Comprehensive molecular profiling of pulmonary pleomorphic carcinoma.
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ABSTRACT:
SUBMITTER: Nagano M
PROVIDER: S-EPMC8219709 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Glucose metabolism is necessary for tumor progression, metastasis, and survival in various human cancers. Glucose transporter 1 (GLUT1), in particular, plays an important role in the mechanism of ¹⁸F-FDG (2-[¹⁸F]-fluoro-2-deoxy-d-glucose) within tumor cells. However, little is known about the clinicopathological significance of GLUT1 in patients with pulmonary pleomorphic carcinoma (PPC). Adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, poorly differentiated carcinoma, large cell carcinoma, and others were identified as epithelial components, and spindle-cell type, giant-cell type, and both spindle- and giant-cell types were identified as sarcomatous components. This study was performed to determine the prognostic impact of GLUT1 expression in PPC. Patients with surgically resected PPC (n = 104) were evaluated by immunohistochemistry analysis to detect GLUT1 expression and determine the Ki-67 labeling index using specimens of the resected tumors. GLUT1 was highly expressed in 48% (50/104) of all patients, 42% (20/48) of the patients with an adenocarcinoma component, and 53% (30/56) of the patients with a nonadenocarcinoma component. High expression of GLUT1 was significantly associated with advanced stage, vascular invasion, pleural invasion, and tumor cell proliferation as determined by Ki-67 labeling. GLUT1 expression and tumor cell proliferation were significantly correlated according to the Ki-67 labeling in all patients (Spearman's rank; r = 0.25, p < 0.01). In multivariate analysis, GLUT1 was identified as a significant independent marker for predicting a poor prognosis. GLUT1 is an independent prognostic factor for predicting the poor prognosis of patients with surgically resected PPC.
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Project description:We report a case of a 73-year-old man diagnosed with pulmonary pleomorphic carcinoma who showed profound durable response after a single treatment with pembrolizumab. The patient underwent a diagnostic workup in our hospital due to a hoarseness of voice. Chest computed tomography revealed a massive pulmonary tumor in the left upper lobe and multiple nodules in the both lung fields. Histological examination of a transbronchial lung biopsy specimen revealed pulmonary pleomorphic carcinoma. First-line treatment with pembrolizumab was discontinued after a single administration due to treatment-related pneumonitis. However, durable response has been observed over 17 months to date.
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Project description:BACKGROUND: potential epigenetic biomarkers for malignant transformation to carcinoma ex pleomorphic adenoma (Ca ex PSA) have been sought previously with and without specific comparison with the benign variant, pleomorphic salivary adenoma (PSA). Previous analysis has been limited by a non-quantitative approach. We sought to demonstrate quantitative promoter methylation across a panel of tumour suppressor genes (TSGs) in both Ca ex PSA and PSA. METHODS: quantitative methylation-specific real-time polymerase chain reaction (qMSP) analysis of p16(INK4A), CYGB, RASSF1, RAR?, human telomerase reverse transcriptase (hTERT), Wilms' tumour 1 (WT1) and TMEFF2 gene promoters was undertaken on bisulphite-converted DNA, previously extracted from archival fixed tissue specimens of 31 Ca ex PSA and an unrelated cohort of 28 PSA. All target regions examined had formerly been shown to be hypermethylated in salivary and/or mucosal head and neck malignancies. RESULTS: the qMSP demonstrated abnormal methylation of at least one target in 20 out of 31 (64.5%) Ca ex PSA and 2 out of 28 (7.1%) PSA samples (P<0.001). RASSF1 was the single gene promoter for which methylation is shown to be a statistically significant predictor of malignant disease (P<0.001) with a sensitivity of 51.6% and a specificity of 92.9%. RAR?, TMEFF2 and CYGB displayed no apparent methylation, while a combinatory epigenotype based on p16, hTERT, RASSF1 and WT1 was associated with a significantly higher chance of detecting malignancy in any positive sample (odds ratio: 24, 95% CI: 4.7-125, P<0.001). CONCLUSIONS: we demonstrate the successful application of qMSP to a large series of historical Ca ex PSA samples and report on a panel of TSGs with significant differences in their methylation profiles between benign and malignant variants of pleomorphic salivary adenoma. qMSP analysis could be developed as a useful clinical tool to differentiate between Ca ex PSA and its benign precursor.
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Project description:BackgroundCarcinoma of unknown primary origin (CUP) accounts for 2%-5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm.Materials and methodsCentrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture-based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death-ligand 1 (PD-L1) positivity were determined.ResultsA total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabase of DNA; 34 patients (11.6%) had a TMB ?16 mutations per megabase. Three patients (1%) had high MSI, and 42 (14%) displayed high PD-L1 expression (tumor proportion score ?50%). gLOH could be assessed in 199 of 303 specimens; 19.6% had a score of >16%.ConclusionsThirty-two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD-L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP-informed treatment. Clinical trial identification number. NCT03498521 IMPLICATIONS FOR PRACTICE: The findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, such as programmed death-ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling-informed treatment.
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Project description:Background Pulmonary pleomorphic carcinoma (PPC) is a rare type of non-small cell lung cancer characterized by high malignancy and a poor prognosis. PPC is associated with a high frequency of postoperative relapse, and shows resistance to chemotherapy. The high malignancy of cancers is associated with genomic instability, which is related to mutations of tumor suppressor genes, such as tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM). In addition, signaling pathways involving the oncogenes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and epidermal growth factor receptor (EGFR) are associated with resistance to chemotherapy. However, the association of PPC with these gene mutations remains unknown. We investigated the impact of TP53, ATM, PIK3CA, and EGFR mutations on the postoperative prognosis of PPC. Methods Fifty-five patients with PPC who underwent complete resection were studied. A gene mutation analysis was performed using next-generation sequencing. Postoperative overall survival of patients with gene mutations was evaluated using a multivariable Cox proportional hazards model in which the explanatory variables were the presence of each gene mutation, and the confounding factors were pathological stage and age. The robustness of the results was evaluated by a sensitivity analysis. Results The frequencies of pathogenic mutations in TP53, ATM, PIK3CA, and EGFR were 47, 0, 7, and 9%, respectively. A multivariable analysis adjusted for pathological stage and age showed a significant difference for only PIK3CA mutations. The hazard ratio (HR) for overall survival in cases with pathogenic mutations of PIK3CA for wild type or non-pathogenic mutations was 4.5 (95% confidence interval [CI] 1.1–18.8). Likewise, sensitivity analyses adjusted for pathological stage and sex (HR, 7.5; 95% CI 1.7–32.4) and for age and sex (HR, 5.4; 95% CI 1.4–21.7) resulted in similar findings. Although three patients with pathogenic mutations of PIK3CA that recurred postoperatively were treated by chemotherapy or immunotherapy, they survived for less than 2 years. Conclusions The postoperative prognosis of PPC with PIK3CA pathogenic mutations is particularly poor. Pathogenic mutations of PIK3CA may be a postoperative prognostic marker. Inhibition of signaling pathways associated with PIK3CA mutations may also be a target for chemotherapy after relapse of PPC. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10176-4.
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