The tumour immune microenvironment (TIME) is critical for lymphoma progression and therapy resistance, yet causal relationships between specific immune cell types and lymphoma subtypes remain poorly defined. In this study, using bidirectional Mendelian randomization (MR), genetic correlation (LDSC), and expression-QTL integration (SMR), we systematically evaluated causal relationships and genetic correlation between immune cells and various lymphomas. Additionally, we utilised the Mendelian randomization-based method of summary data-based MR (SMR), which incorporated genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) data from immune cells to identify genes associated with lymphoma. Furthermore, colocalization analysis and genetic correlation analysis were conducted for further validation of our findings. The two-sample mendelian randomization approach was employed to identify the immune cell types that exhibit a causal relationship with different lymphomas. Additionally, the genetic correlation between these immune cells and lymphomas was further analysed using the linked disequilibrium score regression method, thereby enhancing the reliability of our findings. The SMR and colocalisation analyses revealed several genes associated with these immune cells, thereby providing additional support for their putative role in the pathogenesis of lymphoma. Our study elucidates the intricate interplay between immune cells by employing genetic methodologies, thus suggesting novel therapeutic candidates that warrant experimental validation and risk predictors in different subtypes of lymphoma treatments.

Understanding regional distribution of HLA frequencies is crucial for optimizing enrollment in HLA-restricted clinical trials and to promote trial diversity per the Food and Drug Administration's 2020 mandate. Using US HLA frequency data and census demographics we developed a method to create high-resolution HLA class 1 genotypic frequency maps. Analyzing HLA-A*11:01 and HLA-B*58:01 as alleles of interest, we found significant US regional variations. HLA-A*11:01, which presents KRAS neoantigen mutations targeted by TCR T-cell therapies, showed 10-15% genotypic frequency (national average 11.2%), with western US states 1.5 times higher than average and local variations within California (10-19%). These insights can be used to guide clinical trial site selection, for example, in National Cancer Institute (NCI) cancer center catchment areas. For HLA-B*58:01, which reacts pharmacogenetically with allopurinol and results in severe cutaneous adverse reactions, Mississippi had a high frequency among US states, which could be used to guide potential public safety campaigns. This method can identify regions with high HLA type representation, aiding efficient patient identification and enrollment for HLA-specific clinical trials and health-awareness efforts.

Micronuclei exhibit defective proteomes rendering their chromatin vulnerable to fragmentation. This fragmentation process, known as chromothripsis, promotes tumorigenesis by catalysing the activation of oncogenes and the silencing of tumor suppressors. With this role in mind, micronuclei serve as promising targets for therapeutic intervention. This review will explore recent discoveries regarding how micronuclei form, their function in catalysing chromothripsis and how chromothripsis provides a selective advantage for cancer cells.

While the clinical course of radiation-induced meningioma (RIM) is considered to be more aggressive than that of sporadic meningioma (SM), the genetic predisposition for RIM is not established well. The present study aimed to analyze the clinical and genetic characteristics of RIMs to increase understanding of the tumorigenesis and prognosis of RIMs.

While ferroptosis induction emerges as a therapeutic strategy for solid tumors, its role in acute myeloid leukemia (AML) remains unexplored. This study aimed to investigate the role of MLN4924 in modulating ferroptosis and its molecular targets in AML.

Accurate population stratification of colorectal cancer risk enables identification of individuals who would benefit from screening and risk-reducing interventions. We conducted a population-based cohort study using almost 400,000 unaffected UK Biobank participants who were aged 40-69 years at their baseline assessment and who had genetically determined UK ancestry. For women and men separately, we developed (i) a multivariable risk prediction model using family history, a polygenic risk score (PRS) and clinical risk factors, and (ii) a simple model comprising family history and a PRS. We then compared their performance to that of existing models. The models were developed using Cox regression with age as the time axis in a 70% training dataset. The performance of the 10-year risk of colorectal cancer was assessed in a 30% testing dataset using Cox regression to estimate the hazard ratio per standard deviation of risk, Harrell's C-index to assess discrimination and logistic regression to assess calibration. There were 214,183 women and 181,889 men in the dataset with 1,913 women and 2,598 men diagnosed with colorectal cancer during the follow-up period. The mean age at diagnosis was 66.4 years (standard deviation = 7.3 years) for women and 67.3 years (standard deviation = 6.7 years) for men. In the 30% testing dataset, the new multivariable models discriminated better (Harrell's C-index = 0.690, 95% CI = 0.669 to 0.712 for women; 0.699, 95% CI = 0.681 to 0.717 for men) than the new family history and PRS models (Harrell's C-index = 0.683, 95% CI = 0.663 to 0.704 for women; 0.692, 95% CI = 0.673 to 0.710 for men; change in discrimination P = 0.02 for women and P = 0.01 for men). Our models identify individuals who are at increased risk of colorectal cancer and who would benefit from personalised screening and risk-reduction options.

