RESUMO
Background: KRAS mutations are present in up to 30% of patients with lung adenocarcinoma. The two most common KRAS mutations in non-small cell lung cancer (NSCLC) are G12C (~40%) and G12V (~22%). We describe the case of a 63-year-old Asian male patient with a very aggressive lung adenocarcinoma harbouring two coexisting missense mutations in the same exon. Methods: The patient presented with a 6 cm spiculated lung mass and bilateral mediastinal lymphadenopathy on imaging. A cytology sample was obtained from EBUS-TBNA of mediastinal lymph nodes, and mutation screening was performed by next-generation sequencing using the Ion Torrent Cancer Hotspot panel. Results: Cytological examination and immunocytochemistry confirmed the presence of metastatic lung adenocarcinoma. The molecular analysis revealed the coexistence of two missense mutations: c.34G > T; p.(Gly12Cys) and c.38G > T; A; p.(Gly13Asp) in exon 2 of the KRAS gene. The two independent variants were confirmed on Integrative Genomic Viewer (IGV), suggesting molecularly independent clones. The patient was treated with palliative care and died within two months of the diagnosis. Conclusions: The present case showed aggressive clinical behaviour. It is questionable whether this aggressive course was due to the coexistence of multiple mutations or to a specific single mutation. Data in the literature regarding the outcome of polyclonal KRAS polyclonal lung adenocarcinomas are scarce, but some evidence seems to indicate that specific mutations may have prognostic value, possibly depending on the disease setting.
Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas ras/genéticaRESUMO
BACKGROUND/AIM: Better diagnostic and prognostic markers are required for a more accurate diagnosis and an earlier detection of glioma progression and for suggesting better treatment strategies. This retrospective study aimed to identify actionable gene variants to define potential markers of clinical significance. MATERIALS AND METHODS: 56 glioblastomas (GBM) and 44 grade 2-3 astrocytomas were profiled with next generation sequencing (NGS) as part of routine diagnostic workup and bioinformatics analysis was used for the identification of variants. CD34 immunohistochemistry (IHC) was used to measure microvessel density (MVD) and Log-rank test to compare survival and progression in the presence or absence of these variants. RESULTS: Bioinformatic analysis highlighted frequently occurring variants in genes involved in angiogenesis regulation (KDR, KIT, TP53 and PIK3CA), with the most common ones being KDR (rs1870377) and KIT (rs3822214). The KDR variant was associated with increased MVD and shorter survival in GBM. We did not observe any correlation between the KIT variant and MVD; however, there was an association with tumour grade. CONCLUSION: This study highlights the role of single-nucleotide variants (SNVs) that may be considered non-pathogenic and suggests the prognostic significance for survival of KIT rs3822214 and KDR rs1870377 and potential importance in planning new treatment strategies for gliomas.
Assuntos
Astrocitoma/patologia , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/patologia , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-kit/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Astrocitoma/genética , Neoplasias Encefálicas/genética , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
It remains unclear whether targeted next-generation sequencing (tNGS) conveys a reliable estimate of tumor mutational burden (TMB). We sequenced 79 archival samples of immune checkpoint inhibitors (ICPIs) recipients (57% lung cancer, 43% melanoma) using Ion Ampliseq Cancer Hotspot Panel. Employing multiple cutoff values, we verified that TMB by tNGS did not correlate with response or survival following ICPI. We found enrichment of ATM mutations in ICPI-refractory tumors (P=0.01) to correlate with worse survival (4.2 vs. 10 mo, P=0.03). Limited-coverage tNGS delivers an imprecise estimate of patients' TMB but may aid identification of candidate somatic variants of predictive/prognostic significance.
