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Virchows Archiv : An International... Feb 2024Colorectal cancer (CRC) has a broad range of molecular alterations with two major mechanisms of genomic instability (chromosomal instability and microsatellite... (Review)
Review
Colorectal cancer (CRC) has a broad range of molecular alterations with two major mechanisms of genomic instability (chromosomal instability and microsatellite instability) and has been subclassified into 4 consensus molecular subtypes (CMS) based on bulk RNA sequence data. Here, we update the molecular pathological classification of CRC with an overview of more recent bulk and single-cell RNA data analysis for development of transcriptional classifiers and risk stratification methods, taking into account the marked inter-tumoural and intra-tumoural heterogeneity of CRC. The importance of the stromal and immune components or tumour microenvironment (TME) to prognosis has emerged from these analyses. Attempts to remove the contribution of the tumour microenvironment and reveal neoplastic-specific transcriptional traits involved identification of the CRC intrinsic subtypes (CRIS). The use of immunohistochemistry and digital pathology to implement classification systems are evolving fields. Conventional adenoma versus serrated polyp pathway transcriptomic analysis and characterisation of canonical LGR5+ crypt base columnar stem cell versus ANXA1+ regenerative stem cell phenotypes emerged as key properties for improved understanding of transcriptional signals involved in molecular subclassification of colorectal cancers. Recently, classification by three pathway-derived subtypes (PDS1-3) has been developed, revealing a continuum of intrinsic biology associated with biological, stem cell, histopathological, and clinical attributes.
Topics: Humans; Colorectal Neoplasms; Gene Expression Profiling; Transcriptome; Tumor Microenvironment
PubMed: 38319359
DOI: 10.1007/s00428-024-03746-3 -
International Journal of Molecular... Sep 2023Approximately 20-30% of endometrial carcinomas (EC) are characterized by mismatch repair (MMR) deficiency (dMMR) or microsatellite instability (MSI), and their testing...
Approximately 20-30% of endometrial carcinomas (EC) are characterized by mismatch repair (MMR) deficiency (dMMR) or microsatellite instability (MSI), and their testing has become part of the routine diagnosis. The aim of this study was to establish and compare the MMR status using various approaches. Immunohistochemistry (IHC), PCR-based MSI, and the detection of defects in the four key MMR genes (MLH1, PMS2, MSH2, and MSH6) via methylation-specific multiplex ligation-dependent probe amplification (MLPA) and targeted next-generation sequencing (NGS) were performed. MSH3 expression was also evaluated. A set of 126 early-stage EC samples were analyzed, 53.2% of which were dMMR and 46.8% of which were proficient MMR (pMMR) as determined using IHC, whereas 69.3% were classified as microsatellite stable, while 8.8% and 21.9% were classified MSI-low (MSI-L) and MSI-high (MSI-H), respectively. In total, 44.3% of the samples showed genetic or epigenetic alterations in one or more genes; MLH1 promoter methylation was the most common event. Although acceptable concordance was observed, there were overall discrepancies between the three testing approaches, mainly associated with the dMMR group. IHC had a better correlation with MMR genomic status than the MSI status determined using PCR. Further studies are needed to establish solid conclusions regarding the best MMR assessment technique for EC.
Topics: Female; Humans; DNA Mismatch Repair; Endometrial Neoplasms; Colorectal Neoplasms; Neoplastic Syndromes, Hereditary; Microsatellite Instability
PubMed: 37833916
DOI: 10.3390/ijms241914468 -
Oncology Letters Sep 2023Src homology-2 domain-containing protein tyrosine phosphatase (SHP2), encoded by protein tyrosine phosphatase non-receptor type 11 (PTPN11), is widely expressed in...
