KMT2A Mutations and High Prevalence of dMMR-associated Mutational Signatures as Prognostic Indicators in Metastatic Colorectal Cancer.

The conventional treatment strategies for patients with metastatic colorectal cancer (mCRC) are predominantly guided by the status of RAS and BRAF mutations. Although patients may exhibit analogous pathological characteristics and undergo similar treatment regimens, notable disparities in their prognostic outcomes can be observed. Therefore, tissue and plasma samples from 40 mCRC patients underwent next-generation sequencing targeting 425 cancer-relevant genes. Genomic variations and canonical oncogenic pathways were investigated for their prognostic effects in association with progression-free survival (PFS) of these patients. We found that patients with BRCA2 and KMT2A mutations exhibited worse prognostic outcomes after chemotherapy-based treatment (univariate, P < 0.01). Further pathway analysis indicated that alterations in the homologous recombination pathway and in the KMT2A signaling network were also significantly associated with shortened PFS (univariate, P < 0.01). Additionally, mutation signature analysis showed that patients with higher proportions of defective mismatch repair (dMMR)-related mutational signatures. Had a worse prognosis (univariate, P = 0.02). KMT2A mutations (hazard ratio [HR], 4.47; 95% confidence interval [CI], 1-19.93; P =0.050) and dMMR signature proportions (HR, 3.57; 95% CI, 1.42-8.96; P = 0.007) remained independently associated with PFS after multivariate analysis and the results were further externally validated. These findings may enhance our understanding of this disease and may potentially facilitate the optimization of its treatment approaches.

Development and validation of the chemotherapy-induced peripheral neuropathy integrated assessment - oxaliplatin subscale: a prospective cohort study.

BACKGROUND: Current chemotherapy-induced peripheral neuropathy (CIPN) assessment tools mostly have poor sensitivity and weak anti-interference, so that it is sometimes difficult to provide substantive guidance for clinical intervention. This study aimed to develop an assessment tool dedicated for oxaliplatin to address these limitations. METHODS: This study screened 445 OIPN-related literatures for producing a symptom list, and developed the questionnaire module through expert supplement, item generation, content correlation analysis, pre-testing, and item improvement. The validation phase used a Chinese population-based prospective cohort study from June 2021 to July 2022. Patients were requested to complete the tested questionnaire, QLQ-CIPN20 and the CTCAE grading one day before cycles 2-6 of chemotherapy. Cronbach's α coefficient and intraclass correlation coefficient (ICC) were calculated for the internal consistency and stability analysis, respectively. Exploratory factor analysis was conducted to investigate the construct validity. The correlations among the tested questionnaire, QLQ-CIPN20 and CTCAE were compared for the criterion validity analysis. Wilcoxon signed-rank sum test was utilized to compare the sensitivity between the tested questionnaire and QLQ-CIPN20. RESULT: A 20-item CIPN assessment tool named chemotherapy-induced peripheral neuropathy integrated assessment - oxaliplatin subscale (CIPNIA-OS) was developed. The validation phase included 186 patients. Cronbach's α coefficient of CIPNIA-OS was 0.764 (> 0.7), and ICC was 0.997 (between 0.9 and 1). The structure of CIPNIA-OS containing seven factors was examined. The correlation coefficient between CIPNIA-OS and CTCAE was 0.661 (95%CI 0.623 to 0.695), which was significantly higher than that between QLQ-CIPN20 and CTCAE (0.417, 95%CI 0.363 to 0.469, p < 0.01). Besides, the total score of CIPNIA-OS was mostly higher than QLQ-CIPN20, with an average difference of 2.189 (CI 95% 2.056 to 2.322), and the difference gradually expanded with the progress of chemotherapy (p < 0.05). CONCLUSION: This study developed an original CIPN questionnaire which was dedicated for OIPN assessment. It was a comprehensive tool that covered acute OIPN symptoms and integrated features from several proven CIPN assessment tools. The validation results supported that CIPNIA-OS had satisfactory reliability, stability, construct, criterion validity, and was more accuracy and sensitive than QLQ-CIPN20 in the evaluation of OIPN.

Functional genetic variant of HSD17B12 in the fatty acid biosynthesis pathway predicts the outcome of colorectal cancer.

