Comprehensive analyses of genomic features and mutational signatures in adenosquamous carcinoma of the lung

Abstract

Adenosquamous carcinoma (ASC) of the lung is a relatively rare tumor with strong aggressiveness and poor prognosis. The analysis of mutational signatures is becoming routine in cancer genomics and has implications for pathogenesis, classification, and prognosis. However, the distribution of mutational signatures in ASC patients has not been evaluated. In this study, we sought to reveal the landscape of genomic mutations and mutational signatures in ASC. Next-generation sequencing (NGS) technology was used to retrieve genomic information for 124 ASC patients. TP53 and EGFR were the most prevalent somatic mutations observed, and were present in 66.9% and 54.8% of patients, respectively. CDKN2A (21%), TERT (21%), and LRP1B (18.5%) mutations were also observed. An analysis of gene fusion/rearrangement characteristics revealed a total of 64 gene fusions. The highest frequency of variants was determined for ALK fusions, with six ALK-EML4 classical and two intergenic ALK fusions, followed by three CD74-ROS1 fusions and one ROS1-SYN3 fusion. EGFR 19del (45.6%), and EGFR L858R (38.2%) and its amplification (29.4%) were the top three EGFR mutations. We extracted mutational signatures from NGS data and then performed a statistical analysis in order to search for genomic and clinical features that could be linked to mutation signatures. Amongst signatures cataloged at COSMIC, the most prevalent, high-frequency base changes were for C > T; and the five most frequent signatures, from highest to lowest, were 2, 3, 1, 30, and 13. Signatures 1 and 6 were determined to be associated with age and tumor stage, respectively, and Signatures 22 and 30 were significantly related to smoking. We additionally evaluated the correlation between tumor mutational burden (TMB) and genomic variations. We found that mutations ARID2, BRCA1, and KEAP1 were associated with high TMB. The homologous recombination repair (HRR) pathway-related gene mutation displayed a slightly higher TMB than those without mutations. Our study is the first to report comprehensive genomic features and mutational signatures in Chinese ASC patients. Results obtained from our study will help the scientific community better understand signature-related mutational processes in ASC.

Comprehensive analysis of clinicopathological profiles in adenosquamous carcinoma of the lung

“…In this study, the EGFR mutation rate of 48.7% in the total population is similar to several previous results of EGFR mutation rate in Chinese ASC patients (48-55.1%) [13][14][15]. According to the PIONEER study, the overall EGFR mutation frequency of lung AC for the mainland China subset was 50.2% [16].…”

Case report: Targeted sequencing facilitates the diagnosis and management of rare multifocal pure ground-glass opacities with intrapulmonary metastasis

“…We describe a rare case of lung cancer with multiple diffuse GGOs involving the SPINK1 c.194 + 2T>C germline mutation. The germline variant of SPINK1 is the most common mutation in Chinese patients with chronic pancreatitis and is closely related to the occurrence of chronic pancreatitis and increased risk of pancreatic cancer ( 23 , 24 ), but few reports on this topic have been published for lung cancer ( 25 ). One patient with the SPINK1 c.194 + 2T>C germline mutation developed multiple primary tumors, including lung cancer, suggesting that SPINK1 germline mutations may contribute to the development of multiple primary tumors ( 26 ).…”

Case report: Dramatic response to alectinib in a lung adenosquamous carcinoma patient harbouring a novel CPE-ALK fusion

“…Because EGFR mutation is the most common genomic anomaly in ASC, some studies ( 4 , 15 ) have focused on the efficiency of EGFR-TKIs in EGFR-positive ASC patients and found that ASC patients had similar efficacy to EGFR TKI compared with adenocarcinoma. Despite the presence of ALK-positive cases and molecular profiling studies of ASC ( 2 , 4 , 16 , 17 ), only a small number of ALK-TKI therapies for EML4-ALK fusion ASC patients have been reported ( 5 ), no non-classical ALK fusions have been reported in ASC. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the canonical and most common ALK gene arrangement found in NSCLC, by which multiple EML4 breakpoints fuse in frame with the kinase domain of ALK ( 18 ).…”