Bladder cancer (BLCA) remains a significant global health concern, being characterized by high incidence, recurrence, and mortality rates. Disease heterogeneity and rapid progression pose major challenges for effective management and identification of actionable biomarkers. Conventional therapies often fail to successfully achieve disease control, urging the development of novel, personalized approaches. In recent years, anti-tumour immunotherapy approaches in both pre-clinical and clinical settings have boomed. However, the efficacy of these strategies has been limited by the low mutational burden in some tumours, which hinders neoantigen presentation and the identification of BLCA-specific signatures. Cancer-associated aberrant glycosylation presents a unique opportunity for identifying BLCA-specific glycosignatures and developing innovative targeted therapeutics. This review provides a comprehensive overview of the clinical challenges in BLCA management and emerging novel therapies. Furthermore, it highlights the potential of glycosylation alterations as a unique opportunity for developing glycan-based therapies, potentially revolutionizing BLCA treatment strategies.

Colorectal cancer (CRC) genetic testing of regions beyond clinical guidelines has revealed a substantial number of likely pathogenic germline mutations (GMs). It remains largely undetermined whether and how these GMs, typically located in non-mismatch repair (non-MMR) genes, are associated with the tumorigenesis of CRC. This study aimed to identify CRC-predisposing GMs among 93 cancer susceptibility genes and investigate their potential influences on CRC somatic mutational features. We secondarily aimed to investigate whether somatic ERBB2 amplification contributes to identifying GM carriers. This study incorporated a total of 3,240 Chinese CRC patients and 10,588 control individuals. CRC patients were subjected to paired tumor-normal sequencing with a 1,021-gene panel. A case-control analysis was conducted to profile the GM-associated CRC risk. A comprehensive germline-somatic association analysis was performed among 2,405 patients, with key findings subsequently validated in an independent 835-patient cohort and the TCGA CRC cohort. The case-control results supported CRC-predisposing effects of GMs in certain homologous recombination repair (HRR) and DNA damage checkpoint factor (CPF) genes, such as BRCA1/2, RecQ helicase genes, ATM, and CHEK2. HRR GMs were associated with an increased copy number alteration burden, more TP53 clonal mutations, and a higher probability of carrying somatic ERBB2 amplification. CPF GMs were inferred to have synergistic effects with ARID1A and KDM6A somatic mutations in CRC tumorigenesis. Among patients with onset age ≥55 years, stable microsatellites, and no cancer family history, ERBB2 amplification was significantly predictive of GM carriers. Our findings elucidate different germline tumorigenic patterns not driven by deficient MMR. Somatic ERBB2 amplification in CRC can serve as an indicator for germline genetic testing when traditional risk features are absent.

Despite extensive research on hypoxia in hepatocellular carcinoma (HCC), previous studies have relied on pre-existing hypoxia gene sets, limiting their specificity. We developed a novel approach using direct comparison of hypoxic versus normoxic HCC cell lines to establish a more precise hypoxia signature.

Through differential gene expression analysis of HCC cells under controlled oxygen conditions (GSE185969) and integration with TCGA-LIHC data, we identified and validated a highly specific 29-gene hypoxia signature. We performed comprehensive immune profiling and genomic instability analyses using multi-omics approaches.

Our HCC-specific hypoxia signature demonstrated superior prognostic value (AUC: 0.805, 0.805, 0.748 at 1/3/5 years) compared to conventional hypoxia markers. High-risk tumors showed distinct immunosuppressive features including reduced CD8 + T cells and elevated Th2 cells, along with significantly increased expression of immune checkpoints CD274 (PD-1, p < 0.05) and CD276 (B7-H3, r = 0.62, p < 0.001). Notably, we uncovered an unexpected inverse relationship between hypoxia-induced genomic instability and PARP inhibitor sensitivity, challenging current therapeutic paradigms.

Our methodology establishes a more precise hypoxia signature specific to HCC, advancing beyond traditional approaches. The paradoxical finding of reduced PARP inhibitor sensitivity in genomically unstable tumors reveals new complexities in hypoxia-driven treatment resistance, suggesting the need for alternative therapeutic strategies in hypoxic HCC.

Thymic epithelial tumors (TETs) are rare malignancies with limited treatment options and underexplored molecular features.

We examined the genomic landscape and therapeutic outcomes in 81 patients with advanced TETs, including thymic carcinomas (TCs), thymomas, and thymic neuroendocrine neoplasms (TNENs), who were enrolled in the MASTER trial, a prospective observational precision oncology trial.

