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3D chromatin architecture-related genes orchestrate LUAD evolution and therapy resistance: insights from integrative machine learning and spatial single-cell mapping.

BACKGROUND: Lung adenocarcinoma (LUAD) is a prevalent and lethal malignancy. The three-dimensional (3D) chromatin architecture significantly influences tumor progression, yet the contribution of 3D chromatin structure-related genes (3DCRGs) in LUAD remains unclear. This study was designed to explore the role of 3DCRGs in postoperative recurrence of early-stage LUAD, response to Sorafenib therapy in advanced LUAD, tumor progression, and the regulation of the tumor microenvironment (TME). METHODS: Based on prior studies of chromatin 3D architecture, we curated 49 3DCRGs. Differential expression

Identification of the key gene for hepatocellular carcinoma based on bioinformatics and machine learning and experimental verification.

BACKGROUND: Hepatocellular carcinoma (HCC) is a severe hazard to human health and has a high fatality rate. While deregulated gene expression has been widely linked to hepatocarcinogenesis, many details of how these alterations drive tumor initiation and progression remain to be elucidated. We therefore combined bioinformatics and machine learning strategies to screen for and validate candidate driver genes in HCC. METHODS: Three datasets (GSE78737, GSE98383, and GSE121248) were obtained from the Gene Expression Omnibus (GEO) database. GSE78737 and GSE98383 were combined to form the training

Early-Onset Gastrointestinal Cancers: A Review.

IMPORTANCE: Early-onset gastrointestinal (GI) cancer is typically defined as GI cancer diagnosed in individuals younger than 50 years. The i … proximately 15% to 30% of early-onset GI cancers have pathogenic germline variants in genes such as DNA mismatch repair genes and BRCA1/2. All patients with early-onset GI cancers should undergo germline and somatic genetic testing to guide treatment, screen for other cancers (eg, endometrial cancer in Lynch syndrome), and assess familial risk. Treatment for early-on …

Total neoadjuvant therapy followed by non-operative management or surgery in stage II-III rectal cancer (NO-CUT): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Rectal surgery after total neoadjuvant therapy is a standard of care for proficient mismatch repair or microsatellite stable (pMMR/MSS) stage II-III rectal cancer. In patients who have clinical complete response, non-operative management (avoidance or delay of surgery and intensive surveillance) offers a patient-centred opportunity. However, its effect on metastatic recurrence remains uncertain. This study aimed to determine whether non-operative management compromises distant relapse-free survival in patients with clinical complete response after total neoadjuvant therapy. METHOD

Morphological, immunohistochemical and molecular features of inflammatory bowel disease associated colorectal carcinoma and associated mucosal lesions - Single institution experience.

BACKGROUND: Patients with inflammatory bowel disease (IBD) - ulcerative colitis (UC) and Crohn's disease (CD) have an elevated risk of developing colorectal carcinoma (CRC). Major risk factor in IBD patients is the continuous chronic inflammation leading to development of dysplasia and carcinoma. Nevertheless, other types of non-conventional but suspicious mucosal changes serrated change/dysplasia, NOS and villous hypermucinous change, have also been reported in IBD patients. Preneoplastic potential of these lesions is still not well elucidated. AIMS: The aim of this study was identification

Receptor tyrosine kinase amplified gastric cancer: Clinicopathologic characteristics and proposed screening algorithm.

Although targeted therapy for receptor tyrosine kinases (RTKs) of advanced gastric cancers (AGCs) has been in the spotlight, guidelines for the identification of RTK-amplified gastric cancers (RA-GCs) have not been established. In this study, we investigate clinicopathologic characteristics of RA-GCs and propose a screening algorithm for their identification. We performed immunohistochemistry (IHC) for MLH1, MSH2, PMS2, MSH6, key RTKs (EGFR, HER2, MET), and p53, in situ hybridization for Epstein-Barr virus encoding RNA, and silver in situ hybridization (SISH) for EGFR, HER2, and MET using tiss

Cost-effectiveness Analysis of Genotype-Specific Surveillance and Preventive Strategies for Gynecologic Cancers Among Women With Lynch Syndrome.

IMPORTANCE: With the expansion of multigene testing for cancer susceptibility, Lynch syndrome (LS) has become more readily identified among women. The condition is caused by germline pathogenic variants in DNA mismatch repair genes (ie, MLH1, MSH2, MSH6, and PMS2) and is associated with high but variable risks of endometrial and ovarian cancers based on genotype. However, current guidelines on preventive strategies are not specific to genotypes. OBJECTIVE: To assess the cost-effectiveness of genotype-specific surveillance and preventive strategies for LS-associated gynecologic cancers, includ…

[Expression profile, immunoregulatory function, and clinical prognostic value of CENPN in breast cancer].