Fatty acids are involved in the development and progression of colorectal cancer (CRC). However, genetic effects of fatty acid biosynthesis pathway on CRC outcome are unclear. Cox regression model was used to evaluate genetic effects on CRC overall survival (OS) and progression-free survival (PFS), accompanied by calculating hazard ratios (HRs) and confidence intervals (CIs). Differential expression analysis, expression quantitative trait loci analysis, dual-luciferase reporter assay and chromatin immunoprecipitation assay were performed to explore the genetically biological mechanism. The rs10838164 C>T in HSD17B12 was significantly associated with an increased risk of death and progression of CRC (OS, HR = 2.12, 95% CI = 1.40-3.22, P = 4.03 × 10-4 ; PFS, HR = 1.64, 95% CI = 1.11-2.44, P = 1.35 × 10-2 ), of which T allele could increase HSD17B12 expression (P = 1.78 × 10-11 ). Subsequently, the functional experiments indicated that rs10838164 T allele could not only enhance the binding affinity of transcription factor YY1 to HSD17B12 region harbouring rs10838164 but also promote the transcriptional activity of HSD17B12, which was significantly up-regulated in colorectal tumour tissues. Our findings suggest that genetic variants in fatty acid biosynthesis pathway play an important role in CRC outcome.

Genetic variants in the Folic acid Metabolic Pathway Genes predict outcomes of metastatic Colorectal Cancer patients receiving first-line Chemotherapy.

Background: The association between genetic variants in the folic acid metabolic pathway genes and survival, as well as the responses to chemotherapy of metastatic colorectal cancer (mCRC) patients has not been reported. Methods: The association between genetic variants in the folic acid metabolic pathway genes and progression-free survival (PFS) and overall survival (OS) of mCRC patients were analyzed using Cox regression model. The false discovery rate (FDR) correction method was conducted. The logistic regression model was used to explore the effects of the interested genetic variants on disease control rate (DCR). The Cancer Genome Atlas (TCGA) database was applied to compare gene expression differences. Results: We found that rs3786362 G allele of thymidylate synthase (TYMS) gene was significantly associated with PFS (P = 1.10 × 10-2), OS (P = 2.50 × 10-2) and DCR (P = 5.00 × 10-3). The expression of TYMS was overexpressed in CRC tissues compared with adjacent normal tissues. Furthermore, TYMS expression level decreased with respect to younger age and advanced tumor stage. Conclusion: Genetic variants in the folic acid metabolic pathway genes might serve as potential prognostic biomarkers for mCRC patients.

Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7.

The positive results of the apatinib phase III trial have cast new light on treatment for patients with advanced gastric cancer (GC). However, in terms of safety, apatinib toxicities may lead to a dose modification or treatment interruption. Therefore, proper intervention is urgently needed to help patients benefit from apatinib treatment. In this study, we found that apatinib promoted autophagy activation via upregulation of ATG7 expression and autophagy inhibition enhanced apatinib-induced apoptosis. With microRNA and circular RNA-sequencing analyses of GC xenograft models, we demonstrated that circRACGAP1 functioned as an endogenous sponge for miR-3657 to inhibit its activity and further upregulate ATG7 expression. Silencing of circRACGAP1 inhibited apatinib-induced autophagy, which was rescued by miR-3657. Moreover, knockdown of circRACGAP1 sensitized GC cells to apatinib via autophagy inhibition in vitro and in vivo. These findings provided the first evidence that the circRACGAP1-miR-3657-ATG7 axis mediates a novel regulatory pathway critical for the regulation of apatinib sensitivity in GC. Thus, specific blockage of circRACGAP1 may be a potential therapeutic strategy to reduce the toxicities of apatinib and enhance its therapeutic effect in human GC.

The molecular mechanism and clinical significance of LDHA in HER2-mediated progression of gastric cancer.

OBJECTIVE: The use of human epidermal growth factor receptor-2 (HER2) as a biomarker for gastric cancer (GC) has greatly helped some patients receive benefit from HER2-targeted therapy. However, the correlation between HER2 and other biochemical markers is unclear. The aim of this study was to examine the relationship between HER2 and lactate dehydrogenase A (LDHA) in GC tissues and GC cells. METHODS: The correlation between clinicopathological features and HER2 was analyzed in 179 cases of GC. The expression of HER2 and LDHA was examined by immunohistochemical staining in 12 pairs of GC tissues and by western blotting in seven pairs of fresh GC tissues and adjacent normal tissues. Wound healing, transwell migration assay, quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR), and LDH activity assays were performed with GC cells. RESULTS: HER2 expression and serum LDH levels were closely correlated (P = 0.027) in 179 GC patient cases. Immunohistochemical staining demonstrated a positive correlation between HER2 and LDHA in 12 pairs of GC tissues (P = 0.0308). Knocking down LDHA suppressed cell migration and invasion in GC cells. In addition, HER2 positively regulated hypoxia-inducible factor-1α (HIF-1α) and LDHA. Furthermore, the expressions of HER2, HIF-1α, and LDHA were consistent in 5/7 pairs of fresh GC tissues and adjacent normal tissues as well as in GC cell lines. CONCLUSIONS: The HER2-HIF-1α-LDHA axis may serve as the basis for new methods and strategies for the treatment of GC.

