暂无摘要。

Given the crucial predictive implications of microsatellite instability (MSI) in colorectal cancer (CRC), MSI screening is commonly performed in those with and at risk for CRC. Here, we compared results from immunohistochemistry (IHC) and the droplet digital PCR (ddPCR) MSI assay on formalin-fixed paraffin-embedded tumor samples from 48 patients who underwent surgery for colon and rectal cancer by calculating Cohen\'s kappa measurement (k), revealing high agreement between the methods (k = 0.915). We performed Kaplan-Meier survival analyses and univariate and multivariate Cox regression to assess the prognostic significance of ddPCR-based MSI and to identify clinicopathological features associated with CRC outcome. Patients with MSI-high had better overall survival (OS; p = 0.038) and disease-free survival (DFS; p = 0.049) than those with microsatellite stability (MSS). When stratified by primary tumor location, right-sided CRC patients with MSI-high showed improved DFS, relative to those with MSS (p < 0.001), but left-sided CRC patients did not. In multivariate analyses, MSI-high was associated with improved OS (hazard ratio (HR) = 0.221, 95% confidence interval (CI): 0.026-0.870, p = 0.042), whereas the loss of DNA mismatch repair protein MutL homolog 1 (MLH1) expression was associated with worse OS (HR = 0.133, 95% CI: 0.001-1.152, p = 0.049). Our results suggest ddPCR is a promising tool for MSI detection. Given the opposing effects of MSI-high and MLH1 loss on OS, both ddPCR and IHC may be complementary for the prognostic assessment of CRC.

UNASSIGNED: Deficient mismatch repair (MMR) leading to microsatellite instability (MSI) in tumors is thought to be present in over 15% of colorectal cancer (CRC) cases. Testing CRC for MSI has traditionally been recommended following the fulfillment of clinical criteria. However, the performance of clinical criteria, especially the family history, as a selection tool for MSI screening in CRC is questionable.
UNASSIGNED: We retrospectively investigated the incidence of high degree MSI (MSI-H) tumors in an unselected population of CRC patients and compared its prevalence between individuals with and without family history of cancers within the spectrum of MSI-H tumors as defined in the revised Bethesda criteria.
UNASSIGNED: The study population included 274 patients, 70 with positive and 204 without family history of MSI-H tumors with complete data including findings from MSI analysis. The overall incidence of MSI-H CRC was 18.98%. There was no statistically significant difference in the incidence of MSI-H CRC amongst both groups. The sensitivity and specificity of family history with regard to the presence of an MSI-H tumor in this collective was 36.5% and 77.5%, respectively.
UNASSIGNED: A relevant number of cases with high MSI-H CRC may be missed secondary to screening based on clinical criteria like family history alone. Thus, systematic screening independent of clinical characteristics, especially family history of cancer should be recommended in all cases with CRC.

UNASSIGNED: Clinical guidelines suggest screening of colorectal cancer (CRC) for microsatellite instability (MSI). However, microsatellite instability-high (MSI-H) CRC is not rare in older patients. This study aimed to investigate the prevalence of MSI-H CRC in an unselected population in an age-based manner.
UNASSIGNED: A retrospective analysis of data from patients undergoing radical surgery for CRC was performed. Only cases with results from MSI testing using immunochemistry (IHC) were analyzed. Age-based analyses were performed using two cut-off ages: 50 years. as stated in Amsterdam II guidelines, and 60 years. as outlined in the revised Bethesda criteria.
UNASSIGNED: The study population included 343 (146 female and 197 male) patients with a median age of 70 years (range 21-90 years). The prevalence of MSI-H tumors in the entire cohort was 18.7%. The prevalence of MSI-H CRC was 22.5% in the group ≤50 years vs. 18.2% in the group >50 years using the age limit in the Amsterdam II guidelines. MSI-H CRC was present in 12.6% of the group aged ≤60 years compared to 20.6% in the control group >60 years.
UNASSIGNED: MSI screening of CRC based on age alone is associated with negative selection of a relevant number of cases. MSI-H CRC is also common in elderly patients, who may be negatively selected secondary to an age-based screening algorithm. Following the results of this study, screening based on clinical criteria should be omitted in favor of systematic screening as is already internationally practiced.

