Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a disorder caused by an autosomal dominant heterozygous germline mutation in one of the DNA mismatch repair (MMR) genes. Individuals with LS are at an increased risk of developing colorectal and extracolonic cancers, such as endometrial, small bowel, or ovarian. In this review, the mutations involved with LS and their diagnostic methods are described and compared, as are their current uses in clinical decision making. Nowadays, LS diagnosis is based on a review of family medical history, and when necessary, microsatellite instability (MSI) or/and immunohistochemistry (IHC) analyses should be performed. In the case of a lack of MMR protein expression (dMMR) or MSI-H (MSI-High) detection in tumor tissue, molecular genetic testing can be undertaken. More and more genetic testing for LS is based mainly on next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA), which provide better and quicker information about the molecular profile of patients as well as individuals at risk. Testing based on these two methods should be the standard and commonly used. The identification of individuals with mutations provides opportunities for the detection of cancer at an early stage as well as the introduction of proper, more effective treatment, which will result in increased patient survival and reduced costs of medical care.

Although many studies have investigated the role of cytokines in bone metastases, our knowledge of their function in spine metastasis is limited. Therefore, we performed a systematic review to map the available evidence on the involvement of cytokines in spine metastasis in solid tumors. A PubMed search identified 211 articles demonstrating a functional link between cytokines/cytokine receptors and bone metastases, including six articles confirming the role of cytokines/cytokine receptors in spine metastases. A total of 68 cytokines/cytokine receptors were identified to mediate bone metastases; 9 (mostly chemokines) played a role in spine metastases: CXC motif chemokine ligand (CXCL) 5, CXCL12, CXC motif chemokine receptor (CXCR) 4, CXCR6, interleukin (IL) 10 in prostate cancer, CX3C motif chemokine ligand (CX3CL) 1 and CX3C motif chemokine receptor (CX3CR) 1 in liver cancer, CC motif chemokine ligand (CCL) 2 in breast cancer, and transforming growth factor (TGF) β in skin cancer. Except for CXCR6, all cytokines/cytokine receptors were shown to operate in the spine, with CX3CL1, CX3CR1, IL10, CCL2, CXCL12, and CXCR4 mediating bone marrow colonization, CXCL5 and TGFβ promoting tumor cell proliferation, and TGFβ additionally driving bone remodeling. The number of cytokines/cytokine receptors confirmed to mediate spinal metastasis is low compared with the vast spectrum of cytokines/cytokine receptors participating in other parts of the skeleton. Therefore, further research is needed, including validation of the role of cytokines mediating metastases to other bones, to precisely address the unmet clinical need associated with spine metastases.

Breast cancer is the most common malignant disease occurring in women. Conservative breast cancer surgery followed by radiation therapy is currently the standard treatment for this type of cancer. The majority of metastases occur within the scar, which initiated a series of studies. As a result, clinical trials aimed to assess whether localized radiotherapy, as intraoperative radiotherapy (IORT), may more effective in inhibiting the formation of local recurrence compared with the standard postoperative whole breast radiotherapy. The present study determined the role of postoperative wound fluids (WFs) from patients diagnosed with breast cancer subsequent to breast conserving surgery or breast conserving surgery followed by IORT on the expression of three microRNAs (miRNAs), consisting of miR‑21, miR‑155 and miR‑221, in distinct breast cancer cell lines that represent the general subtypes of breast cancer. It was determined that the miRNAs responsible for breast cancer progression, induction of tumorigenesis and enrichment of the cancer stem cell phenotype, which is responsible for resistance to tumor therapy, were highly upregulated in the human epidermal growth factor receptor 2‑positive breast cancer SK‑BR‑3 cell line following stimulation with WFs. It is worth emphasizing, that those changes were more significant in WFs collected from patients after surgery alone. The BT‑549 cell line showed altered expression only of miR‑155 following incubation with WFs. Notably, this change was not associated with IORT. Additionally, it was indicated that both WFs and RT‑WF strongly downregulated the expression of miR‑21, miR‑155 and miR‑221 in basal/epithelial and luminal subtypes of breast cancer. It was concluded that the present study contributes to an increased understanding of the role of surgical WFs and IORT treatment in the regulation of miRNA expression. This may enable the development of the current knowledge of breast cancer biology subsequent to IORT treatment and substantially to improve the therapy in the future.