Using whole-genome-sequencing and whole-exome-sequencing analysis, transcriptome analysis, and methylome analysis, we identified distinct molecular features across TET subtypes, including a higher tumor mutational burden in TC and pathogenic germline variants in 18% of cases. We performed transcriptome- and methylome-based unsupervised clustering and were able to divide TCs into immunologically hot and cold subsets, with hot TCs exhibiting higher T cell infiltration and significantly longer overall survival. In 65 out of 76 (86%) patients, we recommended molecularly informed therapies, which were applied in 29 out of 65 (45%) cases, leading to a disease control rate of 62% and an objective response rate of 23% (both n = 26). The progression-free survival ratio (PFSr) was > 1.3 in 8 out of 24 (33%) patients, 7 of them having TC. Among TCs, patients achieved a mean PFSr of 1.4, indicating potential therapeutic advantages in this subgroup. The PFSr between the PFS of immune checkpoint inhibition and preceding therapies was significantly higher in the hot cluster compared to the cold cluster (median 1.7 vs. 0.3; p = 0.01945).

Our findings expand the understanding of TET biology and emphasize the role of precision oncology in informing treatment decisions and improving outcomes for patients with advanced TETs, particularly in TCs.

Endometrial cancer represents a significant gynecologic malignancy affecting women globally, including Taiwan. This study aimed to analyze mutation patterns in endometrial cancer genes related to POLE exonuclease domain mutations and their association with patient prognosis.

We analyzed 100 endometrial cancer tissue samples from patients at MacKay Memorial Hospital (February 2014-February 2017). DNA sequencing was conducted on an Illumina MiSeq platform with subsequent QIAGEN CLC Workbench analysis. We applied Kaplan-Meier analysis and Fisher's exact test for statistical evaluations.

Mutations in POLE were primarily located in the exonuclease domain, with 36 missense variants identified, of which 19 were in this specific domain. Tumors with POLE exonuclease domain mutations (POLEmut) exhibited a significantly higher tumor mutation burden (p < 0.0001), and Kaplan-Meier analysis revealed better overall survival for patients with POLEmut tumors compared to POLE wild-type tumors (POLEwt, p < 0.0388; HR: 3.624). In POLEmut cases, tumor suppressor genes showed scattered mutations with higher nonsense rates (TP53, PIK3R1, FBXW7; all p < 0.01), contrasting with oncogenes (PIK3CA, CTNNB1, KRAS). Mutations in tumor suppressor genes (TP53, PIK3R1, FBXW7) conferred significantly better survival outcomes in POLEmut cases compared to their POLEwt counterparts with identical gene mutations (HR: 3.929-6.598, all p < 0.05).

This exploratory study finds that POLE exonuclease domain mutations are associated with distinct mutational patterns that vary between tumor suppressor genes and oncogenes. These observations provide hypothesis-generating insights into potential mechanisms underlying the favorable prognosis of POLEmut tumors and may inform future molecular investigations in endometrial cancer.

The MAFB protein, a member of the MAF family of bZip transcription factors, plays a pivotal role in various biological processes, including cell differentiation, development, and homeostasis. Characterized by its selective expression in monocytes and macrophages, MAFB has been shown to play a crucial role during myeloid lineage differentiation, acting as a critical determinant in the transition from multipotent progenitors to fully differentiated monocytes. By modulating the expression of genes associated with immune activation and inflammation, MAFB plays a vital role in maintaining immune homeostasis and responding to pathogenic challenges. Dysregulation of MAFB expression or function has been implicated in several pathological conditions, including hematological malignancies and metabolic disorders. In particular, aberrant MAFB activity has been associated with the progression of diseases such as multiple myeloma and acute myeloid leukemia as well as other solid tumors, where it may contribute to the survival and proliferation of malignant cells, thereby promoting disease progression. MAFB and downstream targets of its transcriptional network are now being regarded as predictive biomarkers for certain types of tumors as well as being considered as potential therapeutic targets for cancer treatment. In this review, we summarize current knowledge on both physiological and pathological roles of MAFB and highlight the impact of its deregulation on hematological cancer initiation and progression.

Next-generation sequencing (NGS) has transformed our understanding of oncogenic pathways and mutational processes underlying many breast tumors. Although large-scale NGS studies included mostly common invasive breast carcinomas, the genetic landscapes of several less common or rare special histologic types and other breast tumors have now also been elucidated. Many of these lesions harbor highly specific types of mutations or rearrangements/gene fusions, including invasive lobular carcinoma, tall cell carcinoma with reversed polarity, most salivary gland-like neoplasms, fibroepithelial neoplasms, and mesenchymal tumors such as fibromatosis, nodular fasciitis, and dermatofibrosarcoma protuberans. In some cases, surrogate immunohistochemical or RNA in situ hybridization markers evaluable by light microscopy have been shown to correlate with the underlying genetic alterations. Angiosarcomas and other special breast cancer subtypes, such as triple negative apocrine carcinomas, metaplastic carcinomas, and a subset of ER-positive carcinomas (mucinous and micropapillary carcinomas, neuroendocrine neoplasms) have not been associated with specific genetic underpinnings but are enriched for certain genetic features and oncogenic pathways. The identification of characteristic genetic alterations or their molecular surrogates can be useful to establish an accurate diagnosis, and in some cases, may point to potentially actionable therapeutic targets. This review aims to summarize the genetic landscapes of less common benign and malignant breast tumors, with special attention to genotype-phenotype correlations and to the diagnostic utility of genetics and surrogate markers when applicable. BRCA1/2-associated breast carcinomas will also be discussed due to the association of so-called BRCAness with basal-like histology.

