Clinicopathologic Features and Response to Therapy of NRG1 Fusion–Driven Lung Cancers: The eNRGy1 Global Multicenter Registry

PURPOSE Although NRG1 fusions are oncogenic drivers across multiple tumor types including lung cancers, these are difficult to study because of their rarity. The global eNRGy1 registry was thus established to characterize NRG1 fusion–positive lung cancers in the largest and most diverse series to date. METHODS From June 2018 to February 2020, a consortium of 22 centers from nine countries in Europe, Asia, and the United States contributed data from patients with pathologically confirmed NRG1 fusion–positive lung cancers. Profiling included DNA-based and/or RNA-based next-generation sequencing and fluorescence in situ hybridization. Anonymized clinical, pathologic, molecular, and response (RECIST v1.1) data were centrally curated and analyzed. RESULTS Although the typified never smoking (57%), mucinous adenocarcinoma (57%), and nonmetastatic (71%) phenotype predominated in 110 patients with NRG1 fusion–positive lung cancer, further diversity, including in smoking history (43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated. RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel 5′ partners, 20 unique epidermal growth factor domain–inclusive chimeric events, and heterogeneous 5′/3′ breakpoints were found. Platinum-doublet and taxane-based (post–platinum-doublet) chemotherapy achieved low objective response rates (ORRs 13% and 14%, respectively) and modest progression-free survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low programmed death ligand-1 expressing (28%) and low tumor mutational burden (median: 0.9 mutations/megabase) immunophenotype, the activity of chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3 months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of 25%, not contingent on fusion type, and a 2.8-month median PFS. CONCLUSION NRG1 fusion–positive lung cancers were molecularly, pathologically, and clinically more heterogeneous than previously recognized. The activity of cytotoxic, immune, and targeted therapies was disappointing. Further research examining NRG1-rearranged tumor biology is needed to develop new therapeutic strategies.

Fibroblast Growth Factor—14 Acts as Tumor Suppressor in Lung Adenocarcinomas

Investigation of the molecular dynamics in lung cancer is crucial for the development of new treatment strategies. Fibroblast growth factor (FGF) 14 belongs to the FGF family, which might play a crucial role in cancer progression. We analyzed lung adenocarcinoma (LUAC) patients samples and found that FGF14 was downregulated, correlating with reduced survival and oncogenic mutation status. FGF14 overexpression in lung cancer cell lines resulted in decreased proliferation, colony formation, and migration, as well as increased expression of epithelial markers and a decreased expression of mesenchymal markers, indicating a mesenchymal to epithelial transition in vitro. We verified these findings using small interfering RNA against FGF14 and further confirmed the suppressive effect of FGF14 in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ immunodeficient xenograft tumor model. Moreover, FGF14 overexpressing tumor cell RNA sequencing data suggests that genes affected by FGF14 were related to the extracellular matrix, playing a role in proliferation and migration. Notably, newly identified FGF14 target genes, adenosine deaminase RNA specific B1 (ADARB1), collagen and calcium-binding epidermal growth factor domain-containing protein 1 (CCBE1), α1 chain of collagen XI (COL11A1), and mucin 16 (MUC16) expression was negatively correlated with overall survival when FGF14 was downregulated in LUAC. These findings led us to suggest that FGF14 regulates proliferation and migration in LUAC.

ADAM12 is A Potential Therapeutic Target Regulated by Hypomethylation in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and currently lacks any effective targeted therapy. Since epigenetic alterations are a common event in TNBC, DNA methylation profiling can be useful for identifying potential biomarkers and therapeutic targets. Here, genome-wide DNA methylation from eight TNBC and six non-neoplastic tissues was analysed using Illumina Human Methylation 450K BeadChip. Results were validated by pyrosequencing in an independent cohort of 50 TNBC and 24 non-neoplastic samples, where protein expression was also assessed by immunohistochemistry. The functional role of disintegrin and metalloproteinase domain-containing protein 12(ADAM12) in TNBC cell proliferation, migration and drug response was analysed by gene expression silencing with short hairpin RNA. Three genes (Von Willenbrand factor C and Epidermal Growth Factor domain-containing protein (VWCE), tetraspanin-9 (TSPAN9) and ADAM12) were found to be exclusively hypomethylated in TNBC. Furthermore, ADAM12 hypomethylation was associated with a worse outcome in TNBC tissues and was also found in adjacent-to-tumour tissue and, preliminarily, in plasma from TNBC patients. In addition, ADAM12 silencing decreased TNBC cell proliferation and migration and improved doxorubicin sensitivity in TNBC cells. Our results indicate that ADAM12 is a potential therapeutic target and its hypomethylation could be a poor outcome biomarker in TNBC.