Src homology-2 domain-containing protein tyrosine phosphatase (SHP2), encoded by protein tyrosine phosphatase non-receptor type 11 (PTPN11), is widely expressed in several human tissue types, and plays an important role in a variety of diseases. The present study assessed the impact of SHP2 on the occurrence, development and prognosis of solid tumors. The transcriptome sequencing data of 33 cancer types were downloaded from The Cancer Genome Atlas database. Clinical information of the corresponding patients, tumor mutational burden and information pertinent to microsatellite instability were also downloaded. The log-rank test and univariate Cox's regression test were used to evaluate patient survival. The 'ESTIMATE' method was used to assess the tumor microenvironment, and the 'CIBERSORT' algorithm was used to evaluate tumor immune cell infiltration. Spearman's correlation analysis was used to evaluate the correlation between SHP2 expression and the targets identified. ELISA was used to assess the SHP2 expression levels in peripheral blood samples of patients with breast, ovarian, endometrial and cervical cancer. The data indicated that the expression levels of SHP2 were increased in a variety of tumor tissues, and were associated with tumor progression and prognosis. In peripheral blood, the positive rates of SHP2 expression in breast cancer (71.43%) and ovarian cancer (58.82%) were significantly higher than those in the corresponding control groups. However, the positive rates of SHP2 expression in patients with endometrial cancer (31.03%) and cervical cancer (41.30%) were significantly lower than those in the corresponding control groups. Increased SHP2 expression improved overall survival (OS) and disease free survival (DFS) time in patients with kidney renal clear cell carcinoma. However, increased SHP2 expression reduced OS and DFS in patients with urothelial carcinoma, and cervical and endocervical cancer types. Moreover, the elevated expression of SHP2 could also reduce the OS of patients with breast invasive carcinoma, mesothelioma and liver hepatocellular carcinoma. PTPN11 expression was associated with the tumor microenvironment of various tumor types. The tumor mutational burden of various tumor types was associated with microsatellite instability. PTPN11 inhibited T-cell activation and promoted M2 macrophage activation in several tumors. Therefore, SHP2 may be used in the evaluation of tumor progression and prognosis, and it may be an optimal potential biological target for cancer therapy.
PubMed: 37600341
DOI: 10.3892/ol.2023.13979 -
Cancers Aug 2023Microsatellite instability (MSI) is a biological condition associated with inflamed tumors, high tumor mutational burden (TMB), and responses to immune checkpoint... (Review)
Review
Microsatellite instability (MSI) is a biological condition associated with inflamed tumors, high tumor mutational burden (TMB), and responses to immune checkpoint inhibitors. In colorectal cancer (CRC), MSI tumors are found in 5% of patients in the metastatic setting and 15% in early-stage disease. Following the impressive clinical activity of immune checkpoint inhibitors in the metastatic setting, associated with deep and long-lasting responses, the development of immune checkpoint inhibitors has expanded to early-stage disease. Several phase II trials have demonstrated a high rate of pathological complete responses, with some patients even spared from surgery. However, in both settings, not all patients respond and some responses are short, emphasizing the importance of the ongoing search for accurate biomarkers. While various biomarkers of response have been evaluated in the context of MSI CRC, including and /2 mutations, TMB, pathway mutations, and Lynch syndrome, with mixed results, liver metastases have been associated with a lack of activity in such strategies. To improve patient selection and treatment outcomes, further research is required to identify additional biomarkers and refine existing ones. This will allow for the development of personalized treatment approaches and the integration of novel therapeutic strategies for MSI CRC patients with liver metastases.