Penile squamous cell carcinoma (PSCC) is a rare, aggressive malignancy with a high risk of mortality due to metastasis. A comprehensive understanding of its mutational landscape is critical for improving early detection and therapeutic strategies.

We analyzed tissue samples from 28 patients with PSCC treated at the Cancer Hospital of the Chinese Academy of Medical Sciences between January 2019 and March 2023. DNA from primary tumors and/or matched inguinal lymph nodes underwent targeted sequencing. Somatic mutations were profiled to compare primary and metastatic lesions. Statistical analyses assessed associations between mutational features, clinical outcomes, and treatment responses.

A total of 980 mutations were identified across 354 genes. Frequently mutated genes included TP53 (67.5%), TERT (45%), CDKN2A (40%), FAT1 (37.5%), and NOTCH1 (30%). Copy number variations (CNVs) revealed amplifications in EGFR, SOX2, and MSH6 and deletions in CDKN2B and CDKN2A. A strong correlation was observed between mutational profiles of primary and metastatic lesions (r = 0.61, P < .001). Metastatic tumors exhibited higher tumor mutational burden (TMB) than primary tumors (38.9% vs. 9.5%, P = .030) and displayed a greater prevalence of mismatch repair deficiency-associated mutational signatures. Patients with higher TP53 mutation frequencies responded more favorably to immune checkpoint inhibitors (P = .024), with treatment efficacy strongly correlated (AUC = 0.938).

Key mutational alterations in PSCC, including high TMB and TP53 mutations, have significant implications for early diagnosis and personalized therapies. These findings support the potential use of specific genetic markers to guide targeted therapeutic approaches.

Cancer immunotherapy stimulates and enhances antitumor immune responses to eliminate cancer cells. Neoantigens, which originate from specific mutations within tumor cells, are key targets in cancer immunotherapy. Neoantigens manifest as abnormal peptide fragments or protein segments that are uniquely expressed in tumor cells, making them highly immunogenic. As a result, they activate the immune system, particularly T cell‑mediated immune responses, effectively identifying and eliminating tumor cells. Certain tumor‑associated antigens that are abnormally expressed in normal host proteins in cancer cells are promising targets for immunotherapy. Neoantigens derived from mutated proteins in cancer cells offer true cancer specificity and are often highly immunogenic. Furthermore, most neoantigens are unique to each patient, highlighting the need for personalized treatment strategies. The precise identification and screening of neoantigens are key for improving treatment efficacy and developing individualized therapeutic plans. The neoantigen prediction process involves somatic mutation identification, human leukocyte antigen (HLA) typing, peptide processing and peptide‑HLA binding prediction. The present review summarizes the major current methods used for neoantigen screening, available computational tools and the advantages and limitations of various techniques. Additionally, the present review aimed to summarize experimental strategies for validating the immunogenicity of the predicted neoantigens, which will determine whether these neoantigens can effectively trigger immune responses, as well as challenges encountered during neoantigen screening, providing relevant recommendations for the optimization of neoantigen‑based immunotherapy.

The response to immunotherapy is limited in advanced biliary tract cancer (BTC). Response prediction is a serious challenge in the clinic.

This study included 60 patients with advanced BTC who received anti-PD-1 treatment. Among these patients, 30 were subjected to 520 gene panel sequencing, and 50 were subjected to multiplex circulating cytokine testing. The entropy and mutation features were analysed via the optimized pipeline based on our previous work. The repeated LASSO algorithm was used to identify the optimal features. The associations between sequence features and cell communications were explored by analysing single-cell transcriptome data from BTC (GSE125449). Cox regression was used to develop the integrated model. Time-dependent C-index, Kaplan‒Meier, and receiver operating characteristic (ROC) curves were used to assess the prediction performance.

TP53, NRAS, FBXW7, and APC were identified as prognosis-related genes. The average C-indices of sequence entropy (0.819) and mutation (0.817) for overall survival (OS) were significantly greater than those of tumour mutation burden (TMB, 0.392) and mutation score (0.638). Single-cell transcriptome data revealed that TP53, KRAS, and NRAS were enriched in plasmacytoid dendritic cells (pDCs) and that the communication between pDCs and macrophages was mediated through the CXCL signalling pathway. The integrated model (EM-CXCL10) showed powerful predictive performance for survival status (AUC: 0.863, 95% CI: 0.643-0.972) and objective response rate (AUC: 0.990, 95% CI: 0.822-1.000).