Objective: To investigate the expression profile of Centromere Protein N (CENPN) in invasive breast cancer (BRCA), evaluate its prognostic significance, and assess its involvement in immune regulation. Methods: The expression, prognostic value, and correlation with tumor immunogenicity of CENPN in BRCA tissues were analyzed based on The Cancer Genome Atlas (TCGA) database. Verification was conducted using cancerous and adjacent normal tissues from BRCA patients who underwent surgical treatment at Yantai Mountain Hospital between January 2022 and April 2023. CENPN expression in various immune c

Somatic molecular changes and histo-pathological features of colorectal cancer in Tunisia.

AIM: To determine correlations between family history, clinical features and mutational status of genes involved in the progression of colorectal cancer (CRC). METHODS: Histo-pathological features and molecular changes [KRAS, BRAF and CTNNB1 genes mutations, microsatellite instability (MSI) phenotype, expression of mismatch repair (MMR) and mucin (MUC) 5AC proteins, mutation and expression analysis of TP53, MLH1 promoter hypermethylation analysis] were examined in a series of 51 unselected Tunisian CRC patients, 10 of them had a proven or probable hereditary disease, on the track of new tumor

[Pan-cancer analysis of ubiquitin-specific protease 7 and its expression changes in the carcinogenesis of scar ulcer].

Objective: To explore the biological role and clinical significance of ubiquitin-specific protease 7 (USP7) in the carcinogenesis of scar ul … EPIA2 database, the correlation of USP7 expression in pan-cancer with the expression levels of five DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) and three essential DNA methyltransferases (DNMT)--DNMT1, DNMT3A, and DNMT3B were evaluated. The USP7 expression in CESC, HNSC, LUSC, and SKCM and its correlation with infiltration of immune cells (B cells, …

A systematic review and economic evaluation of diagnostic strategies for Lynch syndrome.

BACKGROUND: Lynch syndrome (LS) is an inherited autosomal dominant disorder characterised by an increased risk of colorectal cancer (CRC) and other cancers, and caused by mutations in the deoxyribonucleic acid (DNA) mismatch repair genes. OBJECTIVE: To evaluate the accuracy and cost-effectiveness of strategies to identify LS in newly diagnosed early-onset CRC patients (aged < 50 years). Cascade testing of relatives is employed in all strategies for individuals in whom LS is identified. DATA SOURCES AND METHODS: Systematic reviews were conducted of the test accuracy of microsatellite instabil

Statewide Retrospective Review of Familial Pancreatic Cancer in Delaware, and Frequency of Genetic Mutations in Pancreatic Cancer Kindreds.

BACKGROUND: Considering the typical rapid progression and high mortality of pancreatic cancer (PC), early detection may lead to an improved outcome. To date, there is no safe, sensitive, and cost-effective screening strategy to detect PC. Currently, screening is focused on individuals at the highest risk of developing PC based on family history. A high-risk individual is defined as having two or more first-degree relatives with PC, or one first- or second-degree relative with PC with a confirmed mutation in a gene associated with PC. The BRCA2 gene is one of the most common genes linked to pan

The Role of DNA Repair in Genomic Instability of Multiple Myeloma.

Multiple Myeloma (MM) is a B cell malignancy marked by genomic instability that arises both through pathogenesis and during disease progression. Despite recent advances in therapy, MM remains incurable. Recently, it has been reported that DNA repair can influence genomic changes and drug resistance in MM. The dysregulation of DNA repair function may provide an alternative explanation for genomic instability observed in MM cells and in cells derived from MM patients. This review provides an overview of DNA repair pathways with a special focus on their involvement in MM and discusses the role th

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… DNA mismatch repair: Molecular mechanism, cancer, and ageing Mech. Ageing Dev. 2008 129 391 407 10.1016/j.mad.2008.02.012 18406444 PMC2574955 53. Huang Y. Li G.-M. … DNA mismatch repair preferentially safeguards actively transcribed genes DNA Repair 2018 71 82 86 10.1016/j.dnarep.2018.08.010 30174300 PMC6340717 54. Liu D. Keijzers G. Rasmussen L.J. DNA mismatch repair and its many roles in eukaryotic cells Mutat. Res. Rev. Mutat. …

DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities.

Resistance to chemo- and radiotherapy is a common event among cancer patients and a reason why new cancer therapies and therapeutic strategies need to be in continuous investigation and development. DNA damage response (DDR) comprises several pathways that eliminate DNA damage to maintain genomic stability and integrity, but different types of cancers are associated with DDR machinery defects. Many improvements have been made in recent years, providing several drugs and therapeutic strategies for cancer patients, including those targeting the DDR pathways. Currently, poly (ADP-ribose) polymera

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… The mismatch repair system in humans includes several proteins: DNA mismatch repair protein Mlh1 (MLH1), DNA mismatch repair protein Msh2 (MSH2), DNA mismatch repair protein Mlh3 (MLH3), DNA mismatch repair protein Msh6 (MSH6), DNA mismatch repair endonuclease PMS2 (PMS2), and DNA mismatch repair protein … Hypermethylation of the DNA mismatch repair gene hMLH1 and Its association with lymph node metastasis and T1799A BRAF mutation in patients with papillary thyroid cancer. Cancer. 2008;113:247–255. doi: 10.1002/cncr.23548. 50. …

Collateral Victim or Rescue Worker?-The Role of Histone Methyltransferases in DNA Damage Repair and Their Targeting for Therapeutic Opportunities in Cancer.