PubMed: 37686520
DOI: 10.3390/cancers15174245 -
American Journal of Cancer Research 2023Gastric cancer is an extremely common digestive tract tumor. The promotion and application of standardized therapy, treatment scheme optimization, and development of new... (Review)
Review
Gastric cancer is an extremely common digestive tract tumor. The promotion and application of standardized therapy, treatment scheme optimization, and development of new targeted drugs and immunotherapies have improved gastric cancer survival somewhat. However, gastric cancer prognosis generally remains non-optimistic. Immune checkpoint inhibitors (ICI) have gradually become a new choice for gastric cancer treatment and can prolong the survival of some patients. Among them, high-microsatellite instability, Epstein-Barr virus-positive status, or high-tumor mutational burden patients with gastric cancer may be the potential population to benefit from immunotherapy. Nevertheless, there remains a lack of unified and effective predictive markers. Accordingly, this review mainly focused on the possible predictive biomarkers of anti-PD-1/PD-L1 in gastric cancer treatment. Furthermore, the application of anti-PD-1/PD-L1 therapy-related clinical trials on gastric cancer is discussed. The current findings suggest that immunotherapy is a promising application in gastric cancer treatment. Therefore, combining immunotherapy and other therapies may be the trend in the future. Nevertheless, exploring biomarkers to predict ICI response remains a major challenge.
PubMed: 37559976
DOI: No ID Found -
Diagnostics (Basel, Switzerland) Aug 2023Despite advances in diagnostic imaging, surgical techniques, and systemic therapy, gastric cancer (GC) is the third leading cause of cancer-related death worldwide.... (Review)
Review
Despite advances in diagnostic imaging, surgical techniques, and systemic therapy, gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Unfortunately, molecular heterogeneity and, consequently, acquired resistance in GC are the major causes of failure in the development of biomarker-guided targeted therapies. However, by showing promising survival benefits in some studies, the recent emergence of immunotherapy in GC has had a significant impact on treatment-selectable procedures. Immune checkpoint inhibitors (ICIs), widely indicated in the treatment of several malignancies, target inhibitory receptors on T lymphocytes, including the programmed cell death protein (PD-1)/programmed death-ligand 1 (PD-L1) axis and cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and release effector T-cells from negative feedback signals. In this article, we review currently available predictive biomarkers (including PD-L1, microsatellite instability, Epstein-Barr virus, and tumor mutational burden) that affect the ICI treatment response, focusing on PD-L1 expression. We further briefly describe other potential biomarkers or mechanisms for predicting the response to ICIs in GC. This review may facilitate the expansion of the understanding of biomarkers for predicting the response to ICIs and help select the appropriate therapeutic approaches for patients with GC.
PubMed: 37685320
DOI: 10.3390/diagnostics13172782 -
Frontiers in Immunology 2023For colorectal cancer (CRC), surgical resection remains essential for achieving good prognoses. Unfortunately, numerous patients with locally advanced CRC and metastatic... (Review)
Review
For colorectal cancer (CRC), surgical resection remains essential for achieving good prognoses. Unfortunately, numerous patients with locally advanced CRC and metastatic CRC failed to meet surgical indications or achieve pathological complete response after surgery. Perioperative therapy has been proven to effectively lower tumor staging and reduce recurrence and metastasis. Immune checkpoint inhibitors (ICIs) have shown unprecedented prolongation of survival time and satisfactory safety in patients with high microsatellite instability/deficient mismatch repair (MSI-H/dMMR), while the therapeutic effect obtained by patients with mismatch repair-proficient or microsatellite stable (pMMR/MSS) was considered minimal. However, recent studies found that certain CRC patients with dMMR/MSI-H presented intrinsic or acquired immune resistance, and pMMR/MSS CRC patients can also achieve better efficacy. Therefore, more predictors are required for screening patients with potential clinical benefits. Since the discovery of synergistic effects between immunotherapy, chemotherapy, and radiotherapy, different immunotherapy-based therapies have been applied to the perioperative therapy of CRC in an increasing number of research. This review comprehensively summarized the past and current progress of different combinations of immunotherapy in perioperative clinical trials for CRC, focusing on the efficacy and safety, and points out the direction for future development.