This study constructed a multidimensional strategy that might indicate the prognosis of BTC immunotherapy, enabling the recognition of BTC patients who would benefit from immunotherapy, thereby guiding personalized clinical decision-making.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with ~7% 5-year overall survival reflecting early metastasis and rapid acquired chemoresistance. Immunotherapy briefly extends overall survival in ~15% cases, yet predictive biomarkers are lacking. Targeted therapies are beginning to show promise, with a recently approved delta-like ligand 3 (DLL3)-targeted therapy impacting the treatment landscape. The increased availability of patient-faithful models, accumulating human tumour biobanks and numerous comprehensive molecular profiling studies have collectively facilitated the mapping and understanding of substantial intertumoural and intratumoural heterogeneity. Beyond the almost ubiquitous loss of wild-type p53 and RB1, SCLC is characterized by heterogeneously mis-regulated expression of MYC family members, yes-associated protein 1 (YAP1), NOTCH pathway signalling, anti-apoptotic BCL2 and epigenetic regulators. Molecular subtypes are based on the neurogenic transcription factors achaete-scute homologue 1 (ASCL1) and neurogenic differentiation factor 1 (NEUROD1), the rarer non-neuroendocrine transcription factor POU class 2 homeobox 3 (POU2F3), and immune- and inflammation-related signatures. Furthermore, SCLC shows phenotypic plasticity, including neuroendocrine-to-non-neuroendocrine transition driven by NOTCH signalling, which is associated with disease progression, chemoresistance and immune modulation and, in mouse models, with metastasis. Although these features pose substantial challenges, understanding the molecular vulnerabilities of transcription factor subtypes, the functional relevance of plasticity and cell cooperation offer opportunities for personalized therapies informed by liquid and tissue biomarkers.

Glioblastoma remains a challenging indication for immunotherapy: the blood-brain barrier hampers accessibility for systemic treatments and the immunosuppressive microenvironment impedes immune attack. Intratumoral therapy with the proinflammatory cytokine interleukin-12 (IL-12) can revert immunosuppression but leakage into the circulation causes treatment-limiting toxicity. Here we engineer an IL-12Fc fusion cytokine with reduced binding to the neonatal Fc receptor FcRn. FcRn-silenced IL-12Fc avoids FcRn-mediated brain export, thus exhibits prolonged brain retention and reduced blood levels, which prevents toxicity. In murine glioblastoma, FcRn-silenced IL-12Fc induces more durable responses with negligible systemic cytokine exposure and boosts the efficacy of radio- and chemotherapy. It triggers anti-tumor responses independently of peripheral T cell influx or lymphopenia and leads to inflammatory polarization of the tumor microenvironment in patient-derived glioblastoma explants. FcRn-silencing of IL-12Fc may unlock the full potential of IL-12 for brain cancer therapy and could be further applied to containing the activity of other therapeutics targeting neurological diseases.

Background/Objectives: The prediction of cancer types is primarily reliant on driver genes and their specific mutations. The advancement in novel omics technologies has led to the acquisition of additional genetic data. When integrated with artificial intelligence models, there is considerable potential for this to enhance the accuracy of cancer diagnosis. As mutational signatures can provide insights into repair mechanism malfunctions, they also have the potential for more accurate cancer diagnosis. Methods: First, we compared unsupervised and supervised machine learning approaches to predict cancer types. We employed deep and artificial neural network architectures with an explainable component like layerwise relevance propagation to extract the most relevant features for the cancer-type prediction. Ten-fold cross-validation and an extensive grid search were used to optimize the neural network architecture using driver gene mutations, mutational signatures and topological mutation information as input. The PCAWG dataset was used as input to discriminate between 17 primary sites and 24 cancer types. Results: Overall, our approach showed that the most relevant mutation information to discriminate between cancer types is increased by >10% using the whole genome or intergenic and intronic genome regions instead of exome information. Furthermore, the most relevant features for most cancer types, except for two, are in the mutational signatures and not the topological mutation information. Conclusions: Informative mutational signatures outperformed the prediction of cancer types in comparison to driver gene mutations and added a new layer of diagnostic information. As the degree of information within the mutational signatures is not solely based on the frequency of occurrence, it is even possible to separate cancer types from the same primary site by the different relevant mutations. Furthermore, the comparison of informative mutational signatures allowed the cancer-type assignment of specific impaired repair mechanisms.

