Integration of whole‐genome sequencing and functional screening identifies a prognostic signature for lung metastasis in triple‐negative breast cancer

Abstract

Lung metastasis is one of the leading causes of death for triple‐negative breast cancer (TNBC). We sought to characterize the genetic alterations underlying TNBC lung metastases by integrating whole‐genome sequencing and functional screening. Furthermore, we aimed to develop a metastasis‐related gene signature for TNBC patients to improve risk stratification. In this prospective observational study, we first conducted whole‐genome sequencing of paired primary tumor and lung metastasis from one TNBC patient to identify potential genetic driver alterations. An in vivo gain‐of‐function screening using an amplified open reading frame library was then employed to screen candidate genes promoting lung metastasis. Finally, we applied Cox proportional hazard regression modeling to develop a prognostic gene signature from 14 candidate genes in TNBC. Compared to the primary tumor, copy number amplifications of chromosomes 3q and 8q were identified in the lung metastasis. We discovered an enrichment of 14 genes from chromosomes 3q and 8q in mouse lung metastases model. We further developed and validated a four‐gene signature (ENY2, KCNK9, TNFRSF11B and KCNMB2) that predicts recurrence‐free survival and lung metastasis in TNBC. Our data also demonstrated that upregulated expression of ENY2 could promote invasion and lung metastasis of TNBC cells both in vitro and in vivo. In conclusion, our study reveals functional genes with copy number amplifications among chromosome 3q and 8q in lung metastasis of TNBC. And we develop a functional gene signature that can effectively stratify patients into low‐ and high‐risk subgroups of recurrence, helping frame personalized treatments for TNBC.

Integrated multi-omics analysis identifies ENY2 as a predictor of recurrence and a regulator of telomere maintenance in hepatocellular carcinoma

“…Ultimately, we identified five genes including ENY2 , GPAA1 , NDUFA4L2 , NEDD9 , and NRP1 as the variables in the multivariate Cox model. Notably, ENY2 was identified as a prognostic signature for lung metastasis in triple-negative breast cancer ( 24 ). Moreover, ENY2, one of the mRNA transcription and export complex subunits, was also observed to have a higher frequency of copy number alterations (CNAs) and a higher mRNA expression level in ovarian cancer ( 25 ), indicating that ENY2 might act as a cancer driver gene.…”

Clinicopathological characteristics and survival outcomes in patients with synchronous lung metastases upon initial metastatic breast cancer diagnosis in Han population

“…A single mutation on microrchidia family CW-type zinc finger 2 (MORC2) promoted TNBC lung metastasis by regulating heterogeneous nuclear ribonucleoprotein M (hnRNPM)- mediated CD44 splicing, which indicated that the knockdown of hnRNPM might reduce lung metastatic potential of TNBC cells with mutant MORC2 [ 20 ]. Another research revealed that the overexpression of transcription and export complex 2 subunit (ENY2) could promote TNBC progression and lung metastasis both in vitro and in vivo [ 21 ]. Further mechanisms clarifying TNBC lung metastasis are certainly worth exploring, which may provide potential targets for new drugs.…”

Multi-Omics Profiling Suggesting Intratumoral Mast Cells as Predictive Index of Breast Cancer Lung Metastasis

“…Tumor mutation burden is largely attributed to genomic instability. Genomic instability generates tumor heterogeneity, from which aggressive variants with strong metastatic ability can form secondary lesions ( 42 ). However, the association between mutations and neoantigen burdens of primary breast tumors and the outcomes of lung metastasis remains unknown.…”