Next generation sequencing targeted detection of somatic mutations in patients with mucinous adenocarcinoma of the appendix.

The aim of this study was to investigate the mutations in mucinous adenocarcinoma of the appendix (MAA). SNV was detected in 15 patients with MAA, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and reactome pathway analyses were performed. Tumor mutational burden (TMB), mutant-allele tumor heterogeneity (MATH), microsatellite instability (MSI) was analysis. Finally, the human leukocyte antigen (HLA) typing of the samples was detected. The results showed that TP53 (27 %) and KRAS (20 %) were the highest mutation frequency in the sample, mainly occur in p53 pathway and RTK-RAS pathway. GO analysis reveals mutated genes are closely related to the regulation of GTPase activity, regulation of small GTPase mediated signal transduction and other BP, related to the CC and MF. Analysis of KEGG pathways indicated that the top canonical pathways associated with SNV was Wnt signaling pathway. Reactome pathway analysis further revealed that the mutant genes were closely related to muscle contraction. Only one patient had moderate TMB level and one patient with high MSI. In conclusion, the most common mutated genes and the signaling pathways closely related to MAA development were detected in this study, which will contribute to the development of immunotherapy for patients with MAA.

Based on whole-exome sequencing to explore the rule of Herceptin and TKI resistance in breast cancer patients.

BACKGROUND: Breast cancer is the second leading cause of cancer-related death in women, and drug resistance during treatment is a major challenge. However, the mechanisms underlying drug resistance are not fully understood. Here we applied whole-exome sequencing (WES) to clarify resistant rules to Herceptin and tyrosine kinase inhibitors (TKIs). METHODS: There are 12 HER2+ breast cancer patients who were done WES. Samples from tumor and surrounding tissues underwent DNA sequencing and analysis. Various experimental and bioinformatics techniques were employed, including genomic capture, mutation analysis (Genome Analysis Toolkit (GATK), etc.), bioinformatics assessments, and drug-gene interaction investigations. Ultimately, the study explored the association of APOB gene expression with breast cancer recurrence rates, immune cell infiltration, and drug response. RESULTS: The C > T mutation frequency was highest in the Herceptin-insensitive (HI) and verification groups, codenamed YI, contrasting with the Herceptin-sensitive (HE) group. No microsatellite instability (MSI)-H patients were in the HE group, but both HI and YI groups had 1 each. Significant differences in transition-transversion (TiTv) were observed in the HI and YI groups rather than the HE group. In the TKI- insensitive (TI) group, C > T mutations were highest, differing from the TKI-sensitive (TE) group. TE group included 2 MSI-H patients. Significant differences in TiTv were found in the TI group rather than the TE group. Mutated APOB may resist Herceptin and TKI, increasing immune infiltration. We identified potential drugs targeting it. CONCLUSIONS: Our study suggested that a higher percentage of C > T mutations, significant differences in TiTv, and MSI-H status may indicate Herceptin resistance, while a higher percentage of C > T mutations, significant differences in TiTv, and the absence of MSI-H may indicate TKI resistance in breast cancer patients. For patients resistant to both Herceptin and TKI, mutated APOB may play a crucial role in resistance.

Case Report: Genetic and immune microenvironmental characteristics of a rectal cancer patient with MSS/PD-L1-negative recurrent hepatopulmonary metastasis who achieved complete remission after treatment with PD-1 inhibitor.

Currently, microsatellite high instability (MSI-H)/mismatch repair protein deletion (dMMR) has become a crucial biomarker for utilizing immune checkpoint inhibitors in patients with advanced colorectal cancer (mCRC). However, the proportion of MSI-H/dMMR in advanced patients is only about 5% and mCRC patients with microsatellite stability (MSS)/proficient mismatch repair (pMMR) exhibit poor responses to immunotherapy. Although diverse immune combination therapy regimens have been examined in patients with advanced colorectal cancer who demonstrate MSS/pMMR, these approaches have not yielded favorable efficacy and only a limited proportion of patients have benefited, especially for advanced colorectal cancer patients with liver metastases. Therefore, the mechanism of benefit and potential biomarkers of immunotherapy in patients with MSS/pMMR mCRC deserve more in-depth exploration. Here, we present a case study of a rectal cancer patient with MSS and PD-L1-negative recurrent hepatopulmonary metastases who attained complete remission (CR) and sustained benefits with immunotherapy after systemic therapy had failed. The analysis of the patient's genetic and immune microenvironmental characteristics revealed that mutations in DNA damage repair (DDR) pathway genes and the existence of abundant tumor-infiltrating lymphocytes could contribute to his potential benefit.