Comprehensive genomic profiling (CGP) via next-generation sequencing is standard clinical practice for advanced and metastatic cancers in the U.S. and can help identify clinically actionable alterations in patients who may benefit from targeted therapies. CGP can also complement clinicopathological findings and in certain cases, may lead to diagnostic recharacterization resulting in more precise therapeutic strategies. Here, we highlight examples where molecular findings resulted in tumor re-evaluation and subsequent recharacterization. Twenty-eight cases where CGP results were inconsistent with initial pathological diagnosis and clinical presentation were selected for secondary clinicopathological review to explore alternative diagnostic explanations more consistent with the genomic results. Genomic profiling identified clinically actionable and prognostic variants leading to more accurate therapeutic recommendations based on the updated diagnoses highlighting the value of CGP beyond biomarker detection for therapy selection and supporting its complementary use in diagnostic confirmation to unveil opportunities for precision medicine strategies.

Every generation, the human genome is shuffled during meiosis and a single fertilized egg gives rise to all of the cells of the body1. Meiotic errors leading to chromosomal abnormalities are known causes of pregnancy loss2,3, but genetic aetiologies of euploid pregnancy loss remain largely unexplained4. Here we characterize sequence diversity in early pregnancy loss through whole-genome sequencing of 1,007 fetal samples and 934 parental samples from 467 trios affected by pregnancy loss (fetus, mother and father). Sequenced parental genomes enabled us to determine both the parental and meiotic origins of chromosomal abnormalities, detected in half of our set. It further enabled us to assess de novo mutations on both homologous chromosomes from parents transmitting extra chromosomes, and date them, revealing that 6.6% of maternal mutations occurred before sister chromatid formation in fetal oocytes. We find a similar number of de novo mutations in the trios affected by pregnancy loss as in 9,651 adult trios, but three times the number of pathogenic small (<50 bp) sequence variant genotypes in the loss cases compared with adults. Overall, our findings indicate that around 1 in 136 pregnancies is lost due to a pathogenic small sequence variant genotype in the fetus. Our results highlight the vast sequence diversity that is lost in early pregnancy.

Genomics can inform both tissue-of-origin (TOO) and precision treatments for patients with cancer of unknown primary (CUP). Here, we use whole genome and transcriptome sequencing (WGTS) for 72 patients and show diagnostic superiority of WGTS over panel testing (386-523 genes) in 71 paired cases. WGTS detects all reportable DNA features found by panel as well as additional mutations of diagnostic or therapeutic relevance in 76% of cases. Curated WGTS features and a CUP prediction algorithm (CUPPA) trained on WGTS data of known cancer types informs TOO in 71% of cases otherwise undiagnosed by clinicopathology review. WGTS informs treatments for 79% of patients, compared to 59% by panel testing. Finally, WGS of cell-free DNA (cfDNA) from patients with a high cfDNA tumour fraction (>7%), enables high-likelihood CUPPA predictions in 41% of cases. WGTS is therefore superior to panel testing, broadens treatment options, and is feasible using routine pathology samples and cfDNA.

B-cell acute lymphoblastic leukemia (B-ALL) is a highly heterogeneous disease with a challenging prognosis, particularly in adult patients. We enrolled 88 adult B-ALL patients with transcriptomic and mutation profiles for classification system identification, and a comprehensive system for B-ALL patients (COMBAT) was developed. COMBAT stratified patients into three cohorts: (1) COMBAT1, characterized by high stem/myeloid antigen expression, low immune infiltration, high infiltration of endothelial cells, and hypo-CIMP (CpG island methylator phenotype); (2) COMBAT2, defined as an inflamed subtype with immune exhaustion, moderate myeloid antigen expression, and hypo-CIMP; and (3) COMBAT3, marked by proliferative profiles with MYC pathway activation and hypomethylation at enhancer regions in patients characterized by CIMP. The molecular features of the three COMBATs were verified in two external cohorts, the GSE34861 (N = 194) and GSE66005 (N = 109) datasets. In univariate analysis, only COMBAT classification presented significance for OS, and patients of COMBAT3 presented significantly superior survival than COMBAT1/2 in Ph-negative ALL. Ph-negative ALL patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the COMBAT3 group showed better overall survival (OS) than those in the COMBAT1-2 groups (estimated 3-year OS: 100% vs. 65.6%, P = 0.034), suggesting a prognostic benefit of this subtype. In summary, the COMBAT system redefines the characteristics of adult B-ALL subtypes and guides the selection of allo-HSCT for Ph-negative patients.

This open-label, investigator-initiated, phase II study was conducted to evaluate the safety, survival, and neoadjuvant outcomes of neoadjuvant chemotherapy (NAC) combined with dual immune checkpoint inhibitors in advanced-stage epithelial ovarian cancer (EOC).