Cholangiocarcinoma (CCA) is one of the most aggressive cancers with a poor prognosis. Current treatment strategies involve hepatobiliary surgery, chemotherapy, radiotherapy, and supportive care; however, the success of these treatments remains limited. Therefore, this study investigated the potential of Atractylodes lancea (Thunb) D.C. (AL) in limiting the progress of CCA by targeting the expression of cancer-related genes involved in immune responses and circulating tumor cells. The study was part of Phase 2A clinical trial in advanced-stage intrahepatic iCCA (iCCA) patients: Group 1 (n = 16) received low-dose AL (capsule formulation of the standardized extract of AL: CMC-AL) with standard supportive care, Group 2 (n = 16) received high-dose AL with standard supportive care, and Group 3 (n = 16) received standard supportive care alone. Venous whole blood samples (EDTA, 5 ml) were collected from each patient on Day 1 and Day 90 and the non-CCA subjects (n = 16) on Day 1. Fifty-nine samples (48 and 11 samples for Day 1 and Day 90, respectively) were processed for total RNA isolation. Gene expression was evaluated using reverse transcription followed by a PCR array. Regardless of dosage, gene expression patterns in the AL-treated groups closely resembled those of the healthy subjects. Specifically, cancer-associated genes, including VEGF-A, NR4A3, Ki-67, and EpCAM, were significantly down-regulated. Additionally, the expression levels of immune-related genes were modulated in AL-treated patients. The treatment groups exhibited lower levels of the pro-inflammatory cytokine IL-6, increased expression of the anti-inflammatory cytokine IL-10, and cell-mediated immune-related molecules such as CTLA4 and PFR1. These findings suggest the potential of AL for iCCA treatment. However, additional studies are required to confirm the correlation between gene and protein expression profiles, as well as CTCs profile.

Bulk transcriptomic analyses of high-grade serous ovarian cancer (HGSOC) so far have not uncovered potential drug targets, possibly because subtle, disease-relevant transcriptional patterns are overshadowed by dominant, non-relevant ones. Our aim was to uncover disease-outcome-related patterns in HGSOC transcriptomes that may reveal novel drug targets. Using consensus-independent component analysis, we dissected 678 HGSOC transcriptomes of systemic therapy naïve patients-sourced from public repositories-into statistically independent transcriptional components (TCs). To enhance c-ICA's robustness, we added 447 transcriptomes from non-serous histotypes, low-grade serous, and non-cancerous ovarian tissues. Cox regression and survival tree analysis were performed to determine the association between TC activity and overall survival (OS). Finally, we determined the activity of the OS-associated TCs in 11 publicly available spatially resolved ovarian cancer transcriptomes. We identified 374 TCs, capturing prominent and subtle transcriptional patterns linked to specific biological processes. Six TCs, age, and tumor stage stratified patients with HGSOC receiving platinum-based chemotherapy into ten distinct OS groups. Three TCs were linked to copy-number alterations affecting expression levels of genes involved in replication, apoptosis, proliferation, immune activity, and replication stress. Notably, the TC identifying patients with the shortest OS captured a novel transcriptional pattern linked to synaptic signaling, which was active in tumor regions within all spatially resolved transcriptomes. The association between a synaptic signaling-related TC and OS supports the emerging role of neurons and their axons as cancer hallmark-inducing constituents of the tumor microenvironment. These constituents might offer a novel drug target for patients with HGSOC.