MiR-346 suppresses cell proliferation through SMYD3 dependent approach in hepatocellular carcinoma.

BACKGROUND & AIMS: The miRNAs are demonstrated to be involved in the carcinogenesis of hepatocellular carcinoma (HCC) and some exhibit potential value for oncotherapy. This study was designed to explore the role of miR-346 in the pathogenesis of hepatocellular carcinoma. METHODS: High throughput screening was employed following with Real time-PCR to investigate the candidate miRNAs. 5-ethynyl-2-deoxyuridine (EdU) assay, CCK-8, transwell assay, cell cycle assay, luciferase reporter assay, western blot and mice xenotransplantation model were performed in the present study. RESULTS: We found miR-346 was significantly down-regulated in the HCC tissues compared with the non-tumor controls and was associated with the tumor size and TNM grade. Additionally, the in vitro and in vivo assays confirmed that miR-346 suppressed the proliferation of HCC. Then, bioinformatic algorithms and luciferase reporter assays proved that miR-346 directly targeted SET and MYND domain containing 3(SMYD3). We also performed the rescue experiments by inhibiting the expression of SMYD3 and found the down-regulation of SMYD3 could neutralize the inhibitory effects of miR-346 on HCC. At last, the cox proportional hazards analysis showed that low expression of miR-346 was an an independent prognostic factor for HCC. CONCLUSION: Our findings illuminated miR-346 targeting SMYD3 to inhibit the proliferation of HCC and its down-regulation predicts a poor prognosis.

JWA down-regulates HER2 expression via c-Cbl and induces lapatinib resistance in human gastric cancer cells.

Human epidermal growth factor receptor 2 (HER2) targeted therapy is currently considered as the standard treatment for HER2-positive advanced gastric cancer (GC). However, unsatisfactory results of recent phase III clinical trials involving lapatinib suggested biomarkers for selection of patients. The aim of this study was to identify JWA as a biomarker for lapatinib resistance in GC cells and elucidate the underlying mechanisms. Lapatinib was effective to the intrinsic cisplatin-resistant GC cells. JWA activation conferred lapatinib unresponsiveness, but reversed cisplatin resistance in GC cells. Whereas, deletion of JWA significantly restored lapatinib suppression on proliferation and lapatinib-induced apoptosis. JWA-induced down-regulation of HER2 and activation of ERK phosphorylation led to lapatinib resistance. Furthermore, c-Cbl represented a novel mechanism for HER2 degradation enhanced by JWA in GC cells. Taken together, JWA is a potential predictive marker for lapatinib resistance, targeting the patients that may benefit from lapatinib treatment in human GC.

JWA loss promotes cell migration and cytoskeletal rearrangement by affecting HER2 expression and identifies a high-risk subgroup of HER2-positive gastric carcinoma patients.

