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Background: About half of adults with acute myeloid leukemia with normal cytogenetics (CN-AML) have NPM1 mutations. There is controversy regarding their prognosis and best therapy. Methods: We studied 150 subjects with these features using targeted regional sequencing. Prognostic stratification was carried out based on risk factors, and we assessed the effects of two post-remission strategies with and without transplant across risk cohorts. Results: In multi-variable analyses, a positive MRD test after the second consolidation cycle (HR = 6.00; 95% CI [3.31, 10.85]; p < 0.001), DNMT3A mutations (HR = 3.01 [1.57, 5.78]; p < 0.001), FLT3-ITD mutation with high variant allele frequency (HR = 4.40 [1.89, 10.24]; p < 0.001) and DDX11 mutations (HR = 4.38 [2.38, 8.04]; p < 0.001) were independently correlated with higher cumulative incidence of relapse (CIR) and worse leukemia-free survival (LFS) (HR = 5.49 [3.01, 10.04]; p < 0.001; HR = 2.99 [1.60, 5.62]; p < 0.001; HR = 4.20 [1.87, 9.40]; p < 0.001; and HR = 4.22, 95% CI [1.99, 8.95], p < 0.001). Subjects with ≥1 high-risk co-variate who received a transplant had a lower CIR and better LFS, whereas others did not. Conclusions: We identified co-variates associated with CIR and LFS in subjects of NPM1-mutated CN-AML. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is a rare but aggressive malignancy. Despite previous reports, molecular characterization of this disease is not well understood, and little is known regarding OS in Chinese patients. Herein, we analyzed the genomic signatures of 73 Chinese OS cases. TP53, NCOR1, LRP1B, ATRX, RB1, and TFE3 were the most frequently mutated gene in our OS cohort. In addition, the genomic analysis of Western OS patients was performed. Notably, there were remarkable disparities in mutational landscape, base substitution pattern, and tumor mutational burden between the Chinese and Western OS cohorts. Specific molecular mechanisms, including DNA damage repair (DDR) gene mutations, copy number variation (CNV) presence, aneuploidy, and intratumoral heterogeneity, were associated with disease progression. Additionally, 30.1% of OS patients carried clinically actionable alterations, which were mainly enriched in PI3K, MAPK, DDR, and RTK signaling pathways. A specific molecular subtype incorporating DDR alterations and CNVs was significantly correlated with distant metastasis‐free survival and event‐free survival, and this correlation was observed in all subgroups with different characteristics. These findings comprehensively elucidated the genomic profile and revealed novel prognostic factors in OS, which would contribute to understanding this disease and promoting precision medicine of this population. [ABSTRACT FROM AUTHOR]

Objective G1 and G2 colorectal neuroendocrine neoplasms (NENs) are a group of rare and indolent diseases. We aimed to delineate their genetic characteristics and explore their metastatic mechanisms. Methods We used next-generation sequencing technology for targeted sequencing for 54 patients with G1 and G2 colorectal NENs. We delineated their genetic features and compared the genetic characteristics between metastatic NENs and nonmetastatic NENs. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was utilized to explore their abnormal pathways and study their potential metastatic mechanisms. Results We collected 23 metastatic NENs and 31 nonmetastatic NENs. In the whole cohort, the common mutated genes were NCOR2, BRD4, MDC1, ARID1A, AXIN2, etc. The common copy number variations (CNVs) included amplification of HIST1H3D, amplification of HIST1H3E, and loss of PTEN. The KEGG enrichment analysis revealed that PI3K-Akt, MAPK, and Rap1 were the major abnormal pathways. There were significantly different genetic features between metastatic NENs and nonmetastatic NENs. The metastatic NENs shared only 47 (22.5%) mutated genes and 6 (13.3%) CNVs with nonmetastatic NENs. NCOR2, BRD4, CDKN1B, CYP3A5, and EIF1AX were the commonly mutated genes in metastatic NENs, while NCOR2, MDC1, AXIN2, PIK3C2G, and PTPRT were the commonly mutated genes in nonmetastatic NENs. Metastatic NENs presented a significantly higher proportion of abnormal pathways of cell senescence (56.5% vs 25.8%, P =.022) and lysine degradation (43.5% vs 16.1%, P =.027) than nonmetastatic NENs. Conclusion G1 and G2 colorectal NENs are a group of heterogeneous diseases that might obtain an increased invasive ability through aberrant cell senescence and lysine degradation pathways. [ABSTRACT FROM AUTHOR]

(C and D) PFS and OS of patients with increased mean ctDNA VAF versus patients with no increased mean ctDNA VAF based on pre- and post-treatment ctDNA change, respectively. Twenty-seven patients had pre- and post-treatment plasma-derived ctDNA, and paired baseline BM DNA NGS assessments were included for both concordance analysis and dynamic ctDNA analysis. Three patients with only pre- and post-treatment ctDNA assessments and one patient with only post-treatment ctDNA assessments were used for dynamic ctDNA analysis (Figure 1). [Extracted from the article]

Background: TP53 mutations are frequent in non‐small cell lung cancer (NSCLC). Different categories of TP53 mutations may be associated with survival in advanced NSCLC, but their effect on prognosis is diverse. To date, a comprehensive comparison of the relationship between different classes of TP53 alterations and survival in advanced NSCLC has rarely been performed. Moreover, the prognostic significance of a novel approach called the evolutionary action of TP53 (EAp53) in advanced NSCLC is unclear. Methods: A total of 210 patients with NSCLC harboring TP53 mutation data were enrolled. Genomic and clinical data for the Memorial Sloan Kettering Cancer Center (MSKCC) cohort with advanced NSCLC were obtained from cBioPortal. Relationship between clinical characteristics and TP53 mutations was performed by Fisher's exact test or χ2 test. Overall survival (OS) analysis was evaluated using Kaplan–Meier method and Cox proportional hazards regression model. Results: TP53 mutations were identified in 51.4% of NSCLC patients and were mainly located in exons 5, 7, and 8. The distribution patterns of missense and truncating mutations of TP53 were remarkably different. Among patients with advanced NSCLC who never received immune checkpoint inhibitor treatments, EAp53 high‐risk mutations were significantly associated with poor OS in both our cohort and the MSKCC cohort. Moreover, marked differences were observed in the mutational landscape between patients with EAp53 high‐risk mutations (HR group) and other patients (OT group). The HR group displayed higher mutation frequencies in the RTK, cell cycle, and DNA damage repair (DDR) pathways than the OT group. In addition, the tumor mutation burden in the HR group was significantly higher than that in the OT group. Conclusions: This study provided important insights into the molecular‐clinical profile of TP53‐mutated NSCLC patients. Moreover, the data revealed that EAp53 high‐risk mutations were an independent prognostic factor for worse OS in advanced NSCLC. [ABSTRACT FROM AUTHOR]