Renal cell carcinoma (RCC) is one of the most common tumors of high malignancy in the urological system. Sunitinib is commonly used to treat RCC, while drug resistance severely limited the therapeutic efficacy. Tumor-derived exosomes play important roles in facilitating cancer development. However, the role of drug-resistant tumor-derived exosomes in tumorigenesis and resistance of RCC has not been elucidated. Here we isolated sunitinib-sensitive/resistant RCC cells-derived exosomes, characterized by transmission electron microscopy (TEM) and western blot. Furthermore, co-culture experiments were performed and we found that sunitinib-resistant RCC cells-derived exosomes (R-exos) promoted cell proliferation and upregulated proliferation-related genes cyclin D1 (CCND1) and proliferating cell nuclear antigen (PCNA) expression, and inhibited apoptosis and the expression of Bax and Caspase-3 of sunitinib-resistant RCC (RCC/R) cells by delivering lncRNA small nuclear RNA host gene 16 (SNHG16). In resistant cell-derived xenograft (CDX-R) models, R-exos induced tumor growth in vivo, while knockdown of SNHG16 effectively diminished the tumorigenesis of RCC. Moreover, SNHG16 positively regulated the expression of trophinin associated protein (TROAP) by sponging miR-106a-5p in RCC cells, whereas inhibition of miR-106a-5p or overexpression of TROAP greatly reversed the suppression of tumorigenesis and sunitinib resistant by silencing SNHG16. R-exos lncRNA SNHG16 promoted sunitinib resistant and malignant progress by regulating the miR-106a-5p/TROAP axis, and targeting SNHG16/miR-106a-5p/TROAP axis may be a novel therapeutic approach for sunitinib-treated patients of RCC.

Here, we present a challenging diagnostic case of a B-cell acute lymphoblastic leukemia (B-ALL) presenting as a rare extramedullary and extranodal presentation without bone marrow or peripheral blood involvement, also classified as B-cell lymphoblastic lymphoma (B-LBL). Our case demonstrated a lack of expression for typical immature B-ALL markers CD34, TdT, and CD99 and instead showed positive expression for CD5, SOX11, BCL-6, and c-MYC, which are markers more often seen in mature aggressive B-cell lymphomas. A distinction between B-ALL and the aggressive B-cell lymphomas, high-grade B-cell Lymphoma (HGBL), and mantle cell lymphoma (MCL), which can show a blastoid morphology, could not be made based on our immunohistochemistry (IHC), flow cytometry, and FISH studies. The diagnosis of B-ALL in our case eventually required extensive molecular methods, with next generation sequencing (NGS)-based DNA and RNA fusion genomic profiling studies to achieve an accurate diagnosis and classification. The molecular studies identified a positive MEF2D::BCL9 gene fusion, a recently described rare abnormality in high-risk B-ALL. These rare B-ALL cases with a MEF2D::BCL9 gene fusion have been categorized as specific B-ALL subtypes in the newest World Health Organization (WHO) 5th edition classification of hematolymphoid tumors and lymphoid neoplasms. We want to share the challenges we faced in making this new diagnosis and the results of our studies, since complete expression profiles for this rare entity have not yet been extensively described.

Rare among male cancers, male breast cancer (MBC) accounts for less than one percent of all male tumors. The prevalence of this illness and female breast cancer (FBC) have both been on the rise in recent years. While reports have implicated hormonal, environmental, and genetic variables in the development of MBC, nothing is known about its aetiology. Radiation exposure, hormonal imbalances caused by other medical conditions, and, most significantly, a positive family history of breast cancer-which indicates a hereditary predisposition-are major risk factors. While low-penetrance gene mutations (such as CHEK-2) are more prevalent, they do not enhance the risk of breast cancer development to the same extent as rare mutations in high-penetrance genes (such as BRCA1 and BRCA2). Speculated risk factors, including BRCA2 and lifestyle changes in the last few decades, are considered in light of the reasons for the rising occurrence. Topics covered include aromatase inhibitors, fulvestrant, and the prolactin and androgen receptor targeting pathways, as well as the therapeutic therapy of male breast cancer. Invasive ductal carcinomas, which account for about 90% of breast cancers in men, express many hormone receptors and show clear signs of treatment benefit. No single therapy method has been supported by published evidence from prospective randomized trials in MBC to yet. The treatment decision should be guided by the primary prognostic markers, which include tumor size and the number of axillary nodes involved. Detailed descriptions of the clinicopathologic characteristics of MBC are included in the present review. Our focus is on molecular profiling of MBC as a means to discover potential biomarkers and potential pharmacologic intervention targets. Endocrine treatment, which includes tamoxifen, aromatase inhibitors, and GnRH analogues, as well as cytotoxic chemotherapy, are characterized in light of the existing research. We also outline the possible function of targeted medications such as HER2-directed treatments, PARP inhibitors, and angiogenesis inhibitors.

