Classification of multiple primary lung cancer in patients with multifocal lung cancer: assessment of a machine learning approach using multidimensional genomic data.

Background: Multiple primary lung cancer (MPLC) is an increasingly well-known clinical phenomenon. However, its molecular characterizations are poorly understood, and still lacks of effective method to distinguish it from intrapulmonary metastasis (IM). Herein, we propose an identification model based on molecular multidimensional analysis in order to accurately optimize treatment. Methods: A total of 112 Chinese lung cancers harboring at least two tumors (n = 270) were enrolled. We retrospectively selected 74 patients with 121 tumor pairs and randomly divided the tumor pairs into a training cohort and a test cohort in a 7:3 ratio. A novel model was established in training cohort, optimized for MPLC identification using comprehensive genomic profiling analyzed by a broad panel with 808 cancer-related genes, and evaluated in the test cohort and a prospective validation cohort of 38 patients with 112 tumors. Results: We found differences in molecular characterizations between the two diseases and rigorously selected the characterizations to build an identification model. We evaluated the performance of the classifier using the test cohort data and observed an 89.5% percent agreement (PA) for MPLC and a 100.0% percent agreement for IM. The model showed an excellent area under the curve (AUC) of 0.947 and a 91.3% overall accuracy. Similarly, the assay achieved a considerable performance in the independent validation set with an AUC of 0.938 and an MPLC predictive value of 100%. More importantly, the MPLC predictive value of the classification achieved 100% in both the test set and validation cohort. Compared to our previous mutation-based method, the classifier showed better κ consistencies with clinical classification among all 112 patients (0.84 vs. 0.65, p <.01). Conclusion: These data provide novel evidence of MPLC-specific genomic characteristics and demonstrate that our one-step molecular classifier can accurately classify multifocal lung tumors as MPLC or IM, which suggested that broad panel NGS may be a useful tool for assisting with differential diagnoses.

circTADA2A inhibited SLC38A1 expression and suppresses melanoma progression through the prevention of CNBP trans-activation.

BACKGROUND: CircTADA2A has been demonstrated to play critical roles in the occurrence and development of human cancer. However, the expression pattern and biological mechanisms of circTADA2A in melanoma remains largely unknown. METHODS: CircTADA2A were detected by quantitative real-time RT-PCR (qRT-PCR) and validated by Sanger sequencing. Function of circTADA2A and its protein partner in melanoma cells was investigated using RNA interference and overexpression assays. Interaction of circTADA2A, CCHC-type zinc finger nucleic acid binding protein (CNBP) and solute carrier family 38 member 1 (SLC38A1) was confirmed by RNA immunoprecipitation, RNA pull-down, and dual-luciferase reporter assay. The expression of genes and proteins were detected by qRT-PCR and western blot assays. RESULTS: Data from the investigation showed that a novel circRNA (circTADA2A, hsa_circ_0043278) was markedly downregulated in melanoma cells. Functionally, circTADA2A repressed cell proliferation, migration, invasion in melanoma cells. Mechanistically, circTADA2A interacted with CNBP, acting to suppress the binding of CNBP to the SLC38A1 promoter and subsequently restrained SLC38A1 transcription, which resulting in repression of melanoma progression. CONCLUSIONS: CircTADA2A suppresses melanoma progression by regulating CNBP/SLC38A1 axis, indicating a potential therapeutic target in melanoma.

Case report: Targeted sequencing facilitates the diagnosis and management of rare multifocal pure ground-glass opacities with intrapulmonary metastasis.

Introduction: Treatments for multiple ground-glass opacities (GGOs) for which the detection rate is increasing are still controversial. Next-generation sequencing (NGS) may provide additional key evidence for differential diagnosis or optimal therapeutic schedules. Case presentation: We first reported a rare case in which more than 100 bilateral pulmonary GGOs (91.7% of the GGOs were pure GGOs) were diagnosed as both multiple primary lung cancer and intrapulmonary metastasis. We performed NGS with an 808-gene panel to assess both somatic and germline alterations in tissues and plasma. The patient (male) underwent three successive surgeries and received osimertinib adjuvant therapy due to signs of metastasis and multiple EGFR-mutated tumors. The patient had multiple pure GGOs, and eight tumors of four pathological subtypes were evaluated for the clonal relationship. Metastasis, including pure GGOs and atypical adenomatous hyperplasia, was found between two pairs of tumors. Circulating tumor DNA (ctDNA) monitoring of disease status may impact clinical decision-making. Conclusions: Surgery combined with targeted therapies remains a reasonable alternative strategy for treating patients with multifocal GGOs, and NGS is valuable for facilitating diagnostic workup and adjuvant therapy with targeted drugs through tissue and disease monitoring via ctDNA.