Genomic Landscape of Pulmonary Sarcomatoid Carcinoma
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Purpose Pulmonary sarcomatoid carcinoma (PSC) is a rare aggressive subtype of non–small cell lung cancer (NSCLC) with limited therapeutic strategies. We attempted to elucidate the evolutionary trajectories of PSC using multiregional and longitudinal tumor samples. Materials and Methods A total of 31 patients were enrolled in this study and 11 longitudinal samples were available from them. Using whole exome sequencing data, we analyzed the mutational signatures in both carcinomatous and sarcomatous areas in primary tumors of the 31 patients and longitudinal samples obtained from 11 patients. Furthermore, digital droplet polymerase chain reaction (ddPCR), and programmed death-ligand 1 (PD-L1) immunohistochemistry using the Ventana SP263 assay were performed. Results TP53 was identified as the most frequently altered gene in the primary (74%) and metastatic (73%) samples. MET exon 14 skipping mutations, confirmed by ddPCR, and TP53 mutations were mutually exclusive; whereas, MET exon 14 skipping mutations frequently co-occurred with MDM2 amplification. Metastatic tumors showed dissimilar genetic profiles from either primary component. During metastasis, the signatures of APOBEC decreased in metastatic lesions compared with that in primary lesions. PSC showed higher MET and KEAP1 mutations and stronger PD-L1 protein expression compared with that recorded in other NSCLCs. Conclusion Decreased APOBEC signatures and subclonal diversity were detected during malignant progression in PSC. Frequent MET mutations and strong PD-L1 expression distinguished PSC from other NSCLCs. The aggressiveness and therapeutic difficulties of PSC were possibly attributable to profound intratumoral and intertumoral genetic diversity. Next-generation sequencing could suggest the appropriate treatment strategy for PSC.
Abstract
Purpose Pulmonary sarcomatoid carcinoma (PSC) is a rare aggressive subtype of non–small cell lung cancer (NSCLC) with limited therapeutic strategies. We attempted to elucidate the evolutionary trajectories of PSC using multiregional and longitudinal tumor samples. Materials and Methods A total of 31 patients were enrolled in this study and 11 longitudinal samples were available from them. Using whole exome sequencing data, we analyzed the mutational signatures in both carcinomatous and sarcomatous areas in primary tumors of the 31 patients and longitudinal samples obtained from 11 patients. Furthermore, digital droplet polymerase chain reaction (ddPCR), and programmed death-ligand 1 (PD-L1) immunohistochemistry using the Ventana SP263 assay were performed. Results TP53 was identified as the most frequently altered gene in the primary (74%) and metastatic (73%) samples. MET exon 14 skipping mutations, confirmed by ddPCR, and TP53 mutations were mutually exclusive; whereas, MET exon 14 skipping mutations frequently co-occurred with MDM2 amplification. Metastatic tumors showed dissimilar genetic profiles from either primary component. During metastasis, the signatures of APOBEC decreased in metastatic lesions compared with that in primary lesions. PSC showed higher MET and KEAP1 mutations and stronger PD-L1 protein expression compared with that recorded in other NSCLCs. Conclusion Decreased APOBEC signatures and subclonal diversity were detected during malignant progression in PSC. Frequent MET mutations and strong PD-L1 expression distinguished PSC from other NSCLCs. The aggressiveness and therapeutic difficulties of PSC were possibly attributable to profound intratumoral and intertumoral genetic diversity. Next-generation sequencing could suggest the appropriate treatment strategy for PSC.
