LIN28A EXPRESSION CORRELATES WITH POOR PROGNOSIS AND THE MYC SUBGROUP IN AT/RTS

Abstract Atypical teratoid/rhabdoid tumors (AT/RTs) are malignant embryonal tumors of the central nervous system, which mainly affect young children. These tumors are defined by loss of SMARCB1 (or SMARCA4 in rare cases) and can be categorized into three main DNA methylation subgroups (i.e. –MYC, -SHH, -TYR). AT/RTs commonly display heterogeneous expression of LIN28A, an RNA-binding protein, which regulates pluripotency and plays critical roles during embryonic development. The biological impact and clinical significance of LIN28A expression in AT/RTs remains unknown. In this study, we investigated 80 samples of molecularly and clinically characterized AT/RTs for LIN28A expression using immunohistochemistry. Staining signal of tumor tissue was assessed and scored via semi-automated digital image analysis. Global LIN28A expression intensity and heterogeneity were tested for correlation with DNA methylation subtype, tumor localization, as well as patient age, gender and overall survival. LIN28A was found with strongly varying staining patterns and intensities across our cohort of AT/RTs, with significantly elevated expression in the MYC subgroup. Moreover, we identified strong global and focal LIN28A expression as an independent negative prognostic factor in AT/RTs. In summary, we show that AT/RT-MYC tumors display significantly increased LIN28A expression in comparison to the other DNA methylation subgroups, suggesting a subgroup-specific intratumoral role of LIN28A. Furthermore, we demonstrate an impact of LIN28A expression on survival in AT/RTs. Further investigations on the functions of LIN28A in AT/RTs in vitro and in vivo are ongoing and aim to uncover potential therapeutic implications in these tumors.