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This article explores the role of Polo-like kinase 1 (PLK1) in tumorigenesis, specifically in colorectal cancer (CRC) and lung cancer. The study analyzes the mutational landscape of PLK1 and concomitant mutations in these cancers. The findings suggest that PLK1 may have tumor-suppressor features and caution should be exercised when using PLK1 inhibitors. The study also identifies different mutation subtypes of PLK1 and their associations with other genetic abnormalities in CRC. However, the study has limitations, such as missing information on cancer stage and treatment data, and further research is needed to validate the findings. [Extracted from the article]

Background: Large fragment deletion (LFD) of EGFR was associated with carcinogenesis in many types of cancers. However, the molecular features of EGFR‐LFD have not been studied in the Asian cancer population. Method: Here we retrospectively analyzed the targeted sequencing data from a large cancer database. Results: EGFR‐LFD was detected at a frequency of 0.03% with EGFRvIII being the most frequently observed LFD. TERTp variants were identified in 60% of the cases. TP53 alterations (33%) were mutually exclusive with TERTp variants and coexisted with EGFR‐LFD in lung cancer and colorectal cancer. EGFR amplification (67%) and chromosome 10p deletion (53%) were the most focal‐level and arm‐level CNV in this cohort. EGFR exon2–17 skipping was found in the tumor tissue of one patient after progressing on osimertinib. Conclusion: Our study provided valuable insights into the distribution and molecular characteristics of EGFR‐LFD, hoping to shed light on the treatment management for EGFR‐LFD carriers. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate age‐dependent tendency of genomic alterations in lung cancer, and also to examine mutational profiles and its association with clinical treatment outcomes in young adenocarcinoma patients. By studying 7858 lung cancer samples using targeted‐gene sequencing, we investigated genomic differences and clinical on‐treatment time (OTT) to different therapies between young (≤ 45 years) and old (> 45 years) patients. The age‐dependent trend test for genomic alterations in all patients revealed steady increases in tumor mutation burden and alterations in a number of genes with age, including KRAS, MET, CDKN2A, PIK3CA and MDM2, while the frequencies of ALK, ROS1 and RET fusions and ERBB2 mutations were decreasing. The highest rate of EGFR alterations was observed in the 45 ~ 50 years age group. Comparisons of young and old adenocarcinoma patients found that young patients were characterized by a higher prevalence of ALK, ROS1 and RET fusions, and ERBB2 exon‐20 insertions and EGFR exon‐19 deletions. Actionable mutations were highly prevalent in young adenocarcinoma patients, with 88% of patients harboring at least one actionable genetic alteration. First‐line therapies in EGFR‐positive patients (n = 979) by EGFR tyrosine kinase inhibitors or chemotherapy resulted in similar OTT between young and old patients. Somatic interaction analyses implied that young EGFR‐positive patients were more likely to also have PIK3CA, MET, TP53 and RB1 mutations than old patients. Lung cancer in young patients, and especially those with adenocarcinoma, exhibited different clinical features and genomic attributes compared to old patients, which should be considered for therapeutic decision‐making purposes. What's new? Young patients with lung cancer represent a sub‐group with distinct clinical features compared to older patients. This large retrospective cohort study with a targeted sequencing panel covering over 400 cancer‐related genes suggests that young adenocarcinoma patients (≤45 years) have a different spectrum of driver mutations and a higher ratio of actionable genetic alterations compared to older patients. Over a third of young patients have multiple drivers, and the co‐mutation rate of EGFR with other oncogenes is high. These findings highlight genetic differences between young and older patients that possibly associate with different treatment outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Pulmonary embolism (PE) is a potentially fatal complication and its morbidity together with fatalness will further increase when in patients with malignant tumors. Fast and accurate early diagnosis of PE thus seems considerably important. Objective: To explore the risk factors of lung cancer complicated with PE. Materials and Methods: A retrospective cohort study consisted of 40 lung cancer patients with PE (PE group) and 60 lung cancer patients without PE (non‐PE group) were analyzed. Results: The white blood cell (WBC) count, D‐dimer and low‐density lipoprotein (LDL) were higher in PE group than those in non‐PE group (P < 0.05), whereas the arterial partial pressure of oxygen (PaO2) in PE group was lower than that in non‐PE group (P < 0.05). Carcinoembryonic antigen (CEA) level between two groups also exhibited statistical difference (P < 0.05). Those lung adenocarcinoma patients with stages III and IV tumor, coupled with deep venous thrombosis (DVT), having experienced bevacizumab treatment or platinum‐based chemotherapy more likely suffered from PE (P < 0.05). The multivariate analysis revealed that high D‐dimer, chemotherapy, DVT, stages III to IV, adenocarcinoma were independent risk factors associated with PE (P < 0.05). The overall survival time of patients in case group was significantly shorter than that in the control group with a median survival duration being 10.5 months (95%CI, 8.95‐12.05) and 16.8 months (95%CI, 14.62‐18.98), respectively, (P < 0.01). Conclusions: High D‐dimer, chemotherapy, DVT, stages III to IV and adenocarcinoma might have a positive correlation with PE, meanwhile, PE always predicted a poor prognosis in lung cancer patients. [ABSTRACT FROM AUTHOR]