BACKGROUND AND AIMS: JWA, a microtubule-associated protein (MAP) involved in apoptosis, has been identified as a suppressor of metastasis, and it affects cell migration in melanoma and its downregulation in tumor is an idependent negative prognostic factor in resectable gastric cancer. HER2 overexpression has been observed in gastric cancer (GC) cells and implicated in the metastatic phenotype. However, the biological role of JWA in migration and its clinical value in HER2-positive GC remain elusive. RESULTS: JWA suppresses EGF-induced cell migration and actin cytoskeletal rearrangement by abrogating HER2 expression and downstream PI3K/AKT signaling in HER2-overexpressing GC cell lines. The modulation of HER2 by JWA is dependent on ERK activation and consequent PEA3 upregulation and activation. Reduced JWA expression is associated with high HER2 expression and with poor survival in patients with AGC, whereas HER2 expression alone is not associated with survival. However, concomitant low JWA and high HER2 expression is associated with unfavorable outcomes. Additionally, when patients were stratified by JWA expression, those with higher HER2 expression in the low JWA expression subgroup exhibited worse survival. METHODS: The impact of JWA on the EGF-induced migration of HER2-positive GC cells was studied using transwell assays and G-LISA assays. Western blotting, real-time PCR, electrophoretic mobility shift assays and luciferase assays were utilized to investigate the mechanisms by which JWA affects HER2. The association of JWA with HER2 and its clinical value were further analyzed by IHC in 128 pairs of advanced gastric cancer (AGC) and adjacent normal tissue samples. CONCLUSIONS: This study characterizes a novel mechanism for regulating cell motility in HER2-overexpressing GC cells involving JWA-mediated MEK/ERK/PEA3 signaling activation and HER2 downregulation. Furthermore, JWA may be a useful prognostic indicator for advanced GC and may help stratify HER2-positive patient subgroups to better identify unfavorable outcomes.

Activity of pemetrexed-based regimen as first-line chemotherapy for advanced non-small cell lung cancer with asymptomatic inoperable brain metastasis: a retrospective study.

This retrospective study was conducted to assess the efficacy of combination of pemetrexed and cisplatin/carboplatin as first-line treatment in inoperable and asymptomatic brain metastasis (BM) from non-small cell lung cancer (NSCLC). A total of 30 patients with adenocarcinoma were included. Nine patients had solitary, and 21 patients had multiple BM. At evaluation after two cycles, the complete response (CR) rate, partial response (PR) rate, and stable disease (SD) for brain lesions was 0, 33.3, and 46.7%, respectively. The overall CR, PR, and SD were 0, 23.3, and 46.7%, respectively. The median time to tumour progression of BM (TTP-BM) was 6.0 months (95% CI 4.068-7.932). The median progression-free survival (PFS) and overall survival (OS) were 5.0 months (95% CI 4.197-5.803) and 11.0 months (95% CI 7.398-14.602), respectively. Pemetrexed has comparable activity on brain lesions as on extracranial tumours in advanced lung adenocarcinoma patients with inoperable and asymptomatic BM.

WT1 promotes invasion of NSCLC via suppression of CDH1.

INTRODUCTION: The Wilms' tumor gene (WT1) has been identified as an oncogene in many malignant diseases, and aberrant WT1 expression has been linked to development, progression, and prognosis of non-small-cell lung cancer (NSCLC). We sought to investigate the underlying mechanism of WT1 and metastasis in NSCLC. METHODS: Real-time polymerase chain reaction was applied to detect WT1 and CDH1 mRNA in 159 NSCLC samples and corresponding adjacent tissues. Stable clones with overexpression and knockdown of WT1 were generated with plasmid and shRNA via lentivirus technology in H1568 and H1650 NSCLC cell lines. Wound-healing assay, transwell assays, and polymerase chain reaction array were carried out for invasion evaluation. Dual luciferase reporter assay was performed to validate the effect of WT1 on CDH1. RESULTS: The level of the WT1 mRNA was negatively correlated with that of E-cadherin (CDH1) and associated with pathological stage, metastasis, and survival rate of 159 NSCLC patients. A series of genes were regulated by WT1, and WT1 could suppress CDH1 transcription via direct binding to its promoter and may enhance the invasive ability of H1568 and H1650 NSCLC cell lines. CONCLUSIONS: WT1 expression was correlated with clinical stage, metastasis, and survival rate in 159 NSCLC patients. Via direct binding to the promoter, WT1 could suppress CDH1 and promote NSCLC invasion.

A case of advanced mycosis fungoides with comprehensive skin and visceral organs metastasis: sensitive to chemical and biological therapy.

Mycosis fungoides is a common cutaneous T-cell lymphoma, which is usually characterized by chronic, indolence progression, with absence of typical symptoms in early stage, metastasis to lymph nodes, bone marrow and visceral organs in later stage and ultimately progression to systemic lymphoma. It can result in secondary skin infection which is a frequent cause of death. At present, no curative therapy existed. Therapeutic purpose is to induce remission, reduce tumor burden and protect immune function of patients. A case of patient with advanced severe mycosis fungoides receiving CHOP plus interferon α-2a was reported here, with disease-free survival of 7 months and overall survival of over 17.0 months, and current status as well as developments of mycosis fungoides were briefly introduced.