Between June 2019 and July 2021, 45 patients with unresectable stage III to IV EOC were enrolled. The patients received three cycles of NAC combined with durvalumab and tremelimumab. All patients underwent interval debulking surgery and received three cycles of durvalumab and adjuvant chemotherapy, followed by 12 cycles of durvalumab as maintenance therapy. The primary endpoint was the 12-month progression-free survival (PFS) rate; the secondary endpoints were the objective response rate after NAC, a chemotherapy response score, pathologic complete response, overall survival, and safety. The preplanned exploratory analyses assessed the lymphocyte infiltration, PD-L1 expression, and genomic profiles of pretreatment tumors.

The 12-month PFS rate was 65.9% [95% confidence interval (CI), 52.8-not estimated (NE)], whereas the 24- and 30-month PFS rates were 38.6% (95% CI, 26.7-NE) and 36.4% (95% CI, 24.7-NE), respectively. After NAC, the objective response rate was 86.7%, whereas 14 patients (31.1%) had a chemotherapy response score of three, and five (11.1%) achieved pathologic complete response. The 30-month overall survival rate was 87.7%. The most common grade ≥3 adverse event was neutropenia (26.7%). In an exploratory analysis, patients with pre-NAC tumors showing PD-L1 (combined positive score) ≥1, high Mutation Signature 3, and a high extracellular matrix signature demonstrated improved PFS outcomes.

NAC combined with dual immune checkpoint inhibitors is feasible for advanced-stage EOC and shows promising activity with a durable clinical response.

Uracil incorporation into DNA, as a result of nucleotide pool imbalances or cytosine deamination (e.g., through APOBEC3A/3B), can result in replication stress and is the most common source of mutations in cancer and aging. Despite the critical role of uracil in genome instability, cancer development, and cancer therapy, only now is there emerging data on its impact on fundamental processes such as DNA replication and genome stability. Removal of uracil from DNA by base excision repair (BER) can generate a DNA single-strand break (SSB), which can trigger homologous recombination (HR) repair or replication fork collapse and cell death. Unprocessed uracil can also induce replication stress directly and independently of BER by slowing down replication forks, leading to single-stranded DNA (ssDNA) gaps. In this perspective, we review how genomic uracil induces replication stress, the therapeutic implications of targeting uracil-induced vulnerabilities, and potential strategies to exploit these mechanisms in cancer treatment.

Constitutional mismatch repair deficiency (CMMRD), caused by bi-allelic germline variants in mismatch repair (MMR) genes, is associated with high cancer incidence early in life. A better understanding of mutational processes driving sequential CMMRD tumors can advance optimal treatment. Here, we describe a genomic characterization on a representative collection of CMMRD-associated tumors consisting of 41 tumors from 17 individuals. Mutational patterns in these tumors appear to be influenced by multiple factors, including the affected MMR gene and tumor type. Somatic polymerase proofreading mutations, commonly present in brain tumors, are also found in a T-cell lymphoblastic lymphoma displaying associated mutational patterns. We show prominent mutational patterns in two second primary hematological malignancies after temozolomide treatment. Furthermore, an indel signature, characterized by one-base pair cytosine insertions in cytosine homopolymers, is found in 54% of tumors. In conclusion, analysis of sequential CMMRD tumors reveals diverse mutational patterns influenced by the affected MMR gene, tumor type and treatment history.

Glioblastoma is invariably lethal and responds poorly to immune checkpoint blockade. Here, we examined the impact of regulatory T (Treg) cell depletion on glioblastoma progression and immunotherapy responsiveness. In human glioblastoma, elevated Treg cell signatures correlated with poorer survival outcomes, with these cells expressing high levels of CD25. In Nf1-/-Pten-/-EGFRvIII+ glioblastoma-bearing mice, a single dose of non-interleukin-2 (IL-2) blocking (NIB) anti-CD25 (anti-CD25NIB) antibody depleted Treg cells and promoted CD8+ T cell clonal expansion and partial tumor control, further enhanced by programmed cell death-1 (PD1)-blockade. Treg cell depletion induced interferon-γ (IFN-γ)-dependent tumor microenvironment remodeling, increasing Fcγ receptor (FcγR) expression on intratumoral myeloid cells and enhancing phagocytosis. Combination of anti-CD25NIB with anti-EGFRvIII tumor-targeting antibodies resulted in complete tumor control. Anti-human CD25NIB treatment of glioblastoma patient-derived tumor fragments effectively depleted Treg cells and activated CD8+ T cells. These findings underscore the therapeutic relevance of Treg targeting in glioblastoma and unveil potent combination strategies for anti-CD25NIB based on innate cell activation.

The nuclear receptor TR4 binding protein, TRA16, has been implicated in lung carcinogenesis; however, its broader role across diverse human cancers remains poorly understood. Understanding TRA16's involvement in cancer biology could uncover novel regulatory mechanisms and potential therapeutic targets.

We conducted a comprehensive pan-cancer analysis of TRA16 expression and function across multiple human malignancies. Gene co-expression networks, pathway enrichment, transcription factor analysis, organoid modeling, and intercellular communication profiling were employed. Tumor mutation burden (TMB) and microenvironmental features were also assessed in relation to TRA16 expression, stratified by TP53 mutation status.

