ECP 2022 Abstract Book

Virchows Archiv (2022) 481 (Suppl 1):S1–S364 13 diagnosed between 1996 and 2021 were evaluated by review of histology slides, review of clinicopathologic data and massively parallel DNA sequencing. Further evaluation by comparative meth- ylation profiling was conducted on a subset of tumours. Results: Cytomorphologic patterns included monophasic spindled (5/26), monophasic epithelioid (10/26), and biphasic or mixed (11/23). Histopathologic features suggestive of malignancy (size >5 cm, invasive growth, necrosis or prominent mitotic activity) were seen in 11 cases. DNA sequencing was successful in 19 tumours. Two molecular patterns emerged, including recurrent whole-chromosome gains of 3, 6, 7, 8, 9, 12, 14, 15, 17 and 20. (5/23), and pathogenic mutations in the WNT signalling pathway (8/19). A subset of WNT-altered tumours showed methylation profiles consistent with Sertoli cell tumours, NOS. Follow-up for fifteen cases included 9 patients alive without disease (median 9 mo), 4 alive with disease (median 7 mo), and 2 dead of disease. Conclusion: The results of this study demonstrate that USCSTs comprise tumours with variable clinicopathologic features and molecular alterations. Two major trends emerged in the cytologic and molecular analysis that facilitated re-classification of ~40% tumours into distinct sex cord stromal tumour entities, including a significant proportion driven by mutations of WNT pathway genes (CTNNB1, APC), some of which could be reclassified as Sertoli Cell tumours, NOS. The remaining unclassified tumours were enriched for aggressive pathological features and malignant clinical behaviour. OFP-05-003 Defining lineage plasticity in androgen indifferent prostate cancer S. Logotheti*, H. Vundavilli, M. Estecio, R. Soundararajan, P. Shepherd, J. Dong, A. Hoang, S. Guo, N. Navone, V. Tzelepi, C. Logothetis, Y. Lu, W. Wang, A. Aparicio *Department of Genitourinary Medical Oncology, UT MD Ander- son Cancer Center, USA Background & objectives: Combined alterations in TP53 with RB1 and/or PTEN characterize aggressive variant prostate cancers (AVPC) and are associated with androgen indifference and lineage plasticity. A measurable definition of lineage plasticity is needed to enable the development of ‘plasticity-inhibiting’ therapies. Methods: MDA PCa-177-B (AR-negative, basal expression pro- file) and MDA PCa-189-1 (AR-positive, luminal expression pro- file) are AVPC PDX models derived from one patient’s prostate tumour, before and after chemotherapy respectively. They share a p.Y163N Tp53 mutation, suggesting a common clonal origin. We performed scRNAseq, DNA methylation profiling and H3K27me3, H3K27ac and H3K4me3 ChIPseq to identify a shared candidate signature of lineage plasticity. Results: scRNAseq analysis revealed clusters with a “high-plastic- ity cell state” (HPCS), in each PDX, characterized by a diversity of lineage identities, similar to that associated with aggressive fea- tures and progression in lung cancer mouse models (Marjanovic et al., 2020). ChIPseq of histone markers (H3K27ac, H3K27me3, H3K4me3) and DNA methylation profiling showed shared chro- matin profiles at enhancer and super-enhancer regions linked to lineage plasticity events. Taken together, these results suggest that lineage plasticity events drive the evolution of lethal PCa and iden- tified a cell plasticity signature for AVPC. Conclusion: We identified shared HPCS clusters and chromatin profiles in phenotypically distinct PDX, which may serve as candidate signatures of lineage plasticity. Ongoing analyses are determining the association between the chromatin profiles and the HPCS clusters to arrive at clinically applicable markers. Future studies will determine the effect of drugs presumed to target plasticity on these candidate signatures. These markers will be tested as prognostic indicators and may help identify tumours destined to follow the aggressive variant pathway of PCa progression. Funding: MD Anderson prostate Cancer Moonshot platform; MD Anderson ATGC Core NCI Grant (CA016672) MD Anderson CPRIT SINGLE CORE Facilities Grant (RP180684) OFP-05-004 RNA-seq profiling of upper tract urothelial carcinoma: relevance of the bladder cancer consensus molecular classification, molecular heterogeneity, and differential immune signatures J. Fontugne*, E. Xylinas, C. Krucker, V. Dixon, C. S. Groeneveld, H. Pinar, G. Califano, M. Bucau, J. Verine, F. Desgrandchamps, J. Hermieu, F. Radvanyi, Y. Allory, A. Masson-Lecomte *Institut Curie, Pathology department, Saint-Cloud, France Background & objectives: Extensive analyses of transcriptomic data in large datasets of muscle-invasive bladder cancer (MIBC) have resulted in a consensus molecular classification. Our objective was to determine the relevance of the consensus classification in ≥pT1 upper tract urothelial carcinoma (UTUC). Methods: We constituted a novel cohort of ≥pT1 UTUC patients with clinico-pathological data. We evaluated GATA3-CK5/6- TUBB2B in multiplex, CK20, p16, MMR proteins and PD-L1 expression by immunohistochemistry (IHC). Heterogeneity was assessed morphologically and/or with subtype marker IHC expres- sion. FGFR3 mutational status was determined using pyrosequenc- ing. Gene expression was profiled using 3’ RNA-seq for each tumour, including multiple samples in heterogeneous cases. Results: In our cohort of 66 patients with ≥pT1 UTUC, the majority were men (77.3%) with pT1 (35.4%) or pT3 (46.2%) stage disease. FGFR3 mutations and MSI-H status were identi- fied in 41.5% and 4.7% of patients, respectively. The consen- sus classifier was robustly applicable to UTUC samples and reflected intrinsic subtypes, determined by unsupervised clus- tering. The proportion of LumP samples (68.4% in ≥pT1, 57.2% in ≥pT2 UTUC) was significantly higher than in MIBC. Ten patients (15.2%) harboured areas of distinct consensus classes. Consensus classes were associated with FGFR3 mutational sta- tus, pT stage, morphology and subtype IHC. The majority of LumP tumours were characterized by low immune infiltration and low PD-L1 IHC expression. Conclusion: We characterized a novel cohort of 66 patients with ≥pT1 UTUC based on morphology, immunohistochemistry, FGFR3 mutation status and transcriptomics. The consensus clas- sification of MIBC efficiently classified UTUC samples, and highlighted intratumoural molecular heterogeneity. In contrast to MIBCs, the majority of ≥pT1 UTUC patients harboured a LumP tumour, a class mostly characterized by low immune infil- tration, low PD-L1 expression and a high proportion of FGFR3 mutations. These findings may suggest differential response to novel therapies between UTUC and MIBC patients. OFP-05-005 Spatial interplay between TIM3+, PD-L1+, PD-1+ and CLTA- 4+ immune/ tumour cells using 18+1 BLEACH&STAIN mfIHC in more than 5 000 tissue samples N.F. Debatin, E. Bady, J.H. Müller, T. Mandelkow, M.C.J. Lurati, R. Simon, C. Hube-Magg, N.C. Blessin* *University Medical Center Hamburg, Germany S19