EGFR exon 20 insertions (EGFR e20ins) account for up to 10% of EGFR mutations in lung cancer; however, tumors with EGFR e20ins had poor response rates to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib, afatinib, and osimertinib, and the heterogeneity of EGFR e20ins further complicates the clinical studies. Here, we retrospectively screened next‐generation sequencing (NGS) data from 24 468 lung cancer patients, and a total of 85 unique EGFR e20ins variants were identified in 547 cases (2.24%), with p.A767_V769dup (25.1%) and p.S768_D770dup (17.6%) being the most prevalent ones. Comprehensive genomic profiling revealed that TP53 mutations frequently coexisted with p.H773dup (77.8%, P = 0.0558) and p.A767_V769dup (62.8%, P = 0.0325), while RB1 mutations usually co‐occurred with p.H773_V774insAH (33.3%, P = 0.0551), implying that different EGFR e20ins variants might require distinct genomic context for tumorigenesis and/or maintenance. Despite that treatment regimens were highly diverse for EGFR e20ins‐positive patients, we observed an overall response rate of 14% and a disease control rate (DCR) of 38.4% in 65 patients who received at least one EGFR TKI. The progression‐free survival (PFS) differs significantly in six representative EGFR e20ins variants (P = 0.017), and EGFR p.A763_Y764insFQEA was associated with better PFS than other EGFR e20ins when treating with various EGFR TKIs. Some EGFR e20ins variants showed at least partial response to first‐generation EGFR TKIs, including p.A767_V769dup, p.S768_D770dup, p.N771_H773dup, p.A763_Y764insFQEA, and p.D770_N771insG. Poziotinib achieved higher DCR for p.S768_D770dup than for p.A767_V769dup, whereas osimertinib showed limited effects for these two insertions when used as the first‐line treatment. Overall, our results demonstrated that EGFR e20ins were highly diversified in terms of insertion patterns and co‐occurring mutations and these EGFR e20ins variants showed different clinical responses to various EGFR TKIs, suggesting the clinical importance of selecting proper EGFR TKI treatment based on the specific EGFR e20ins type. [ABSTRACT FROM AUTHOR]

Background: Patients with brain metastases (BMs) have a poor prognosis and limited therapeutic options. Lung cancer is the most common primary malignancy giving rise to BMs; thus, understanding the molecular mechanisms behind increased BM risk is essential for identifying therapeutic targets and developing effective interventions.Methods: Sixty-one patients who underwent surgical resection of primary non-small cell lung cancer (NSCLC) and BMs were retrospectively studied. Comprehensive genomic profiling of primary NSCLC and matched BMs was performed with next-generation sequencing targeting 416 cancer-relevant genes.Results: Mutations of major drivers, including EGFR, KRAS, TP53, and ALK, were highly concordant between primary NSCLC and matched BMs (>80%), whereas discordance suggested the unique genomic evolution and oncogenic mechanisms of NSCLC BMs. BMs also demonstrated higher levels of copy number variations in comparison with primary NSCLC. Furthermore, the alterations of genes encoding CDK4/CCND1, CDKN2A/2B, and PI3K signaling pathways were enriched in BMs, and this suggested their correlation with increased metastatic risk. Indeed, patients with activated PI3K signaling in their primary NSCLC had significantly shorter BM-free survival (hazard ratio, 8.49; P = .0005). In addition, mutated TP53 or an activated WNT pathway via CTNNB1, APC, and AXIN2 mutations trended toward shorter BM-free intervals but not significantly so.Conclusions: These findings yield detailed insights into the genomic complexity and heterogeneity of primary NSCLC and matched BMs. This study highlights the significant correlation of PI3K signaling with increased metastatic risk in patients with NSCLC and identifies genomic alterations enriched in NSCLC BMs that could serve as prognostic markers and potential therapeutic targets for treating patients with NSCLC BMs. [ABSTRACT FROM AUTHOR]

Background: ALK‐tyrosine kinase inhibitors (TKIs) have been proven effective for treating ALK‐positive non‐small cell lung cancer (NSCLC), although patients present with variable responses and disease progression courses. The detailed underlying molecular mechanisms require further investigation to yield a better prognosis. Methods: Targeted next‐generation sequencing (NGS) mutation profiling was performed on samples from 42 NSCLC patients confirmed positive for ALK rearrangements by fluorescence in situ hybridization or immunohistochemistry who experienced disease progression after crizotinib treatment. Results: ALK rearrangements were not confirmed in six patients (14%) with other potential oncogenic drivers identified by NGS, who therefore did not respond to crizotinib and had significantly shorter overall survival (OS) compared to NGS ALK ‐positive patients. Fifteen ALK activating mutations were detected in 8 out of 26 post‐treatment samples (31%), among which ALK L1196M and G1269A were the most common acquired mutations detected in half of the patients with ALK activating mutations. Dynamic monitoring of the genetic evolution in one patient revealed both spatial and temporal heterogeneity of resistant mechanisms during different ALK‐TKI treatment courses. Activation of ALK downstream or bypass pathways was detected in patients without ALK activating mutations, such as genetic alterations in PIK3CA, MET, and KRAS. Interestingly, we identified two patients with acquired mutations in the DNA mismatch repair gene POLE, which resulted in a dramatically increased tumor mutation burden, and might contribute to the poor response to crizotinib. Conclusions: Heterogeneous resistant mechanisms have been identified and correlate to diverse responses to crizotinib. Comprehensive and dynamic mutation profiling is required to better predict clinical outcomes. [ABSTRACT FROM AUTHOR]