Correlation analysis identified the cell cycle as the top enriched pathway among TRA16-associated genes, with key transcription factors, including RB-E2F, MYC, and TP53, regulating genes co-expressed with TRA16. In liver cancer organoid models, TRA16 and its co-expressed genes were significantly upregulated. Intercellular communication analysis showed that TRA16-positive cells exhibited increased autocrine signaling and overall signaling activity. Importantly, patients with high TRA16 expression demonstrated elevated TMB and decreased stromal and immune features.

These findings highlight TRA16 as a potential master regulator of oncogenic processes, contributing to tumor progression through coordinated regulation of cell cycle genes, intercellular signaling, and genomic instability. Our results provide new insights into TRA16's role across cancers and support its potential as a novel oncogene.

The nexus between aging-associated immune deteriorations and tumorigenesis of lung cancers remains elusive. In a mouse model with Med23 depletion in T cells (Med23 -/-), it is found a strong association between the decline of CD103+ T cells and spontaneous alveolar epithelial type II cell (AT2 cell)-originated lung adenocarcinomas. The reduction of CD103+ T cells in the lung results in an accumulation of AT2 cells bearing oxidative damages, which appears to be the major origin of the lung adenocarcinoma. Functional experiments reveal CD103+ T cells can eradicate oxidative-damage-bearing AT2 cells as well as ROS-dependent, KRAS (G12D)-driven tumorigenesis. In vitro co-cultures prove CD103+ T cells, especially CD103+ CD8+ T cells, exhibit a killing capacity that matches the oxidative stress level in the target cells. In aged animals, it is found the abundance of CD103+ CD8+ T cells in the lung declines with age, accompanied by an accumulation of oxidative-damage-bearing AT2 cells. Collectively, the study establishes the vital function of CD103+ T cells in surveilling epithelial cells under oxidative stress to prevent malignancies, and unravels a potential immuno-dysregulation in the aged lung which contributes to tumorigenesis.

Lung cancer continues to be the primary cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all instances. Recently, immune checkpoint inhibitors (ICIs) have transformed the treatment approach for NSCLC, however, only a subset of patients experiences significant benefits. Therefore, identifying reliable biomarkers to forecast the efficacy of ICIs is crucial for ensuring the safety and effectiveness of treatments, becoming a major focus of current research efforts. This review highlights the recent advances in predictive biomarkers for the efficacy of ICIs in the treatment of NSCLC, including PD-L1 expression, tertiary lymphoid structures (TLS), tumor-infiltrating lymphocytes (TILs), tumor genomic alterations, transcriptional signatures, circulating biomarkers, and the microbiome. Furthermore, it underscores the pivotal roles of liquid biopsy, sequencing technologies, and digital pathology in biomarker discovery. Special attention is given to the predictive value of TLS, circulating biomarkers, and transcriptional signatures. The review concludes that the integration of multiple biomarkers holds promise for achieving more accurate efficacy predictions and optimizing personalized immunotherapy strategies. By providing a comprehensive overview of the current progress, this review offers valuable insights into biomarker-based precision medicine for NSCLC and outlines future research directions.

Chemo-immunotherapy (IO) is the preferred first-line treatment for stage IVB or recurrent cervical cancer. However, limited data exist on the efficacy and safety of using IO-alone as a de-escalation strategy. We report outcomes from a case series of selected patients treated with IO-alone and review the feasibility of de-escalating first-line treatment.

The authors conducted a literature review using Google Scholar and PubMed to identify reports using IO-alone as a de-escalation strategy across malignancies published between 1999 and December 2024 and also reviewed a cervical cancer database from a tertiary academic to identify patients with stage IVB or recurrent disease treated with IO-alone. The authors used the Kaplan-Meier method to estimate progression-free survival (PFS) and overall survival (OS).

Among 582 patients treated between 2015 and 2021, 18 met the inclusion criteria. The median age was 43 years (range 28-84); 67% had squamous cell carcinoma, 11% adenocarcinoma, and 80% expressed PD-L1. CPS scores were <1 in 20%, 1--10 in 33%, and >10 in 47%. Most patients had oligo-metastatic disease (83%). Treatment with IO-alone began a median of 7 months after platinum-based chemotherapy. Indications included prior adjuvant (44%) or neoadjuvant (22%) chemotherapy, clinical trial participation (11%), or patient preference (22%). Median PFS and OS were 27 months and 82 months, respectively.

These findings support the need for clinical trials evaluating IO-alone as a first-line treatment option for de-escalation in stage IVB or recurrent cervical cancer. Biomarker development is needed to better identify candidates for personalized therapy.