Topics: Humans; Immune Checkpoint Inhibitors; Immunotherapy; Brain Neoplasms; Colorectal Neoplasms; Microsatellite Instability
PubMed: 38022667
DOI: 10.3389/fimmu.2023.1269341 -
Cancers Oct 2023Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths in Europe. About 5% of metastatic CRC (mCRC) are... (Review)
Review
Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths in Europe. About 5% of metastatic CRC (mCRC) are characterized by high microsatellite instability (MSI) due to a deficient DNA mismatch repair (dMMR), and this condition has been related to a high sensitivity to immunotherapy, in particular to the Immune Checkpoint Inhibitors (ICIs). In fact, in MSI-H or dMMR mCRC, treatment with ICIs induced remarkable response rates and prolonged survival. However, the majority of mCRC cases are mismatch-repair-proficient (pMMR) and microsatellite-stable (MSS), and unfortunately these conditions involve resistance to ICIs. This review aims to provide an overview of the strategies implemented to overcome ICI resistance and/or define subgroups of patients with MSS or dMMR mCRC who may benefit from immunotherapy.
PubMed: 37958363
DOI: 10.3390/cancers15215189 -
International Journal of Clinical... Jun 2024Cancer of unknown primary site (CUP) is a heterogeneous group of tumors for which the origin remains unknown. Clinical outcomes might be influenced by regulatory...
BACKGROUND
Cancer of unknown primary site (CUP) is a heterogeneous group of tumors for which the origin remains unknown. Clinical outcomes might be influenced by regulatory processes in its microenvironment. Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy and its status, as well as co-occurrence with PD-L1 expression, is poorly evaluated. We aim to evaluate the expression of PD-L1 and the status of MSI in CUP and their possible associations with clinical-pathological features.
METHODS
The combined positive score (CPS) PD-L1 expression was evaluated by immunohistochemistry. MSI status was assessed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis.
RESULTS
Among the 166 cases, MSI analysis was conclusive in 120, with two cases being MSI positive (1.6%). PD-L1 expression was positive in 18.3% of 109 feasible cases. PD-L1 expression was significantly associated with non-visceral metastasis and a dominance of nodal metastasis. The median overall survival (mOS) was 3.7 (95% CI 1.6-5.8) months and patients who expressed PD-L1 achieved a better mOS compared to those who did not express PD-L1 (18.7 versus 3.0 months, p-value: < .001). ECOG-PS equal to or more than two and PD-L1 expression were independent prognostic factors in multivariate analysis (2.37 and 0.42, respectively).
CONCLUSION
PD-L1 is expressed in a subset (1/5) of patients with CUP and associated with improved overall survival, while MSI is a rare event. There is a need to explore better the tumor microenvironment as well as the role of immunotherapy to change such a bad clinical outcome.
Topics: Humans; Microsatellite Instability; Neoplasms, Unknown Primary; B7-H1 Antigen; Male; Female; Middle Aged; Aged; Adult; Aged, 80 and over; Biomarkers, Tumor; Prognosis; Tumor Microenvironment; Immunohistochemistry
PubMed: 38528294
DOI: 10.1007/s10147-024-02494-3 -
Therapeutic Advances in Medical Oncology 2023Immune checkpoint inhibitors (ICIs) are commonly used to treat patients with advanced urothelial cancer. However, a significant number of patients do not respond to ICI,... (Review)
Review
Immune checkpoint inhibitors (ICIs) are commonly used to treat patients with advanced urothelial cancer. However, a significant number of patients do not respond to ICI, and the lack of validated predictive biomarkers impedes the success of the ICI strategy alone or in combination with chemotherapy or targeted therapies. In addition, some patients experience potentially severe adverse events with limited clinical benefit. Therefore, identifying biomarkers of response to ICI is crucial to guide treatment decisions. The most evaluated biomarkers to date are programmed death ligand 1 expression, microsatellite instability/defective mismatch repair phenotype, and tumor mutational burden. Other emerging biomarkers, such as circulating tumor DNA and microbiota, require evaluation in clinical trials. This review aims to examine these biomarkers for ICI response in urothelial cancer and assess their analytical and clinical validation.
PubMed: 37692364
DOI: 10.1177/17588359231192402