Abstract 632P
Background
Bcl-2 anti-apoptotic and pro-apoptotic proteins regulate sensitivity to apoptosis stimuli. Overexpression of Bcl-2 and resistance to apoptosis have been implicated in the development of androgen-independent PCa and disease progression. This project aimed to characterize the transcriptomic profile of BCL2-related genes and investigate distinct sensitivity to apoptosis in PT and MS.
Methods
A total of 2185 PCa specimens (1258 PT; 927 MS) underwent comprehensive molecular profiling (Caris Life Sciences). Analyses included next-generation sequencing of DNA and RNA (592 Gene Panel, NextSeq, WES, NovaSEQ). MS: lymph node (LN; 273), bone (B; 46), liver (Li; 147), lung (Lu; 174). Gene set enrichment analyses (GSEA) were assessed by mRNA (TPM) analysis. Fisher’s exact and Dunnett’s tests after ANOVA were used for multigroup comparison. The results in the table represent statistically significant differences in mRNA expression between PT and MS (adjusted P < 0.05).
Results
The median age of patients (pts) was 68 years old (61-74). Gleason score available in 978 pts; 47% had grade group 5. In comparison to PT, the mRNA expression of anti-apoptotic BCL2 was decreased in LN, Li, Lu and B while pro-apoptotic genes BID and BAK1 were upregulated. MCL1 was downregulated in Li and B. Expression of pro-apoptotic BAX was higher in Li and B, and BAD was increased in LN. MS showed upregulation of G2M checkpoint, E2F pathways and higher rates of TP53 mutations (37%, 55%, 40% for LN, Li and B vs 32% PT). Decreased expression of CCDN1 (Li, B) and increased TP53 mutations suggest a mechanism for BCL2 downregulation. Table: 632P
Genes of interest
| PT | LN | LU | Li | B | |
| BCL2 | 4.3 | 3.2 | 2.6 | 2.6 | 3.0 |
| MCL1 | 17.1 | 16 | 16 | ||
| BAX | 32 | 32 | 36.8 | ||
| BAD | 14.9 | 16 | |||
| BID | 7.5 | 9.2 | 10.6 | 12.1 | 8.6 |
| BAK1 | 3.7 | 4.3 | 4.9 | 4.9 | 4 |
Conclusions
MS exhibit downregulation of anti-apoptotic BCL2 and increased expression of pro-apoptotic genes compared to PT. In contrast to evidence that metastatic PCa displays Bcl-2 overexpression and resistance to apoptosis, our results suggest that MS are primed to apoptosis with site-specific expression profile of BCL2-related genes possibly regulated by microenvironment.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.