Figure and Table | Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer

Table 1. Genetic Polymorphisms Associated with Treatment Outcomes for Hormone-Sensitive Prostate Cancer.

From: Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer

Gene name	Function	rs number	Polymorphism types	Treatment	Validation	Reference
CYP17A1	Androgen metabolism	rs6162	sSNP	ADT		⁽¹²⁾
		rs743572	rSNP	ADT	Validated	^{(13), (14)}
CYP19A1	Androgen metabolism	rs1870050	iSNP	ADT	Almost validated	^{(12), (15), (16)}
		rs4775936	iSNP	ADT		⁽¹⁷⁾
HSD3B1		rs1047303	cSNP	ADT	Validated	^(18)-(22)
				ADT+Docetaxel		⁽²²⁾
		rs1856888	gSNP	ADT	Almost validated	^{(15), (23)}
HSD17B2	Androgen metabolism	rs4243229, rs7201637	iSNP	ADT		⁽¹²⁾
HSD17B3	Androgen metabolism	rs2257157	iSNP	ADT		⁽¹²⁾
HSD17B4	Androgen metabolism	rs7737181	iSNP	ADT		⁽¹⁵⁾
AKR1C3	Androgen metabolism	rs12529	cSNP	ADT	Controversial	^{(24), (25)}
SRD5A2	Androgen metabolism	rs523349	cSNP	ADT		⁽²⁶⁾
SLCO1B3	Androgen transporter	rs4149117	cSNP	ADT	Validated	^(27)-(29)
SLCO2B1	Androgen transporter	rs1077858	iSNP	ADT	Validated	^{(30), (31)}
		rs1789693	iSNP	ADT		⁽³⁰⁾
		rs12422149	cSNP	ADT	Almost validated	^(29)-(32)
GNRH2	Androgen synthesis	rs6051545	cSNP	ADT		⁽³³⁾
SHBG	Androgen-binding protein	rs6259	cSNP	ADT	Controversial	^{(34), (35)}
AR	Steroid receptor	CAG repeat	Coding region	ADT	Almost validated	^{(24), (36), (37)}
ESR1	Steroid receptor	rs1062577	rSNP	ADT		⁽¹²⁾
NR3C2	Steroid receptor	rs5522	cSNP	ADT		⁽³⁸⁾
YB-1	Transcription factor	rs12030724	iSNP	ADT	Validated	^{(39), (40)}
HIF1A	Transcription factor	rs11549465	cSNP	ADT		⁽⁴¹⁾
ARRDC3	Target gene of AR	rs2939244	rSNP	ADT		⁽⁴²⁾
FLT1	Target gene of AR	rs9508016	rSNP	ADT		⁽⁴²⁾
SKAP1	Target gene of AR	rs6054145	rSNP	ADT		⁽⁴²⁾
FBXO32	Target gene of AR	rs7830622	rSNP	ADT		⁽⁴²⁾
BNC2	Target gene of ER	rs16934641	rSNP	ADT		⁽⁴³⁾
TACC2	Target gene of ER	rs3763763	rSNP	ADT		⁽⁴³⁾
ALPK1	Target gene of ER	rs2051778	rSNP	ADT		⁽⁴³⁾
LSAMP	Target gene of NFκB	rs13088089	rSNP	ADT		⁽⁴⁴⁾
CCL17	Target gene of NFκB	rs223899	rSNP	ADT		⁽⁴⁴⁾
PSMD7	Target gene of NFκB	rs2387084	rSNP	ADT		⁽⁴⁴⁾
MON1B	Target gene of NFκB	rs284924	rSNP	ADT		⁽⁴⁴⁾
GSTM3	Antioxidant	rs7483	cSNP	ADT	Validated	⁽⁴⁵⁾
CAT	Antioxidant	rs564250	gSNP	ADT		⁽⁴⁵⁾
SLC28A3	Nucleoside transporter	rs56350726	cSNP	ADT		⁽⁴⁶⁾
LRP2	Sterol and steroid transporter	rs6433107, rs3944004, rs830994, rs3770613, rs831003	iSNP	ADT		⁽⁴⁷⁾
EGF	Growth factor	rs4444903	rSNP	ADT		⁽⁴⁸⁾
IRS2	Growth factor	rs7986346	gSNP	ADT		⁽⁴⁹⁾
TGFBR2	TGF-β signaling	rs3087465	iSNP	ADT		⁽⁵⁰⁾
BMP5	TGF-β signaling	rs317027	gSNP	ADT		⁽⁴⁹⁾
IL18	Cytokine	rs187238	rSNP	ADT		⁽⁵¹⁾
APC	Wnt signaling	rs2707765, rs497844	iSNP	ADT		⁽⁵²⁾
BGLAP	Bone metabolism	rs1800247	rSNP	ADT		⁽⁵³⁾
EDN1	Vasoconstrictor	rs1800541, rs2070699	iSNP	ADT		⁽⁵⁴⁾
CASP3	Apoptosis	rs4862396	gSNP	ADT		⁽⁴⁹⁾
TRMT11	Methyltransferase	rs1268121, rs6900796	iSNP	ADT		⁽⁵⁵⁾
COMT	Methyltransferase	rs4680	cSNP	Estramustine phosphate		⁽⁵⁶⁾
KIF3C	miRNA target site	rs6728684	rSNP	ADT		⁽⁵⁷⁾
CDON	miRNA target site	rs3737336	rSNP	ADT		⁽⁵⁷⁾
IFI30	miRNA target site	rs1045747	rSNP	ADT		⁽⁵⁷⁾
PALLD	miRNA target site	rs1071738	rSNP	ADT		⁽⁵⁷⁾
GABRA1	miRNA target site	rs998754	rSNP	ADT		⁽⁵⁷⁾
SYT9	miRNA target site	rs4351800	rSNP	ADT		⁽⁵⁷⁾
-	-	rs16901979, rs7931342	gSNP	ADT		⁽⁵⁸⁾

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Table 2. Outcome and Frequencies of the rs1047303 Variant Allele of HSD3B1.

