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or RNA-seq data. TransIndel exhibits competitive or superior performance over eight state-of-the-art indel detection tools on benchmarks using both synthetic and real DNA-seq data. We applied transIndel to DNA- seq and RNA-seq datasets from 333 primary pros- tate cancer patients from The Cancer Genome Atlas (TCGA) and 59 metastatic prostate cancer patients from AACR-PCF Stand-Up- To-Cancer (SU2C) studies.
TransIndel enhanced the taxonomy of DNA- and RNA-level alterations in prostate cancer by identifying recurrent FOXA1 indels (Figure 1).
Delineating lncRNA landscape in
prostate cancer genome
Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the United States, with significant health impact. Clinically, it is complicated with the lack of biomarkers and effective treatments for aggressive disease, particularly castrationresis- tant prostate cancer (CRPC). We have gained much in-sight into the biology of PCa through studying protein-coding genes, but they represent only a small fraction of our genome. It is now well accepted that the vast majority of human genome (about 75%) is actively transcribed, but protein- coding genes only account for about 2% the genome. This means the majority of the human transcriptome is comprised of noncoding RNAs (ncRNAs).
Our current research is developing novel computation- al methods to achieve the first complete compendia of CRPC-associated lncRNAs and reveal the dynam- ic interplay between lncRNAs and tumorigenesis, progression and metastasis, which will highlight the importance of lncRNAs in the etiology of PCa.
Detecting novel biomarkers for cancer immunotherapy
Immune checkpoint blockade therapy has proved to be effective on a number of cancer types such as skin, lung and kidney cancer. However, only some of the patients have a response to immunotherapy drugs. We have developed a novel computational algorithm which can sensitively detect previously missed novel splicing events in human transcriptome from RNA-seq data. We utilize whole exome sequencing and RNAseq from renal cell carcinoma, lung cancer and melanoma to correlation of the expression of our detected splic- ing event with immune checkpoint therapy response or resistance. This study aims to improve the com- putational methodology to detect and quantify novel alternative splicing events and to determine their involvement in immunotherapy associated pheno- types. Integrative analysis of DNA mutations and RNA splicing events in the responders and non-responder patients is able to identify a list of candidate genomic independent alternative splicing events that play a role underlying the resistance of immunotherapy in the non-responders or the effects in the responders.
Publications:
• Wang TY, Wang L, Alam SK, Hoeppner LH, Yang R. ScanNeo: identifying indel-
derived neoantigens using RNA-Seq data. Bioinformatics. 2019 Mar 18. PMID: 30887025
• Wang TY, Yang R. ScanITD: Detecting internal tandem duplication with robust variant allele frequency estimation, GigaScience, Volume 9, Issue 8, August 2020, giaa089. PMID: 32852038
• Wang TY, Liu Q, Ren YN, Alam SK, Wang L, Zhu Z, Hoeppner LH, Dehm SM, Cao Q, Yang R. A pan-cancer transcriptome analysis of exitron splicing identifies novel cancer driver genes and neoepitopes. Molecular Cell. 2021 Apr 13:S1097- 2765(21)00223-9. PMID: 33861991
F254_G257delinsC R262Sfs*57
2 E255_N256del
2 Q263Afs*60
A423Dfs*17
2
S472Aext*70 X473Mext*22
FRAMESHIFT
INFRAME
MISSENSE
UTR_3
Figure 1. TransIndel identified novel deletions in FOXA1 from ten prostate cancer specimens that were missed by original TCGA study (lower panel)
50 100 150
200
250
00 450
300 350 4
V82GfsX140
Detected by transIndel, 10 mutations FOXA1 NM_004496
G279PfsX34
Forkhead_N
FH FORKHEAD
DNA binding
HNF_C HNF3 C-terminal domain
Forkhead N-terminal region
DNA binding site [nucleotide binding]
D226N
D249V M253K F254V
Y460X
L379_Q385delinsW
F266QfsX5
K264_G283delinsR
N252_C258del D249_M253delinsV