Genomic origin and EGFR-TKI treatments of pulmonary adenosquamous carcinoma

Abstract

Background: Adenosquamous carcinoma (ASC) of the lung is a heterogeneous disease that is composed of both adenocarcinoma components (ACC) and squamous cell carcinoma components (SCCC). Their genomic profile, genetic origin, and clinical management remain controversial. Patients and methods: Resected ASC and metastatic tumor in regional lymph nodes (LNs) were collected. The ACC and SCCC were separated by microdissection of primary tumor. The 1021 cancer-related genes were evaluated by nextgeneration sequencing independently in ACC and SCCC and LNs. Shared and private alterations in the two components were investigated. In addition, genomic profiles of independent cohorts of adenocarcinomas and squamous cell carcinomas were examined for comparison. We have also carried out a retrospective study of ASCs with known EGFR mutation status from 11 hospitals in China for their clinical outcomes. Results: The most frequent alterations in 28 surgically resected ASCs include EGFR (79%), TP53 (68%), MAP3K1 (14%) mutations, EGFR amplifications (32%), and MDM2 amplifications (18%). Twenty-seven patients (96%) had shared variations between ACC and SCCC, and pure SCCC metastases were not found in metastatic LNs among these patients. Only one patient with geographically separated ACC and SCCC had no shared mutations. Inter-component heterogeneity was a common genetic event of ACC and SCCC. The genomic profile of ASC was similar to that of 170 adenocarcinomas, but different from that of 62 squamous cell carcinomas. The incidence of EGFR mutations in the retrospective analysis of 517 ASCs was 51.8%. Among the 129 EGFR-positive patients who received EGFR-TKIs, the objective response rate was 56.6% and the median progression-free survival was 10.1 months (95% confidence interval: 9.0e11.2). Conclusions: The ACC and SCCC share a monoclonal origin, a majority with genetically inter-component heterogeneity. ASC may represent a subtype of adenocarcinoma with EGFR mutation being the most common genomic anomaly and sharing similar efficacy to EGFR TKI.

Deciphering the clonal relationship between glandular and squamous components in adenosquamous carcinoma of the lung using whole exome sequencing

“…Most mutated cancer genes were known as typical for LUAD such as EGFR, MET and BRAF. P118 harbored a deletion in EGFR exon 19, a well-known driver gene in LUAD [6,22]. We found only KMT2D in P120, but not any other mutations in LUSC typical driver genes (Fig.…”

“…Previous studies focusing on oncogenic driver mutations revealed that ASC have similar mutation profiles and therapeutic targets as LUAD including EGFR mutations [5,6]. Yet, to the best of our knowledge, the genomic profiles of the LUAD and LUSC components within ASC and the inferred evolutionary trajectories have not been explored previously, beyond the use of single gene and gene panel testing [5,6]. Being defined by its distinct morphological heterogeneity, ASC represents an ideal model to study morphological transdifferentiation and clonal evolution in NSCLC.…”

“…Common LUAD is considered to originate from stem cells at the bronchoalveolar junction, whereas LUSC derive from the more proximally located basal cell compartment of the bronchial epithelium [7]. Based on targeted sequencing, several mutations were detected in both components LUAD and LUSC of ASC suggesting the two entities share the same ancestor cell [5,6]. It has been hypothesized that they are likely to arise at the bronchoalveolar junction as LUAD and that the LUSC phenotype develops subsequently [5,6].…”

“…Based on targeted sequencing, several mutations were detected in both components LUAD and LUSC of ASC suggesting the two entities share the same ancestor cell [5,6]. It has been hypothesized that they are likely to arise at the bronchoalveolar junction as LUAD and that the LUSC phenotype develops subsequently [5,6]. The molecular mechanisms of this adenosquamous transdifferentiation (AST) remain unknown.…”

Adenocarcinomatous-predominant subtype associated with a better prognosis in adenosquamous lung carcinoma

“…And we hypothesized that AC-predominant ASC might be in a later, better-differentiated phase in this transition and thus be with a better prognosis. However, recent data suggested that Asian pulmonary ASC might originate from adenocarcinoma and that squamous cell carcinoma components might be transformed from adenocarcinoma components [19]. Thus, further research is needed to explore this issue.…”