PhD Scientific Days 2022

Budapest, 6-7 July 2022

Pathology and Oncology I. (Poster discussion will take place in the Aula during the Coffee Break)

Characterization of Molecular Subtypes in Primary and Brain Metastatic Small Cell Lung Carcinomas

Dániel Sztankovics1, Ildikó Krencz1, Titanilla Dankó1, Gábor Petővári1, Dorottya Moldvai1, Fatime Szalai1, Judit Pápay1, Anna Sebestyén1
1Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary

Text of the abstract

Introduction. Small cell lung carcinoma (SCLC) is a neuroendocrine tumor characterized by high metastatic rate, poor prognosis, representing 15% of all lung cancer cases. Platinum-based chemotherapy is still the backbone of the therapy; however, acquired resistance develops in most cases. Although SCLC has been formerly considered a homogeneous disease, recently four major subtypes have been identified based on the expression of the transcription factors: achaete-scute homologue 1 (ASCL1, SCLC-A), neurogenic differentiation 1 (NEUROD1, SCLC-N), POU class 2 homeobox 3 (POU2F3, SCLC-P), and yes-associated protein 1 (YAP1, SCLC-Y). SCLC-A and SCLC-N subtypes are associated with high expression of neuroendocrine (NE) markers, whereas SCLC-P and SCLC-Y have been reported as NE-low SCLCs. The newly described SCLC subtypes are characterized by distinct biological behavior that can be therapeutically exploited.
Aims. Our goal was to compare the four molecular subtypes in primary, brain metastatic, and matched SCLC patient tumor samples.
Method. We collected tissue samples of patients diagnosed with SCLC between 2009-2019 (altogether 109 patients, 50 primary tumors, 50 brain metastases and 9 matched samples). Immunohistochemistry (IHC) was used to assess the four molecular subtypes. H-score and intratumoral heterogeneity were evaluated.
Results. The expression of NEUROD1, POU2F3, and YAP1 was higher in brain metastatic SCLCs as compared to primary tumors. We found differences in the intratumoral heterogeneity between primary and brain metastatic SCLC samples. We observed higher intratumoral heterogeneity in POU2F3 and YAP1 expression in brain metastases as compared to primary tumors. These could not be confirmed in ASCL1, NEUROD1, and YAP1 expression changes of matched SCLC samples, however, a slight decrease in the expression of POU2F3 was observed in the second tumor samples compared to their primary ones.
Conclusion. SCLC is one of the tumor types with the highest metastatic potential that determines the high mortality of the disease. Our study underlines the importance of the developing intratumoral heterogeneity and subtype-specific differences in tumor evolution and metastatic progression. Detecting alteration of these markers could help the future therapeutic treatment development.
Funding. NKFI-FK-128404, NTP-NFTÖ-21-B-0179, EFOP-3.6.3-VEKOP-16-2017-00009