We used four-color ImmunoSpot® assays, in conjunction with peptide pools that cover the sequence of tyrosinase (Tyr), melanoma-associated antigen A3 (MAGE-A3), melanocyte antigen/melanoma antigen recognized by T cells 1 (Melan-A/MART-1), glycoprotein 100 (gp100), and New York esophageal squamous cell carcinoma-1 (NY-ESO-1) to characterize the melanoma antigen (MA)-specific CD8 + cell repertoire in PBMC of 40 healthy human donors (HD). Tyr triggered interferon gamma (IFN-γ)-secreting CD8 + T cells in 25% of HD within 24 h of antigen stimulation ex vivo. MAGE-A3, Melan-A/MART-1, and gp100 also induced recall responses in 10%, 7.5%, and 2.5% of HD, respectively. At this time point, these CD8 + T cells did not yet produce GzB (granzyme B). However, they engaged in GzB production after 72 h of antigen stimulation. By this 72-h time point, 57.5% of the HD responded to at least one, and typically several, of the MA. A closer characterization of the Tyr-specific CD8 + T cell repertoire indicated that it was low-affinity, and to primarily entail a stem cell-like subpopulation. Collectively, our data reveal pre-existing endogenous T cell immunity against melanoma antigens in healthy donors, and analogous to natural autoantibodies, we have termed this “natural T cell autoreactivity”.

Healthy human subjects develop spontaneous CD8+ T cell responses to melanoma associated antigens (MA) expressed by normal melanocytes, such as Tyrosinase, MAGE-A3, Melan/Mart-1, gp100, and NY-ESO-1. This natural autoimmunity directed against melanocytes might confer protection against the development of malignant melanoma (MM), where MA are present as overexpressed tumor-associated antigens. Consistent with this notion we report here that functional T cell reactivity to MA was found to be significantly diminished to MAGE-A3, Melan-A/Mart-1, and gp100 in untreated MM patients. Three lines of evidence suggest that the MA-reactive T cells present in healthy subjects undergo exhaustion once MM establishes itself. First, only the MA-specific T cell reactivity was affected in the MM patients; that to third party recall antigens was not. Second, in these patients, the residual MA-specific T cells, unlike third party antigen reactive T cells, were functionally impaired, showing a diminished per cell IFN-γ productivity. Third, we show that immunization with MA restored natural CD8+ T cell autoimmunity to MA in 85% of the MM patients. The role of natural T cell autoimmunity to tumor-associated MA is discussed based on discrete levels of T cell activation thresholds.

Background: High-risk human papillomavirus (HPV) contributes to oropharyngeal cancers through mechanisms involving the deregulation of host cell functions by oncoproteins E6 and E7. Changes in the epigenome, particularly involving long non-coding RNAs (lncRNAs), are crucial for understanding HPV-related carcinogenesis. Methods: This study aimed to analyze the expression levels of lncRNAs in HPV-related head and neck squamous cell carcinoma (HNSCC) to determine their biological and clinical significance, addressing the current gap in clinically validated biomarkers for early screening and therapeutic interventions. Results: The study highlights the significant overexpression of the EGOT gene in HPV-positive HNSCC samples, suggesting its potential as a marker to distinguish between HPV-negative and HPV-positive cases. Furthermore, high EGOT expression correlates with better overall survival (OS) and indicates possible resistance to therapy, making it a valuable prognostic factor. Conclusions: These findings underscore the potential of incorporating EGOT expression analysis in clinical practice for improved patient stratification and treatment outcomes in HNSCC.