Human Leukocyte Antigen Class I and Programmed Death-Ligand 1 Coexpression Is an Independent Poor Prognostic Factor in Adenocarcinoma of the Lung

한연비,권현정,박수영,김은선,김효진,정진행 대한병리학회 2019 Journal of Pathology and Translational Medicine Vol.53 No.2

Background: Both human leukocyte antigen (HLA) class I and programmed death-ligand 1 (PDL1) molecules are known to play important roles in cancer immunity. In this study, we evaluated HLA class I expression in resected adenocarcinoma of the lung, and investigated its prognostic impact in correlation with PD-L1 expression. Methods: HLA class I and PD-L1 expression was evaluated by immunohistochemistry in a total of 403 resected lung adenocarcinomas using tissue microarray. Correlations between the expression of HLA class I/PD-L1 and clinicopathologic features and prognostic significance were analyzed. Results: HLA class I expression was reduced in 91.6% of adenocarcinoma, and more frequently reduced in patients with younger age, absence of vascular invasion, and low pathologic stage (p = .033, p = .007, and p = .012, respectively). Positive PD-L1 expression in tumor cells was 16.1% (1% cut-off), and associated with poor differentiation, presence of vascular invasion and nodal metastasis (p < .001, p = .002, and p = .032, respectively). On survival analysis, HLA class I or PD-L1 expression alone did not show any statistical significance. On the integrated analysis, HLA class I (+)/PD-L1 (+) subgroup showed a significantly shorter overall survival than other groups (p = .001). Multivariate analysis revealed that coexpression of HLA class I and PD-L1 was an independent poor prognostic factor of lung adenocarcinoma. (p < .001; hazard ratio, 6.106; 95% confidence interval, 2.260 to 16.501). Conclusions: Lung adenocarcinoma with coexpression of HLA class I and PD-L1 was associated with poor prognosis. This subgroup may evade immune attack by expressing PD-L1 protein despite HLA expression.

Landscape of EGFR mutations in lung adenocarcinoma: a single institute experience with comparison of PANAMutyper testing and targeted next-generation sequencing

이정효,한연비,권현정,이송국,김효진,정진행 대한병리학회 2022 Journal of Pathology and Translational Medicine Vol.56 No.5

Background: Activating mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) are predictive biomarkers for response to EGFR–tyrosine kinase inhibitor (TKI) therapy in lung adenocarcinoma (LUAD). Here, we characterized the clinicopathologic features associated with EGFR mutations via peptide nucleic acid clamping-assisted fluorescence melting curve analysis (PANAMutyper) and evaluated the feasibility of targeted deep sequencing for detecting the mutations.Methods: We examined EGFR mutations in exons 18 through 21 for 2,088 LUADs from July 2017 to April 2020 using PANAMutyper. Of these, we performed targeted deep sequencing in 73 patients and evaluated EGFR-mutation status and TKI clinical response.Results: EGFR mutation was identified in 55.7% of LUADs by PANAMutyper, with mutation rates higher in females (69.3%) and never smokers (67.1%) and highest in the age range of 50 to 59 years (64.9%). For the 73 patients evaluated using both methods, next-generation sequencing (NGS) identified EGFR mutation–positive results in 14 of 61 patients (23.0%) who were EGFR-negative according to PANAMutyper testing. Of the 10 patients reportedly harboring a sensitizing mutation according to NGS, seven received TKI treatment, with all showing partial response or stable disease. In the 12 PANAMutyper-positive cases, NGS identified two additional mutations in exon 18, whereas a discordant negative result was observed in two cases.Conclusions: Although PANAMutyper identified high frequencies of EGFR mutations, targeted deep sequencing revealed additional uncommon EGFR mutations. These findings suggested that appropriate use of NGS may benefit LUAD patients with otherwise negative screening test results.

Differences in Clinical and Immunological Characteristics According to the Various Criteria for Tissue Eosinophilia in Chronic Rhinosinusitis With Nasal Polyps

양승구,조성우,한연비,김정훈,원태빈,이재서 대한이비인후과학회 2023 Clinical and Experimental Otorhinolaryngology Vol.16 No.4

Objectives. Several criteria exist for classifying chronic rhinosinusitis with nasal polyps (CRSwNP) as eosinophilic or non-eosinophilic. This study attempted to evaluate several criteria for defining eosinophilic CRSwNP from clinical andimmunological perspectives. Methods. A cohort of 84 patients (73 patients with CRSwNP and 11 control patients) was retrospectively analyzed. Patientswere divided into eosinophilic and non-eosinophilic CRSwNP based on four different criteria: eosinophils (EOS) ac-counting for more than 20% of the total inflammatory cells; ≥70 EOS per high-power field (HPF); >55 EOS/HPF;and ≥10 EOS/HPF. Preoperative clinical characteristics, the immunological profiles of 14 cytokines from nasal tissue,and postoperative outcomes were compared between eosinophilic and non-eosinophilic CRSwNP based on each cri-terion. These criteria were immunologically validated by using 14 cytokines to predict the performance of tissue eo-sinophilia with a random forest model. Results. Patients with eosinophilic CRSwNP were significantly older when the criterion of ≥10 EOS/HPF or EOS >20%was used. The number of patients with aspirin intolerance was significantly higher in eosinophilic CRSwNP based onthe criterion of EOS >20%. From an immunological perspective, non-type 2 inflammatory cytokines were significantlyhigher in non-eosinophilic CRSwNP with the criterion of EOS >20% of the total inflammatory cells. In addition, thecriterion of EOS >20% of the total inflammatory cells resulted in the best prediction of eosinophilic CRSwNP, withan accuracy of 88.10% and area under the curve of 0.94. Conclusion. Clinical and immunological characteristics were different between eosinophilic and non-eosinophilic CRSwNPdepending on a variety of criteria, and the results of this study should be taken into account when choosing the crite-rion for defining eosinophilic CRSwNP and interpreting the data accordingly.

Genomic Landscape of Pulmonary Sarcomatoid Carcinoma

권현정,이세준,한연비,이정효,권수현,김효진,정진행 대한암학회 2024 Cancer Research and Treatment Vol.56 No.2

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.

Genetic Alterations in Preinvasive Lung Synchronous Lesions

안소연,임지선,박수영,김효진,권현정,한연비,이춘택,조석기,정진행 대한암학회 2020 Cancer Research and Treatment Vol.52 No.4

Purpose Despite advances in treatment, lung cancer remains the leading cause of cancer mortality. This study aimed to characterise genome-wide tumorigenesis events and to understand the hypothesis of the multistep carcinogenesis of lung adenocarcinoma (LUAD) Materials and Methods We conducted multiregion whole-exome sequencing of LUAD with synchronous atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ, or minimally invasive adenocarcinoma of 19 samples from three patients to characterize genome-wide tumorigenesis events and validate the hypothesis of the multistep carcinogenesis of LUAD. We identified potential pathogenic mutations preserved in preinvasive lesions and supplemented the finding by allelic variant level from RNA sequencing. Results Overall, independent mutational profiles were observed per patient and between patients. Some shared mutations including epidermal growth factor receptor (EGFR , p.L858R) were present across synchronous lesions. Conclusion Here, we show that there are driver gene mutations in AAH, and they may exacerbate as a sequence in a histological continuum, supporting the Darwinian evolution model of cancer genome. The intertumoral and intratumoral heterogeneity of synchronous LUAD implies that multi-biomarker strategies might be necessary for appropriate treatment.