Small-cell lung cancer (SCLC) remains one of the deadliest cancers worldwide. Patients' survival remains poor due to its rapid growth, high metastatic rate and limited possibilities of treatment. For many years, SCLC management has been based mostly on chemo and radiotherapy. However, new therapeutic approaches have been proposed in the past few years, including immunotherapy, which is currently implemented in clinical practice. Unfortunately, in many cases, response to therapy, especially chemotherapy, remains poor, or the patient becomes resistant to initially effective treatment. One of the crucial problems during SCLC patient care is a lack of appropriate predictive biomarkers for various therapeutic approaches. Another critical issue is the scarcity of collected tissue during biopsy, which may be insufficient or of too poor quality for analysis. A liquid biopsy might be the key to solving both of those problems as it is collected in a non-invasive way and enables the measurement of various biomarkers, including circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs). In this review, we discuss various approaches to potentially incorporating liquid biopsy into clinical application - as a companion to imaging during SCLC diagnostics, a new approach to molecular subtyping, and a material enabling predictive or prognostic biomarkers assessment. We also summarize ongoing clinical trials encompassing SCLC patients in which liquid biopsy is collected and examined.

Rectal cancer accounts for approximately 40% of colorectal cancer cases, and lateral pelvic lymph node (LPLN) metastasis in rectal cancer significantly increases the local recurrence rate. Despite its clinical significance, studies on the molecular biology of LPLN metastasis are relatively scarce. In this study, we aimed to elucidate the underlying mechanisms by identifying hub regulatory genes in LPLN tissues and analyzing differentially expressed genes shared between tumor and pericarcinomatous tissues within our clinical cohort. To investigate the biological functions of these hub regulatory genes, we performed GSEA, GO, and KEGG pathway analyses on mRNA-Seq data. Among the identified hub genes, KLF12 emerged as a pivotal regulatory gene in rectal cancer. We further explored its clinical relevance and biological function. Our findings, validated using public databases, clinical cohort data, and immunohistochemistry (IHC), identified KLF12 as a specific marker for LPLN. Additionally, KLF12 expression exhibited a strong correlation with disease-free survival (DFS). According to clinical data, significant differences in KLF12 expression exist between groups based on factors such as age, gender, tumor location, pathological N stage, and postoperative tumor residue. Both treatment outcomes (DFS) and receiver operating characteristic curves (AUCs) were significantly associated with KLF12 expression. Furthermore, KLF12 demonstrated a strong association with immune cell infiltration, immune checkpoint expression, and immunophenoscore (IPS), indicating its potential regulatory role in immunotherapy. Functional molecular experiments revealed that KLF12 overexpression inhibited the proliferation, migration, and invasion of SW620 cells. In conclusion, leveraging mRNA-Seq data, TCGA database analysis, immune infiltration data, and biological function assessments, we confirmed that KLF12 could serve as an effective predictive marker and potential therapeutic target for LPLN metastasis. These findings suggest that KLF12 may be instrumental in assessing predictive risk and identifying novel therapeutic targets for patients with rectal cancer.

Germ cell tumors of the testis (GCTs) provide an ideal tumor model to investigate the cellular versus genetic origin of cancers. In this single institutional study, we evaluated 38 patients with bilateral GCT, including tumors that occurred simultaneously (synchronous) and those occurring at different times (metachronous). For nine of these patients, DNA was isolated from the right and left GCT to determine the genomic and epigenetic differences between tissues using whole-exome sequencing (WES) and reduced representation bisulfite sequencing (RRBS). We found that seminomas and non-seminomas are molecularly distinct based on DNA methylation and not due to synchronous or metachronous disease. In addition, we did not observe conservation of genetic mutations in right and left GCT in either synchronous or metachronous disease. Our data suggest a cellular origin for bilateral GCT.

