Abstract 3142: Determination of molecular patterns associated with the expression of the TMPRSS2-ERG fusion and ERG, EZH2, NKX3.1 and SPINK-1 genes to evaluate the clonal origin of multifocal prostate cancer and its association with disease progression

To represent the molecular heterogeneity of PCa, which could improve medical decision-making, we aim to study it through the expression of ERG, EZH2, NKX3.1 and SPINK-1; as well as the TMPRSS2-ERG fusion status, in order to assess the clonality of the foci in each patient and also the possible association of this alteration with different degrees of differentiation and lymph node metastasis. FFPE samples of different foci with different lesion degrees: High-Grade Prostatic Intraepithelial Neoplasia (n=17), PCa foci with different Gleason scores (n= 53; GL3: (n=23); GL4: (n=23) and GL5: (n=7)), and positive lymph node (LN) (n=13) from radical prostatectomy from twenty patients were used to analyze the presence of TMPRSS2-ERG fusion and expression levels of ERG, EZH2 and NKX3.1 using RT-PCR. The molecular concordance between the different prostatic foci of the same patient was determined, taking into account subclonal events. The LN were compared with prostatic foci to try to establish its clonal origin. Molecular alterations were analyzed by comparing them across all the histopathological groups. The molecular concordance per each alteration was the predominant status (75% to 90%), but the concordance decreased to 50% when all the alterations were taken into account. The ERG(+) subtype was found in 54.7% of the foci and 70% of the patients, and 20% showed overexpression of the EZH2 gene ERG-independent. None of the thirteen analyzed LN showed the same pattern of other prostatic foci from each patient. All the LN samples were characterized by low expression of the NKX3.1 gene; and for some patients, these levels varied in comparison with other prostatic foci samples from the same patient. Only the expression of NKX3.1 was found inversely proportional to the progression of PCa when it was made the analysis by histopathological groups. In this study, the frequency of SPINK-1 cases overexpressed in ERG(-) coincides with that expected (11%), but it was not found to be exclusive with ERG (+), as in other studies that have not taken into account patients from Colombia, a greater relationship was found with ERG (+).The combination of ERG, EZH2 and SPINK-1 overexpression with low expression of NKX3.1 was the predominant pattern in the most advanced lesion (LN), while the opposite pattern was the most frequent in the HGPIN samples. Metastasis have less molecular heterogeneity than pre-neoplastic lesions. We found important molecular heterogeneity in PCa foci that could be related with the prognosis of the disease; for example, low expression of NKX3.1 was associated to metastasis. This highlights the need for searching personalized treatment. Multifocal PCa may have monoclonal or multiclonal origin. Citation Format: Yenifer Yamile Segura Moreno, Maria Carolina SANABRIA SALAS, Jorge Andres MESA LOPEZ DE MESA, Rodolfo VARELA RAMIREZ, Natalia Lizeth ACOSTA VEGA, Martha Lucia SERRANO. Determination of molecular patterns associated with the expression of the TMPRSS2-ERG fusion and ERG, EZH2, NKX3.1 and SPINK-1 genes to evaluate the clonal origin of multifocal prostate cancer and its association with disease progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3142.