UNASSIGNED: Microsatellite instability-high (MSI-H) is an important biomarker for predicting the effects of immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC) patients. However, due to the low mutation rate of MSI-H/deficient mismatch repair (dMMR) in the overall population, some doctors are of the view that testing this indicator increases the burden on patients, and consequently some patients fail to receive the most beneficial treatment methods. In order to provide testing criteria for younger patients with a higher proportion of MSI-H, we designed this retrospective controlled study.
UNASSIGNED: A retrospective analysis was conducted of 1,901 patients who were admitted to the Affiliated Cancer Hospital of Zhengzhou University from January 2017 to December 2019 and underwent CRC-related gene testing. For this analysis, 100 patients aged 40 or younger are defined as the young group, and 305 patients aged 71 and older but younger than 80 are defined as the elderly group. We included patients who met the following criteria: (I) underwent preoperative colonoscopy or gastroscopy and were diagnosed with CRC; (II) received perioperative adjuvant therapy; (III) underwent curative surgery for CRC. Each patient was followed up from the time of surgery until April 30, 2023, or death, with follow-up visits scheduled every 3 months for the first 2 years after surgery, and every 6 months thereafter. Clinical characteristics such as age, gender, body mass index (BMI), tumor depth (T), number of metastatic lymph nodes (N), distant metastasis (M), tumor, node, metastasis (TNM) stage, extent of surgical resection, tumor size, tumor location, differentiation grade, and carcinoembryonic antigen (CEA) levels were collected. The microsatellite instability (MSI) status was analyzed using fluorescence in situ hybridization (FISH).
UNASSIGNED: In young CRC patients, the proportion of MSI-H is higher than in elderly CRC patients (33% vs. 10.16%, P<0.001). The proportion of poorly differentiated tumors is also higher in young CRC patients compared to elderly CRC patients (53% vs. 31.15%, P<0.001). However, there were no significant differences in clinical characteristics between young and elderly CRC patients. In terms of prognosis, survival analysis of the young group showed that MSI status [hazard ratio (HR) =0.26, 95% confidence interval (CI): 0.08-0.88, P=0.03], TNM staging (HR =3.84, 95% CI: 1.38-10.71, P=0.010) were associated with the prognosis of CRC patients.
UNASSIGNED: The mutation rate of MSI-H is higher in young CRC patients compared to older. Our study further confirms that MSI-H can serve as a favorable prognostic marker for CRC patients. This finding may provide valuable guidance for clinicians in terms of prognosis assessment and treatment selection. If feasible, we hope that MSI testing can be performed for all CRC patients to enable targeted testing, with particular attention to monitoring the MSI status in young patients. This will aid clinicians in selecting appropriate treatment strategies for these patients.

Keratin 7 (KRT7), also known as cytokeratin-7 (CK-7) or K7, constitutes the principal constituent of the intermediate filament cytoskeleton and is primarily expressed in the simple epithelia lining the cavities of the internal organs, glandular ducts, and blood vessels. Various pathological conditions, including cancer, have been linked to the abnormal expression of KRT7. KRT7 overexpression promotes tumor progression and metastasis in different human cancers, although the mechanisms of these processes caused by KRT7 have yet to be established. Studies have indicated that the suppression of KRT7 leads to rapid regression of tumors, highlighting the potential of KRT7 as a novel candidate for therapeutic interventions. This review aims to delineate the various roles played by KRT7 in the progression and metastasis of different human malignancies and to investigate its prognostic significance in cancer treatment. Finally, the differential diagnosis of cancers based on the KRT7 is emphasized.

Microsatellite instability (MSI), a type of genetic hypermutability arising from impaired DNA mismatch repair (MMR), is observed in approximately 3% of all cancers. Preclinical work has identified the RecQ helicase WRN as a promising synthetic lethal target for patients with MSI cancers. WRN depletion substantially impairs the viability of MSI, but not microsatellite stable (MSS), cells. Experimental evidence suggests that this synthetic lethal phenotype is driven by numerous TA dinucleotide repeats that undergo expansion mutations in the setting of long-standing MMR deficiency. The lengthening of TA repeats increases their propensity to form secondary DNA structures that require WRN to resolve. In the absence of WRN helicase activity, these unresolved DNA secondary structures stall DNA replication forks and induce catastrophic DNA damage.

