Analysis of Tumor Genomic Pathway Alterations Using Broad-Panel Next-Generation Sequencing in Surgically Resected Lung Adenocarcinoma

Abstract

Purpose: The majority of broad-panel tumor genomic profiling has used a gene-centric approach, although much of that data is unused in clinical decision making. We hypothesized that a pathway-centric approach using next-generation sequencing (NGS), combined with conventional clinicopathologic features, may better predict disease-free survival (DFS) in early stage lung adenocarcinoma.Experimental Design: Utilizing our prospectively maintained database, we analyzed 492 patients with primary, untreated, completely surgically resected lung adenocarcinoma. Ten canonical pathways were analyzed using broadpanel NGS. The correlations of DFS and number (and type) of pathway (NPA) were analyzed using the Kaplan-Meier method and log-rank test. Associations between altered pathways and clinicopathologic variables, as well as identification of actionable therapeutic strategies were explored.Results: Median NPA for the cohort was two (range, 0-5). Smoking status, solid morphologic appearance on preoperative CT, maximal standardized uptake value, pathologic tumor size, aggressive histologic subtype, lymphovascular invasion, visceral pleural invasion, and positive lymph nodes were significantly associated with NPA (P < 0.05). Of 543 actionable genetic alterations identified, 455 (84%) were within the RTK/RAS pathway. A total of 86 tumors had actionable therapeutic genomic alterations in >1 pathway. On multivariable analysis, higher NPA was significantly associated with worse DFS (HR, 1.31; P ¼ 0.014).Conclusions: NPA and specific pathway alterations are associated with clinicopathologic features in patients with surgically resected lung adenocarcinoma. Cell cycle, Hippo, TGFb, and p53 pathway alterations are associated with poor DFS. Finally, NPA is an independent risk factor for poor DFS in our cohort.See related commentary by Blakely, p. 7269

Identification of 4 immune cells and a 5-lncRNA risk signature with prognosis for early-stage lung adenocarcinoma

“…A study [ 34 ] showed that LINC00857 promoted the progression of LUAD, it regulated the cell proliferation, glycolysis and apoptosis of LUAD cells by targeting miR-1179/SPAG5 axis. Another study showed that LINC00857 regulated the progression of lung cancer through cell cycle regulation [ 35 ], there was also a study indicated that cell cycle, Hippo, TGFβ, and p53 pathway alterations were associated with poor disease-free survival (DFS) in early-stage LUAD [ 36 ], these results consistent with our results that cell cycle and p53 signaling pathway were the predicted pathways. LINC01116 was overexpressed in various tumors, such as osteosarcoma, nasopharyngeal carcinoma and some others [ 37 – 39 ], another study found that LINC01116 was overexpressed in LUAD tissues and cell lines and suggested that LINC01116 may act as an oncogene in LUAD [ 40 ].…”

Targeted Next-Generation Sequencing Analysis Predicts the Recurrence in Resected Lung Adenocarcinoma Harboring EGFR Mutations

“…This allows the generation of comprehensive genetic profiles in one assay, identifying multiple oncogenic alterations missed in previous conventional assays. Recent NGS studies have shown that EGFR mutations and co-mutations appear to influence the prognosis of advanced EGFR -mutated lung cancers [ 12 , 13 , 14 ]; however, there have been only a few targeted NGS analysis studies regarding the prognosis of resected early stage EGFR -mutated lung cancer that focused on recurrence [ 15 , 16 , 17 ].…”

Preoperative clinical and tumor genomic features associated with pathologic lymph node metastasis in clinical stage I and II lung adenocarcinoma

“…MSK-IMPACT sequencing was performed and analyzed as previously described 46 , 48 . TMB was defined as the fraction of nonsynonymous single-nucleotide or insertion/deletion mutations divided by the length of the coding region (in Mb) sequenced by each panel (0.98, 1.06, and 1.22 Mb in the 341-, 410-, and 468-gene panels, respectively).…”