NOTCH2NLA gene amplification is associated with poor prognosis in breast cancer

Recently, a high-frequency gain of the human-specific NOTCH2NL gene was found in anaplastic thyroid cancer, yet its amplification status in other cancers is still unknown. In our study, we discovered that NOTCH2NLA, a paralog of the NOTCH2NL gene, exhibited a recurrent genetic alteration (101/1071) in breast cancer (BRCA), with amplification being the primary alteration type (100/1071). Furthermore, BRCA patients with NOTCH2NLA amplification had a significantly worse prognosis in terms of disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). Weight correlation network analysis (WGCNA) showed that PRCC and VPS72 genes were the hub genes in co-expression network of NOTCH2NLA amplification in the BRCA cohort. Moreover, Gene Set Enrichment Analysis (GSEA) indicated that NOTCH2NLA amplification was involved in the regulation of multiple signaling pathways such as cell cycle, ribosome biogenesis, and the Notch signaling pathway. Finally, we found that cell cycle inhibitors such as Flavopirdol, AT-7519, and PHA-793,887 were more sensitive for cells with NOTCH2NLA amplification, whereas MEK inhibitors were just on the contrary. In vitro experiments demonstrated that overexpression of NOTCH2NLA in breast cancer cells promoted cell growth and enhanced sensitivity to AT-7519 treatment. Collectively, our findings suggest that NOTCH2NLA amplification may be a new prognostic marker of BRCA and cell cycle inhibitors were more suitable for therapy on BRCA patients with NOTCH2NLA amplification.