暂无摘要。

Mismatch-repair (MMR)/microsatellite instability (MSI) status has therapeutic implications in endometrial cancer (EC). The authors evaluated the concordance of testing and factors contributing to MMR expression heterogeneity.
Six hundred sixty-six ECs were characterized using immunohistochemistry (IHC), MSI testing, and mut-L homolog 1 (MLH1) methylation. Select samples underwent whole-transcriptome analysis and next-generation sequencing. MMR expression of metastatic/recurrent sites was evaluated.
MSI testing identified 27.3% of cases as MSI-high (n = 182), MMR IHC identified 25.1% cases as MMR-deficient (n = 167), and 3.8% of cases (n = 25) demonstrated discordant results. A review of IHC staining explained discordant results in 18 cases, revealing subclonal loss of MLH1/Pms 1 homolog 2 (PMS2) (n = 10) and heterogeneous MMR IHC (mut-S homolog 6 [MSH6], n = 7; MLH1/PMS2, n = 1). MSH6-associated Lynch syndrome was diagnosed in three of six cases with heterogeneous expression. Subclonal or heterogeneous cases had a 38.9% recurrence rate (compared with 16.7% in complete MMR-deficient cases and 9% in MMR-proficient cases) and had abnormal MMR IHC results in all metastatic recurrent sites (n = 7). Tumors with subclonal MLH1/PMS2 demonstrated 74 differentially expressed genes (determined using digital spatial transcriptomics) when stratified by MLH1 expression, including many associated with epithelial-mesenchymal transition.
Subclonal/heterogeneous MMR IHC cases showed epigenetic loss in 66.7%, germline mutations in 16.7%, and somatic mutations in 16.7%. MMR IHC reported as intact/deficient missed 21% of cases of Lynch syndrome. EC with subclonal/heterogeneous MMR expression demonstrated a high recurrence rate, and metastatic/recurrent sites were MMR-deficient. Transcriptional analysis indicated an increased risk for migration/metastasis, suggesting that clonal MMR deficiency may be a driver for tumor aggressiveness. Reporting MMR IHC only as intact/deficient, without reporting subclonal and heterogeneous staining, misses opportunities for biomarker-directed therapy.
Endometrial cancer is the most common gynecologic cancer, and 20%-40% of tumors have a defect in DNA proofreading known as mismatch-repair (MMR) deficiency. These results can be used to guide therapy. Tests for this defect can yield differing results, revealing heterogeneous (mixed) proofreading capabilities. Tumors with discordant testing results and mixed MMR findings can have germline or somatic defects in MMR genes. Cells with deficient DNA proofreading in tumors with mixed MMR findings have DNA expression profiles linked to more aggressive characteristics and cancer spread. These MMR-deficient cells may drive tumor behavior and the risk of spreading cancer.

Introduction Colorectal cancer (CRC) is the third most common cancer in the world among men and second among women worldwide. One of the major molecular pathways responsible for the development of colorectal cancer (CRC) is the microsatellite instability (MSI) pathway. During carcinogenesis, the tumor cells express programmed death ligand-1 (PD-L1), which reduces the immunogenicity leading to the escape of immune attack. Anti-PD-L1 interaction is an upcoming line of research for the treatment of colorectal carcinoma patients. Materials and methods The present study was an ambispective study where the mismatch repair deficiency status (MMR) and programmed death ligand-1 (PD-L1) expression were studied using immunohistochemistry and then later analyzed and compared with the clinicopathological parameters and MSI status in relation to the expression of programmed death ligand-1 (PD-L1) in neoplastic and immune cells in a total of 55 biopsy specimen. MMR expression was reported as retained or loss of nuclear staining, and PD-L1 expression was taken as positive with a cut-off of more than or equal to 5% membranous positivity in both tumor cells and immune cells. Results The analysis showed a significant correlation of microsatellite instability (MSI) status with two of the clinicopathological parameters, which were the site of the tumor (p-value<0.001) and M stage (p-value<0.001). PD-L1 expression in neoplastic cells showed no significant correlation with the clinicopathological parameters, whereas PD-L1 expression in immune cells showed a significant association with gender (p-value=0.043). Also, MSI status showed a significant association with PD-L1 expression in tumor cells (p-value <0.001).