Disrupted DNA damage signaling greatly threatens cell integrity and plays significant roles in cancer. With recent advances in understanding the human genome and gene regulation in the context of DNA damage, chromatin biology, specifically biology of histone post-translational modifications (PTMs), has emerged as a popular field of study with great promise for cancer therapeutics. Here, we discuss how key histone methylation pathways contribute to DNA damage repair and impact tumorigenesis within this context, as well as the potential for their targeting as part of therapeutic strategies in ca

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… Visualization of eukaryotic DNA mismatch repair reveals distinct recognition and repair intermediates. Cell 147 1040–1053. 10.1016/j.cell.2011.10.025 Huang A., Garraway L. A., Ashworth A., Weber B. (2020). Synthetic lethality as an engine for cancer drug target discovery. Nat. Rev. … The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα. Cell 153 590–600. 10.1016/j.cell.2013.03.025 Li F., Ortega J., Gu L., Li G. M. (2016). …

Immune System and DNA Repair Defects in Ovarian Cancer: Implications for Locoregional Approaches.

In the last few years, substantial progress has been made in the treatment of ovarian cancer, with increased knowledge about the biology of the disease. Ovarian cancer is a neoplasm strongly linked to defects in DNA repair mechanisms, where deficiency in the homologous recombination (HR) system results in a better response of ovarian cancers to therapy, whether platinum-based chemotherapy, anthracyclines, or poly (ADP-ribose) polymerase (PARP) inhibitors. More recently, it has been demonstrated that different ovarian cancer histotypes may have different immunogenicity. Interestingly, defects i

Synthetic lethality and DNA damage response targeting in cancer stem cells: a comprehensive review.

This comprehensive review explores the critical intersection of Synthetic Lethality (SL) and DNA Damage Response (DDR) targeting within Cancer Stem Cells (CSCs), a subpopulation central to tumor initiation, metastasis, and therapeutic resistance. CSCs exhibit unique biological properties, including enhanced DNA repair mechanisms and metabolic plasticity, rendering them intrinsically resistant to conventional therapies. The fundamental mechanisms of DDR pathways and their dysregulation in cancer are delineated, highlighting how these vulnerabilities can be exploited through SL. The review synth

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… Schofield MJ Hsieh P DNA mismatch repair: molecular mechanisms and biological function Annu Rev Microbiol 2003 57 1 579 608 10.1146/annurev.micro.57.030502.090847 14527292 Schofield MJ, Hsieh P. DNA mismatch repair: molecular mechanisms and biological function. …

Navigating through novelties concerning mCRC treatment-the role of immunotherapy, chemotherapy, and targeted therapy in mCRC.

Over the course of nearly six decades since the inception of initial trials involving 5-FU in the treatment of mCRC (metastatic colorectal cancer), our progressive comprehension of the pathophysiology, genetics, and surgical techniques related to mCRC has paved the way for the introduction of novel therapeutic modalities. These advancements not only have augmented the overall survival but have also positively impacted the quality of life (QoL) for affected individuals. Despite the remarkable progress made in the last two decades in the development of chemotherapy, immunotherapy, and target the

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… The trials focused on patients with DNA mismatch repair and microsatellite stability status, revealing promising outcomes in terms of response to PD-1/PD-L1 inhibitor therapy among mCRC patients ( 12 ). … Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. (2017) 18(9):1182–91. 10.1016/S1470-2045(17)30422-9. Erratum in: Lancet Oncol. (2017) 18(9): e510. …

Staying Abreast of New Biomarkers in Hematology/Oncology.

There has been an increasing number of approvals for targeted therapies in oncology in the past decade, changing the treatment paradigm for many solid tumors and hematologic malignancies. At JADPRO Live 2023, presenters provided an in-depth review of cancer biomarkers, including testing methodology, recommended therapies, and how advanced practitioners can integrate results into clinical decision-making.

Advances of DNA Damage Repair-Related Drugs and Combination With Immunotherapy in Tumor Treatment.

Cancer therapy has been an important and popular area in cancer research. With medical technology developing, the appearance of various targeted drugs and immunotherapy offer more choices to cancer treatment. With the increase in drug use, people have found more and more cases in which tumors are resistant to DNA damage repair (DDR)-based drugs. Recently, the concept of combination therapy has been brought up in cancer research. It takes advantages of combining two or more therapies with different mechanisms, aiming to benefit from the synergistic effects and finally rescue patients irresponsi