참고문헌 (30)
- Travis WD, "WHO classification of tumours of the lung, pleura, thymus and heart" (2015), IARC Press
- Lococo F, "Inter-relationship between PD-L1 expression and clinic-pathological features and driver gene mutations in pulmonary sarcomatoid carcinomas", Lung Cancer, 113, pp.93~101 (2017)
- Liang X, "Clinical, pathological and treatment factors associated with the survival of patients with pulmonary sarcomatoid carcinoma", Oncol Lett, 19, pp.4031~4039 (2020)
- Vieira T, "Efficacy of first-line chemotherapy in patients with advanced lung sarcomatoid carcinoma", J Thorac Oncol, 8, pp.1574~1577 (2013)
- Yang J, "Guidelines and definitions for research on epithelial-mesenchymal transition", Nat Rev Mol Cell Biol, 21, pp.341~352 (2020)
- Lococo F, "Deep sequencing analysis reveals that KRAS mutation is a marker of poor prognosis in patients with pulmonary sarcomatoid carcinoma", J Thorac Oncol, 11, pp.1282~1292 (2016)
- Terra SB, "Molecular characterization of pulmonary sarcomatoid carcinoma : analysis of 33 cases", Mod Pathol, 29, pp.824~831 (2016)
- Liu X, "Nextgeneration sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations", J Clin Oncol, 34, pp.794~802 (2016)
- Yang Z, "Integrated molecular characterization reveals potential therapeutic strategies for pulmonary sarcomatoid carcinoma", Nat Commun, 11, pp.4878~ (2020)
- Velcheti V, "Sarcomatoid lung carcinomas show high levels of programmed death ligand-1(PDL1)", J Thorac Oncol, 8, pp.803~805 (2013)
- Domblides C, "Efficacy of immune checkpoint inhibitors in lung sarcomatoid carcinoma", J Thorac Oncol, 15, pp.860~866 (2020)
- Amin MB, "AJCC cancer staging manual" (2017), Springer
- Zhao M, "dbEMT 2. 0 : an updated database for epithelial-mesenchymal transition genes with experimentally verified information and precalculated regulation information for cancer metastasis", J Genet Genomics, 46, pp.595~597 (2019)
- Zhao M, "dbEMT : an epithelial-mesenchymal transition associated gene resource", Sci Rep, 5, pp.11459~ (2015)
- Favero F, "Sequenza : allele-specific copy number and mutation profiles from tumor sequencing data", Ann Oncol, 26, pp.64~70 (2015)
- Yu Y, "Analysis of canonical and noncanonical splicing site mutation of MET that causes exon 14 skipping", J Clin Oncol, 38(15 Suppl), pp.e21513~ (2020)
- Awad MM, "MET exon 14 mutations in non-smallcell lung cancer are associated with advanced age and stagedependent MET genomic amplification and c-Met overexpression", J Clin Oncol, 34, pp.721~730 (2016)
- Chen J, "Genomic landscape of lung adenocarcinoma in East Asians", Nat Genet, 52, pp.177~186 (2020)
- Li C, "Whole exome sequencing identifies frequent somatic mutations in cell-cell adhesion genes in Chinese patients with lung squamous cell carcinoma", Sci Rep, 5, pp.14237~ (2015)
- Mehrad M, "KRAS mutation is predictive of outcome in patients with pulmonary sarcomatoid carcinoma", Histopathology, 73, pp.207~214 (2018)
- Nakagomi T, "New therapeutic targets for pulmonary sarcomatoid carcinomas based on their genomic and phylogenetic profiles", Oncotarget, 9, pp.10635~10649 (2018)
- Li X, "Pulmonary sarcomatoid carcinoma : progress, treatment and expectations", Ther Adv Med Oncol, 12, pp.1758835920950207~ (2020)
- Salgia R, "The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping", Cancer Treat Rev, 87, pp.102022~ (2020)
- Kim S, "PD-L1expression is associated with epithelial-to-mesenchymal transition in adenocarcinoma of the lung", Hum Pathol, 58, pp.7~14 (2016)
- Dong P, "Tumor-intrinsic PD-L1 signaling in cancer initiation, development and treatment : beyond immune evasion", Front Oncol, 8, pp.386~ (2018)
- Goh JY, "Chromosome 1q21. 3 amplification is a trackable biomarker and actionable target for breast cancer recurrence", Nat Med, 23, pp.1319~1330 (2017)
- Wang S, "APOBEC3B and APOBEC mutational signature as potential predictive markers for immunotherapy response in non-small cell lung cancer", Oncogene, 37, pp.3924~3936 (2018)
- Chen H, "The immune response-related mutational signatures and driver genes in non-small-cell lung cancer", Cancer Sci, 110, pp.2348~2356 (2019)
- Selenica P, "APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas", Ann Oncol, 33, pp.1284~1295 (2022)
- Venkatesan S, "Perspective : APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution", Ann Oncol, 29, pp.563~572 (2018)