Validity of Signal Peptide-CUB-EGF Domain-containing Protein-1 (SCUBE-1) in the Diagnosis of Aortic Dissection

Introduction: Diagnosing aortic dissection (AD) in emergency services still represents a challenging issue as it may manifest not only well-known clinical findings such as sudden onset and severe chest pain but also atypical findings similar to ST elevation myocardial infarction or renal colic. Contrast-enhanced imaging investigations, which are expensive and risky due to possible complications, are necessary for diagnosis. Ultrasonography is not always reliable, which necessitates noninvasive diagnostic tests to support a clinical suspicion. Signal peptide-CUB (complement C1r/C1s, Uegf, and Bmp1)-EGF (epidermal growth factor) domain-containing protein 1 (SCUBE-1) is a cell surface protein produced during embryogenesis. This study was conducted to compare the levels of this novel biomarker between patients with AD and healthy volunteers. Methods: This prospective study was conducted on 20 patients diagnosed with AD using contrast-enhanced thoracoabdominal computed tomography angiography. Average age-matched 20 healthy subjects as a control group were included as a reference for biochemical parameters. Results: The mean SCUBE-1 levels were significantly higher in patients with AD [24.51 ( ± 3.01) ng/dL] than in the control group [12.11 ( ± 5.31) ng/dL] (p < 0.001). Receiver-operating characteristic (ROC) curve was plotted to analyze the specificity and sensitivity of AD diagnosis (with 95% confidence intervals), which revealed 95% sensitivity and 76% specificity when the SCUBE-1 level was >19.75 ng/dL.A significant correlation was also observed between dissection types and mortality, as well as extravasation state. Conclusions: This preliminary study demonstrated that plasma SCUBE-1 level is a better and specific biomarker for AD and may be used for diagnosing AD in emergency services. Wider case series and further clinical studies are required to confirm these findings.

The Inhibitory Effect of (−)-Epigallocatechin-3-Gallate on Breast Cancer Progression via Reducing SCUBE2 Methylation and DNMT Activity

Epigenetic modifications are important mechanisms responsible for cancer progression. Accumulating data suggest that (−)-epigallocatechin-3-gallate (EGCG), the most abundant catechin of green tea, may hamper carcinogenesis by targeting epigenetic alterations. We found that signal peptide-CUB (complement protein C1r/C1s, Uegf, and Bmp1)-EGF (epidermal growth factor) domain-containing protein 2 (SCUBE2), a tumor suppressor gene, was hypermethylated in breast tumors. However, it is unknown whether EGCG regulates SCUBE2 methylation, and the mechanisms remain undefined. This study was designed to investigate the effect of EGCG on SCUBE2 methylation in breast cancer cells. We reveal that EGCG possesses a significantly inhibitory effect on cell viability in a dose- and time-dependent manner and presents more effects than other catechins. EGCG treatment resulted in enhancement of the SCUBE2 gene, along with elevated E-cadherin and decreased vimentin expression, leading to significant suppression of cell migration and invasion. The inhibitory effect of EGCG on SCUBE2 knock-down cells was remarkably alleviated. Further study demonstrated that EGCG significantly decreased the SCUBE2 methylation status by reducing DNA methyltransferase (DNMT) expression and activity. In summary, this study reported for the first time that SCUBE2 methylation can be reversed by EGCG treatment, finally resulting in the inhibition of breast cancer progression. These results suggest the epigenetic role of EGCG and its potential implication in breast cancer therapy.