Abstract 1409: RNA sequencing reveals that African Americans carrying wild-type CYP3A5 differentially express genes known to promote aggressive prostate cancer
Authors: Sharma Jeetesh , Tillett Richard , Shen Shirley , Johnson Jabril , Kittles Rick A. , Bhat Mohammad Saleem , Goodman Oscar , Oh Edwin C. , Mitra Ranjana 
Published: June 2023

Background: African American men (AAs) have the highest incidence of prostate cancer (PC) and often develop therapeutic resistance leading to high mortality. The androgen receptor (AR) is paramount in the growth and progression of PC, and insufficient blockade of AR leads to therapeutic resistance. Our previous work shows that CYP3A5 facilitates the activation of AR, promoting the transcription of genes supporting PC growth. CYP3A5 is polymorphic, and the wild-type (wt; *1) variant encoding the full-length active protein is expressed in 73% of AAs and only in 5% of non-Hispanic White Americans (NHWA). The race-linked expression of wt-CYP3A5*1 in AAs can lead to hyperactive AR contributing to therapeutic resistance. We performed an RNA sequencing study utilizing samples from AAs and NWHA patients to understand the allelic influence of CYP3A5 on PC severity.

Methods: Illumina RNA sequencing was performed using RNA from 13 AA and 12 NHWA prostatic adenocarcinomas. CYP3A5 genotyping separated them into two groups: a) carrying wt-CYP3A5 (*1/*1 and *1/*3; N=14); and b) mutant CYP3A5 (*3/*3; N=11) variants. The samples’ ancestry was confirmed using markers previously described. Differentially expressed genes (DEGs) between wt-*1 and mutant-*3 CYP3A5 carrying groups were identified using DESeq2, at a false discovery rate of adjusted p &lt; 0.05. Alternately we also used the Kallisto method for quantifying the abundances of the transcript from RNA seq data.

Results: Aligned RNA reads with the human genome using DESeq2 resulted in the identification of 30 DEGs between the two groups, of these, 14 genes are known to be dysregulated in PC and promote aggressive disease (SEMG2, ZNRF3, CCL18, U3, MT-ND6, SCARNA9, NRCAM, LINC00853, TCF4, SLC38A6, HHLA3, DECR1, THTPA, and NEFH). Aberrant TCF4 along with ZNRF3 is known to promote PC growth via Wnt-beta catenin signaling. SLC38A6 is a glutamine transporter and is often upregulated in PC to promote glutamine uptake in an AR-dependent manner. NEFH is an intermediate filament protein that is downregulated in PC metastasis. Kallisto method identified 84 DEGs, 11 of those genes overlap with the previous DFGs identified using the transcriptome alignment method. The additional DFGs identified with the Kallisto method include aberrant expression of multiple genes (MT-CO1/2, MT-ND1/6) involved in mitochondrial dysfunction known to contribute towards cell growth and tumorigenesis beyond the Warburg effect. The wt-*1 CYP3A5 expressing group also shows increased expression of several pseudogenes, dysregulation of pseudogenes has been observed in several cancers and can act as a master regulator for gene expression, promoting tumorigenesis.

Conclusion: The presence of wt-*1 CYP3A5 may be one of the factors leading to aggressive PC in AAs as it shows differential expression of several genes known to accelerate PC growth.

Citation Format: Jeetesh Sharma, Richard Tillett, Shirley Shen, Jabril Johnson, Rick A. Kittles, Mohammad Saleem Bhat, Oscar Goodman Jr, Edwin C. Oh, Ranjana Mitra. RNA sequencing reveals that African Americans carrying wild-type CYP3A5 differentially express genes known to promote aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1409.