Klára Pavlíčková, J. Hojný, Nikola Hájková, Petr Waldauf, Pavel Dundr, Marie Drösslerová, Marián Švajdler, Pavel Fabián, Ivana Stružinská, Eva Krkavcová, Jiří Dvořák, Romana Michálková, Iva Staniczková Zambo, Miroslava Flídrová, Jan Laco, Helena Hornychová, Patricie Delongová, Jozef Škarda, Jan Hrudka, Radoslav Matěj
Small cell neuroendocrine carcinomas occur in both pulmonary (SCLC) and extrapulmonary sites (EP-SCNC). Although morphologically similar, they may differ biologically, but these differences are not well characterized. The aim of this study was to compare cohorts of SCLC (n = 215) and EP-SCNC(n = 184) with respect to molecular alterations, RNA and protein expression in tumor tissue. The median survival for SCLC was 6.3 months and 8.9 months for EP-SCNC patients (p < 0.0001). Genetic alterations of TP53, RB1, and KMT2D were the most common in both groups. The TP53 mutation was associated with worse survival in EP-SCNC (HR = 1.62; p = 0.043), while KMT2D was associated with worse survival in SCLC (HR = 1.62; p = 0.003). The tumor mutation burden (TMB) was higher in SCLC (p < 0.001). In RNA-Seq analyses, SCLC and EP-SCNC formed distinct RNA clusters. A total of 553 genes were differentially expressed. snoRNAs and tRNAs were predominantly upregulated in SCLC. GOAT analysis revealed upregulation in cell signaling and cellular plasticity in EP-SCNC, whereas SCLC showed enhanced transcriptional activity, including RNA processing and nuclear functions. Immunohistochemistry revealed higher expression of ASCL1 and NEUROD1 in SCLC than in EP-SCNC. YAP1 and POU2F3 expressions were higher in EP-SCNC. In multivariate analyses, EP-SCNC was associated with better survival, greater molecular heterogeneity, and distinct genetic, transcriptional, and immunohistochemical profiles. These findings demonstrate that, despite their morphological similarity, the two tumor groups are biologically distinct.