Corrigendum: Correlation analysis of MRD positivity in patients with completely resected stage I-IIIA non-small cell lung cancer: a cohort study.

[This corrects the article DOI: 10.3389/fonc.2023.1222716.].

Correlation analysis of MRD positivity in patients with completely resected stage I-IIIA non-small cell lung cancer: a cohort study.

Background: The primary objective of this study is to thoroughly investigate the intricate correlation between postoperative molecular residual disease (MRD) status in individuals diagnosed with stage I-IIIA non-small cell lung cancer (NSCLC) and clinicopathological features, gene mutations, the tumour immune microenvironment and treatment effects. Methods: The retrospective collection and analysis were carried out on the clinical data of ninety individuals diagnosed with stage I-IIIA NSCLC who underwent radical resection of lung cancer at our medical facility between January 2021 and March 2022. The comprehensive investigation encompassed an evaluation of multiple aspects including the MRD status, demographic information, clinicopathological characteristics, results from genetic testing, the tumor immune microenvironment, and treatment effects. Results: No significant associations were observed between postoperative MRD status and variables such as gender, age, smoking history, pathological type, and gene mutations. However, a statistically significant correlation was found between MRD positivity and T (tumor diameter > 3 cm) as well as N (lymph node metastasis) stages (p values of 0.004 and 0.003, respectively). It was observed that higher proportions of micropapillary and solid pathological subtypes within lung adenocarcinoma were associated with increased rates of MRD-positivity after surgery (p = 0.007;0.005). MRD positivity demonstrated a correlation with the presence of vascular invasion (p = 0.0002). For the expression of programmed cell death ligand 1 (PD-L1), tumour positive score (TPS) ≥ 1% and combined positive score (CPS) ≥ 5 were correlated with postoperative MRD status (p value distribution was 0.0391 and 0.0153). In terms of ctDNA elimination, among patients identified as having postoperative MRD and lacking gene mutations, postoperative adjuvant targeted therapy demonstrated superiority over chemotherapy (p = 0.027). Conclusion: Postoperative ctDNA-MRD status in NSCLC patients exhibits correlations with the size of the primary tumor, lymph node metastasis, pathological subtype of lung adenocarcinoma, presence of vascular invasion, as well as TPS and CPS values for PD-L1 expression; in postoperative patients with MRD, the effectiveness of adjuvant EGFR-TKI targeted therapy exceeds that of chemotherapy, as evidenced by the elimination of ctDNA.

TP53 or CDKN2A/B covariation in ALK/RET/ROS1-rearranged NSCLC is associated with a high TMB, tumor immunosuppressive microenvironment and poor prognosis.

INTRODUCTION: ALK-rearranged lung adenocarcinomas with TP53 mutations have more unstable genomic features, poorer ALK-TKI efficacy and a worse prognosis than ALK-rearranged lung adenocarcinomas with wild-type TP53. Here, we examine the gene variations that co-occur with ALK/RET/ROS1 rearrangements in NSCLC and the corresponding tumor immune microenvironment, as well as their association with prognosis. METHODS: A total of 155 patients with ALK/RET/ROS1 fusions were included retrospectively. Tumor genome mutation analysis was performed by next-generation sequencing. PD-L1 expression and tumor-infiltrating lymphocytes were assessed by multiplex immunohistochemistry. The correlations among gene covariation, the tumor immune microenvironment, and clinicopathological characteristics were analyzed. RESULTS: Among the 155 patients, concomitant TP53 mutation appeared most frequently (31%), followed by CDKN2A/B copy number loss (15%). The ALK/RET/ROS1 fusion and TP53 or CDKN2A/B covariation group had more males and patients with stage IV disease (p < 0.001, p = 0.0066). Patients with TP53 or CDKN2A/B co-occurrence had higher tumor mutation burdens and more neoantigens (p < 0.001, p = 0.0032). PD-L1 expression was higher in the tumor areas of the TP53 or CDKN2A/B co-occurring group (p = 0.00038). However, the levels of CD8+, CD8+PD1-, and CD8+PD-L1- TILs were lower in the tumor areas of this group (p = 0.043, p = 0.029, p = 0.025). In the TCGA NSCLC cohorts, the top 2 mutated genes were CDKN2A/B (24%) and TP53 (16%). The TP53 or CDKN2A/B co-occurring group had higher tumor mutation burdens and shorter OS (p < 0.001, p < 0.001). CONCLUSIONS: Patients with co-occurring TP53/CDKN2A/B variations and ALK/RET/ROS1 rearrangements are associated with high TMB, more neoantigens, an immunosuppressive microenvironment and a worse prognosis.