Analysis of the Genomic Landscape in ALK+ NSCLC Patients Identifies Novel Aberrations Associated with Clinical Outcomes

Abstract

Rearrangements in the anaplastic lymphoma kinase (ALK) gene are found in approximately 5% of non-small cell lung carcinoma (NSCLC). Here, we present a comprehensive genomic landscape of 11 patients with ALKþ NSCLC and investigate its relationship with response to crizotinib. Using wholeexome sequencing and RNAseq data, we identified four rare ALK fusion partners (HIP1, GCC2, ERC1, and SLC16A7) and one novel partner (CEP55). At the mutation level, TP53 was the most frequently mutated gene and was only observed in patients with the shortest progression-free survival (PFS). Of note, only 4% of the genes carrying mutations are present in more than 1 patient. Analysis of somatic copy number aberrations (SCNA) demonstrated that a gain in EML4 was associated with longer PFS, and a loss of ALK or gain in EGFR was associated with shorter PFS. This study is the first to report a comprehensive view of the ALKþ NSCLC copy number landscape and to identify SCNA regions associated with clinical outcome. Our data show the presence of TP53 mutation as a strong prognostic indication of poor clinical response in ALKþ NSCLC. Furthermore, new and rare ALK fusion partners were observed in this cohort, expanding our knowledge in ALKþ NSCLC.

Proteomic analysis of lung cancer cells reveals a critical role of BCAT1 in cancer cell metastasis

“…Biology pathways of proteins listed in Figure 2 C are shown in Figure 2 D and S2D. We also examined the expression of BCAT1 from publicly available datasets 5 , 32 , 33 and found that BCAT1 was expressed at higher levels (but not statistically significant presumably due to small sample size) in metastatic tissues compared to primary tissues in both proteomic and transcriptomic data ( Figure S3 A). To gain additional insights on the potential role of BCAT1 dysregulation in lung cancer, we utilized TCGA data and performed Kaplan-Meier survival analysis based on mRNA expression of BCAT1.…”

Longitudinal therapy monitoring of ALK-positive lung cancer by combined copy number and targeted mutation profiling of cell-free DNA

“…Moreover, t-MAD scores correlate with established molecular features of higher risk, i.e. with the presence of TP53 mutations and the EML4-ALK variant 3, which themselves portend worse survival, both in carefully controlled retrospective [ 5 , [54] , [55] , [56] ] and prospective trials [57] . While the EML4-ALK variant does not change during the disease, TP53 mutations do emerge under treatment, and their appearance is a marker of increased risk [6] .…”

Discovery of a putative blood-based protein signature associated with response to ALK tyrosine kinase inhibition

“…Twenty-four ALK fusion positive NSCLC patients were enrolled and administered crizotinib, with the aim of identifying prognostic proteomic and genomic biomarkers of response to crizotinib [19]. This study showed that there are likely multiple prognostic genomic biomarkers besides ALK mutations, that could be reflected in proteins other than ALK fusion-related protein products.…”