Ovarian carcinoma is a gynecological cancer with poor long-term survival rates when detected at advanced disease stages. Early symptoms are non-specific, and currently, there are no adequate strategies to identify this disease at an early stage when much higher survival rates can be expected. Ovarian carcinoma is a heterogeneous disease, with various histotypes originating from different cells and tissues, and is characterized by distinct somatic mutations, progression profiles, and treatment responses. Our study presents a targeted metabolomics approach, characterizing seven different ovarian (cancer-) cell lines according to their extracellular, intracellular, and RNA-derived modified nucleoside profiles. Moreover, these data were correlated with transcriptomics data to elucidate the underlying mechanisms. Modified nucleosides are excreted in higher amounts in cancer cell lines due to their altered DNA/RNA metabolism. This study shows that seven different ovarian cancer cell lines, representing different molecular subtypes, can be discriminated according to their specific nucleoside pattern. We suggest modified nucleosides as strong biomarker candidates for ovarian cancer with the potential for subtype-specific discrimination. Extracellular modified nucleosides have the highest potential in the distinguishing of cell lines between control cell lines and themselves, and represent the closest to a desirable, non-invasive biomarker, since they accumulate in blood and urine.

The urokinase-receptor (uPAR) exerts multiple functions supporting most cancer hallmarks. Increased uPAR expression is associated with an unfavorable prognosis in several cancer types, including hematologic malignancies. We previously reported that three oncosuppressor microRNAs (miRNAs) can target the 3'untranslated region (3'UTR) of the uPAR mRNA and that uPAR mRNA is a competitive endogenous RNA (ceRNA) able to recruit oncosuppressor miRs, thus impairing their activity. We now show that uPAR mRNA can also be targeted by oncosuppressor members of the let-7 miRNA family in acute myeloid leukemia (AML) cell lines. Indeed, let-7a, let7d and let-7g directly target the 3'UTR of uPAR mRNA, thus down-regulating uPAR expression. These let-7 miRNAs are expressed in KG1 and U937 AML cells; their levels are high in KG1 cells, which express low uPAR levels, and low in the U937 cell line, expressing high levels of uPAR. Overexpression of these miRNAs down-regulates uPAR expression and impairs the adhesion to fibronectin and migration of U937 cells, without affecting their proliferation. Accordingly, the overexpression of specific inhibitors targeting these let-7 miRNAs efficiently increases uPAR expression in KG1 cells. These results indicate that selected let-7 miRNAs regulate uPAR expression and impair the adhesion and migration of AML cells.

5-Fluorouracil (5-FU) and the Folate Leucovorin (LV) form the chemotherapy backbone for metastatic colorectal cancer (mCRC). Tumoral expression of specific folate-associated genes is associated with the risk of recurrence in stage III CRC following adjuvant 5-FU/LV (FLV)-based combination chemotherapy according to the Nordic bolus regimen. The aim was to evaluate whether expression of folate-associated genes in Pre-therapeutic tumor samples is associated with outcomes of patients with mCRC undergoing palliative FLV-based combination chemotherapy.

The liver often serves as the principal site for metastatic spread from a variety of solid tumors, and metastasis to the liver markedly diminishes patient survival. Single-cell RNA sequencing (scRNA-seq) has helped uncover the complexity of liver tumor metastasis. However, the key cellular subtypes of breast cancer and pancreatic ductal adenocarcinoma (PDAC) with liver metastasis and their mechanisms of action are unclear, making treatment difficult.

As an important component in preventing the progression of endometrial cancer, CD8 T cells play a crucial role in this process and are important targets for immunotherapy. However, the status of CD8+ T cells in endometrial cancer and the key genes influencing their activation still remain to be elucidated.

The prognosis of hepatocellular carcinoma (HCC) remains challenging, and immune activation plays a critical role in cancer treatment. Identifying reliable immune activation-related prognostic markers is critical for predicting HCC patient outcomes.