The addition of a programmed death-ligand 1 (PD-L1) inhibitor, either atezolizumab or durvalumab, to platinum-etoposide prolonged survival in a limited subset of patients with extensive-stage small-cell lung cancer (ES-SCLC). Preclinical studies demonstrated synergistic antitumor activity of combined vascular endothelial growth factor receptor and PD-L1 inhibition in SCLC. Since bevacizumab added to platinum-etoposide was safe and active in ES-SCLC, we investigated the efficacy of atezolizumab, bevacizumab, carboplatin, and etoposide as first-line treatment of ES-SCLC.

The CeLEBrATE study is an Italian multicentric single-arm phase II trial of carboplatin (area under the curve 5 ml/min), etoposide (100 mg/sqm), bevacizumab (7.5 mg/kg), and atezolizumab (1,200 mg) every 3 weeks (q3w) for four to six courses, followed by bevacizumab and atezolizumab maintenance q3w in patients with ES-SCLC and no contraindications to immunotherapy or antiangiogenic therapy. Patients with asymptomatic brain metastases were eligible. Prophylactic cranial irradiation and consolidation thoracic external radiotherapy were not permitted while on study treatment. Primary endpoint was overall survival (OS) rate at 1 year.

53 patients were enrolled (45.3% women, median age 65 years) and received at least one dose of study treatment. At a median follow-up time of 23.4 months (95% CI: 21.1 to 26.0), the 1-year OS rate was 61.8% (90% CI: 50.7% to 72.8%; p=0.04), with a median OS of 12.9 months (95% CI: 11.6 to 17.5). Median progression-free survival was 6.2 months (95% CI: 5.4 to 6.6) and objective response rate was 83.3% (95% CI: 69.8% to 92.5%). Grade 3-4 adverse events were reported in 34 patients (64.2%) leading to dose reductions in 24 (45.3%), and dose delays in 39 (73.9%) and 32 (69.6%) during the induction and maintenance phase, respectively. 19 (35.8%) treatment-related serious adverse events were reported.

The CeLEBrATE study met its primary objective demonstrating a signal of efficacy of bevacizumab, atezolizumab, carboplatin, and etoposide in the first-line treatment of patients with ES-SCLC.

GOIRC-01-2019 ML41241, Eudract Number: 2019-003798-2.

In the present study, molecular subtypes were determined, programmed death-ligand 1 (PD-L1) and tumor-associated immune cells (TAICs) were quantitatively detected, and their effect on prognosis in uterine carcinosarcoma (UCS) was analyzed.

The study included 65 UCS cases. Direct sequencing of POLE exonuclease domain and immunohistochemistry of mismatch repair (MMR) deficiency proteins and p53 were used to stratify molecular subtypes. QuPath was used for quantitative immunohistochemical detection of PD-L1 and TAICs. The chi square test was used to determine the association between molecular subtypes and expression of PD-L1 and TAICs. The Kaplan-Meier method and Cox proportional hazards regression were used for plotting and survival analysis.

In 65 UCS cases, 1 case (1.5%) was POLE ultramutated (POLEmut) subtype, 11 cases (16.9%) were deficient MMR (dMMR) subtype, 32 cases (49.3%) were p53 mutant (p53mut) subtype, and 21 cases (32.3%) were nonspecific molecular profile (NSMP) subtype. The positive density of PD-L1 in tumor (p=0.022), CD8 in stroma (p=0.036), and CD163 in stroma (p=0.025) were significantly associated with molecular subtypes. The patients with POLEmut and dMMR subtypes had a relatively better prognosis trend than patients with NSMP and p53mut subtypes. The patients with high positive density of PD-L1 in tumor had significantly better prognosis; however, high positive density of CD163 in stroma showed significantly worse prognosis.

UCS could be classified into four molecular subtypes associated with prognosis. PD-L1 and M2 macrophages could effectively predict the prognosis of patients with UCS.

Identifying host genetic factors modulating immune checkpoint inhibitor (ICI) efficacy is experimentally challenging. Our approach, utilizing the Collaborative Cross mouse genetic resource, fixes the tumor genomic configuration while varying host genetics. We find that response to anti-PD-1 (aPD1) immunotherapy is significantly heritable in four distinct murine tumor models (H2: 0.18-0.40). For the MC38 colorectal carcinoma system, we map four significant ICI response quantitative trait loci (QTLs) with significant epistatic interactions. The differentially expressed genes within these QTLs that define responder genetics are highly enriched for processes involving antigen processing and presentation, allograft rejection, and graft vs. host disease (all p < 1 × 10-10). Functional blockade of two top candidate immune targets, GM-CSF and IL-2RB, completely abrogates the MC38 transcriptional response to aPD1 therapy. Thus, our in vivo experimental platform is a powerful approach for discovery of host genetic factors that establish the tumor immune microenvironment propitious for ICI response.