. Author manuscript; available in PMC: 2020 Apr 20.

Published in final edited form as: Trends Mol Med. 2019 Jul 25;25(11):1024–1038. doi: 10.1016/j.molmed.2019.07.001

Table 1. Genetic Alterations and Therapeutic Interventions Targeting Different Molecular Subtypes in PCa.

Molecular subtype	Frequencies	Causal genetic alterations/drivers	Proposed drug therapies	Clinical trials	Refs
ETS-fusion-positive PCa
TMPRSS2–ERG	45–50%	AR and its coactivator BET proteins regulate expression of these oncogenic fusion proteins ETS factor interacts with DNA repair enzyme PARP and DNA-PKs and upregulates DNA repair genes	Antiandrogens PARPis ERG peptidomimetics BET inhibitors PROTACs	PARPi- NCI 9012-NCT01576172ⁱ BETi- NCT02711956ⁱⁱ, NCT03150056ⁱⁱⁱ AR PROTACs-NCT03888612^ix	[3,5,16,22–24,28,97,101]
ETV-1	~8%
ETV-5	~4%
FLI-1	~1%
ETS-fusion-negative PCa
SPINK1 overexpression	10–15%	AR signaling transcriptionally represses SPINK1, while SOX2 and HNF1A transcriptionally activate SPINK1 SPINK1-positive cases show increased EZH2 expression, which epigenetically silences miR-338-5p/-421 which negatively regulate SPINK1	EGFR inhibitors, Epigenetic inhibitors or miR-338-5p/-421 replacement therapies	—	[36,39,40,43]
RAF rearrangements	2–6%	Upregulates downstream oncogenic MEK and ERK signaling	Sensitive to RAF kinase inhibitor sorafenib, and MEK inhibitors	—	[7]
SPOP mutations (SPOP^mut)	6–15%	Increased expression of BET proteins, confers resistance to BET inhibitors Activates AKT and AR signaling.	Sensitive to abiraterone therapy or PI3K inhibition	—	[5,8,50,52,61]
CHD1 deletions (CHD1^del)	15–17%	Show increased AR activity Activates NHEJ repair pathway.	Sensitive to DNA damage agents	—	[6,59,60]
SPOP^mut/CHD1^del	~25%	Show a higher response to AR inhibitors due to increase in AR activity	Sensitive to abiraterone therapy	—	[61]
CHD1^del/MAP3K7^del	20–25%	Show loss of AR, and increased levels of SYP and CHGA, associates with neuroendocrine and neural features	—	—	[65]
IDH1 mutations	~1%	IDH1 R132 mutations; increase in oncometabolite D-2-hydroxyglutarate	AG-221 and AG-120	NCT02074839^iv, NCT02073994^v	[5,72,73]
FOXA1 mutations	~4%	Show C-terminal truncating and forkhead domain missense mutations, disrupting its interactions with other cofactors	—	—	[5,8,69]
Epigenetic regulators	~15%	Mutations in KMT2C (7%), KMT2D (6%), KDM6A (3%), KMT2A (1.2%)	—	—	[10]
Chromatin remodelers	~5%	Mutations in SWI/SNF nucleosome-remodeling members ARID1A, ARID4A, ARID2, SMARCA1	—	—	[10]
Splicing pathway	~4%	Mutation in SF3B1 (1.1%), U2AF1 (0.5%), GEMIN5 (0.5%), TCERG1 (0.8%) and PRPF8 (1.2%)	—	—	[10]
Ubiquitin–proteasome and ligase family	~12%	Mutations in USP28 (1.4%), USP7 (1.2%), and CUL3 (1.3%), also SPOP (9%)	—	—	[5,8,10]
DDR pathway alterations	19–23%	Somatic and germline mutations in genes involved in, HR pathway (~19%): BRCA1, BRCA2, RAD51C, FANCD2, ATM. MMR pathway (8–12%): MSH2, MSH6, MLH1	HR defects: PARPi therapy such as olaparib or veliparib MMR defects Immunogenic therapies such as anti-PD-1 and anti-CTLA-4 therapy	HR DDR defects: NCT01682772^vi, NCT01576172ⁱ, NCT02966587^xii For MMR defects: NCT03061539^xi, NCT02484404^xiii	[5,11,23,77,83–86,103]
CDK12 mutations	1.2–7%	Show frequent focal tandem duplications, increased expression of neoantigens, T cell infiltration, and dendritic cell migration to the tumor microenvironment.	Immune checkpoint inhibitors against PD-1 and CTLA-4	IMPACT-NCT03570619^vii	[5,87]