025. The studies were considered to be eligible if they used glioma patients and healthy controls and compared their miRNA levels, indicating sensitivity and specificity values. Risk of bias was assessed using the QUADAS-2 tool. The collected data was pooled by the STATA 19.0 MP bivariate random effects model and indicated heterogeneity using the I2 statistic value. To identify possible reasons for heterogeneity, we utilized subgroup analysis and meta-regression. Publication bias was assessed with Deeks' funnel plot, and the test diagnostic potential was evaluated with Fagan's nomogram. We analyzed 31 original reports covering 2299 glioma patients and 1719 healthy controls. A meta-analysis on 59 data points extracted from the analyzed papers was conducted. The combined pooled sensitivity was found to be equal to 0.83 (95%CI: 0.80-0.86), the specificity 0.88 (95%CI: 0.85-0.90), the positive likelihood ratio 6.7 (95%CI: 5.4-8.5), the negative likelihood ratio 0.19 (95%CI: 0.16-0.23), and the diagnostic odds ratio 35 (95%CI: 25-50). An SROC analysis revealed an AUC equal to 0.92 (95%CI: 0.90-0.94). The reported diagnostic parameters imply that blood-circulating miRNAs hold the potential to be developed into diagnostic biomarkers for glioma identification. However, the high heterogeneity in the analyzed studies suggests that the results should be considered as exploratory only.

Mismatch repair deficiency (dMMR) and microsatellite instability (MSI-H) cancers exhibit high immunogenicity and are highly responsive to immune checkpoint inhibitors. In patients with locally advanced dMMR/MSI-H colorectal cancer (CRC), neoadjuvant immunotherapy (NIT) has demonstrated unprecedented pathological complete response (pCR) rates, suggesting nonoperative management strategies may be possible. There remains a discrepancy between radiological assessment and pathological responses to NIT in CRC.

Genetic mutations and their phenotypic manifestation have been recognized as critical factors in tumorigenesis. However, the relationship between these mutations and the pathogenesis of uterine leiomyomas (UL) remains inadequately characterized. There is compelling evidence to suggest a genetic underpinning in UL development, alongside influences from epigenetics, environmental stimuli, growth hormones, and growth factors. A plethora of studies have tried to elucidate the genetic and epigenetic etiologies associated with UL, but the definitive implications of these findings remain unclear. An extensive systematic review was conducted to investigate the genetic etiologies of UL. This systematic review aimed to consolidate current knowledge on genetic and epigenetic causes of UL, offering a comprehensive perspective on the evidence and its relevance in other solid tumors. A secondary focus was to identify the most significant genetic association with the genesis of UL. A total of 60 articles were identified, and 10 chromosomes and 51 genes were found to be implicated in the development of UL. The main trend in fibroid research focuses on genetic abnormalities and aberrations as the etiology of UL development. It has been estimated that 40% of UL can be associated with chromosome-specific aberrations. Chromosomal gain, loss, rearrangement, single nucleotide polymorphism (SNP), and translocation are the most common aberrations associated with UL development. The most recurrent ones include chromosome X and 7q deletions, and rearrangements of 12q15, 6p21 and 10q22. MED12 has been identified as a gene of particular importance in the development of UL.

Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis. O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation is a critical biomarker for guiding chemotherapy decisions, yet current testing requires invasive tissue sampling. This study aimed to systematically evaluate the diagnostic accuracy of artificial intelligence (AI) models using MRI for non-invasive prediction of MGMT promoter methylation status in GBM.