From: Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer

Outcome	Variant carrier	Number	Frequency carrying a variant allele	Reference
Prostate cancer susceptibility	High	626	48% (AC/CC, US)	⁽⁶²⁾
Hereditary prostate cancer susceptibility	High	98	53% (AC/CC, US)	⁽⁶³⁾
Prognosis in primary ADT	Poor	118/137/118	51% (AC/CC, US)	⁽¹⁸⁾
Prognosis in primary ADT	Poor	102	53% (AC/CC, US)	⁽¹⁹⁾
Prognosis in primary ADT	Poor	218	54% (AC/CC, US)	⁽²⁰⁾
Prognosis in Abiraterone	Insignificant	76	45% (AC/CC, US)	⁽⁶⁴⁾
Progression in primary ADT or ADT+Docetaxel	Poor in low volume	475	53% (AC/CC, US)	⁽²²⁾
Prognosis in Ezalutamide or Abiraterone	Poor	266	8% (CC, US/UK)	⁽⁶⁵⁾
Prognosis in Ezalutamide or Abiraterone	Poor	547	15% (CC, Canada/Europe)	⁽⁶⁶⁾
Prognosis in primary ADT	Insignificant	103	18% (AC/CC, China)	⁽⁶⁷⁾
Prognosis in primary ADT	Poor	104	9% (AC/CC, Japan)	⁽²¹⁾
Prognosis in Abiraterone	Favorable	99	14% (AC/CC, Japan)	⁽²¹⁾

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Table 3. Genetic Polymorphisms Associated with the Prognosis of Patients with Castration-Resistant Prostate Cancer Treated with Androgen Receptor-Pathway Inhibitors.

From: Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer

Gene name	Function	rs number	Polymorphism types	Treatment	Validation	Reference
CYP17A1	Androgen metabolism	rs2486758	rSNP	Abiraterone	Validated	^{(68), (69)}
		rs10883783	iSNP	Abiraterone		⁽⁷⁰⁾
HSD3B1	Androgen metabolism	rs1047303	cSNP	Abiraterone		⁽²¹⁾
				Abiraterone or Enzalutamide	Validated	^{(65), (66)}
SRD5A2	Androgen metabolism	rs523349	cSNP	Abiraterone		⁽⁷¹⁾
SLCO2B1	Androgen transporter	rs1077858, rs1789693, rs34550074	iSNP, iSNP, cSNP	Abiraterone		⁽⁷²⁾
		rs12422149	cSNP	Abiraterone		⁽⁷³⁾
YB-1	Androgen receptor regulator	rs10493112	iSNP	Abiraterone		⁽⁷⁴⁾
CYB5A	CYP17A1 activity regulator	rs1790834	iSNP	Abiraterone		⁽⁷⁵⁾
TSPYL1	CYP17A1 and CYP3A4 regulator	rs3828743	cSNP	Abiraterone		⁽⁷⁶⁾
SULT1E1	Estrogen metabolism	Group 1 (rs3775777, rs4149534, rs10019305)	iSNP	Abiraterone		⁽⁷⁷⁾
SULT1E1	Estrogen metabolism	Group 2 (rs3775770, rs4149527, rs3775768)	iSNP	Abiraterone		⁽⁷⁷⁾

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Table 4. Genetic Polymorphisms Associated with the Outcomes of Multiple Treatments.

From: Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer

Gene name	rs number	Treatment regimen	Risk allele	Outcome	Reference
CYP17A1	rs6162	ADT	G	OS	⁽¹²⁾
	rs743572	ADT	A	OS	⁽¹³⁾
		ADT	A	PFS	⁽¹⁴⁾
	rs2486758	Abiraterone	C	PFS	⁽⁶⁸⁾
		Abiraterone	C	PFS	⁽⁶⁹⁾
	rs10883783	Abiraterone	A	PFS	⁽⁷⁰⁾
HSD3B1	rs1047303	ADT	C	PFS, MFS, OS	⁽¹⁸⁾
		ADT	C	PFS	⁽¹⁹⁾
		ADT	C	MFS	⁽²⁰⁾
		ADT	C	PFS	⁽²¹⁾
		ADT	C	PFS, OS	⁽²²⁾
		ADT+Docetaxel	C	PFS, OS	⁽²²⁾
		Abiraterone	Null	PFS	⁽⁶⁴⁾
		Abiraterone	A	PFS, OS	⁽²¹⁾
		Abiraterone/Enzalutamide	C	OS	⁽⁶⁵⁾
		Abiraterone/Enzalutamide	C	PFS	⁽⁶⁶⁾
	rs1856888	ADT	A	PFS	⁽¹⁵⁾
		ADT	G	OS	⁽²³⁾
SRD5A2	rs523349	ADT	G	PFS, OS	⁽²⁶⁾
		Abiraterone	G	PFS	⁽⁷¹⁾
SLCO1B3	rs4149117	ADT	T	OS	⁽²⁷⁾
			T	PFS	⁽²⁸⁾
			T	CSS	⁽²⁹⁾
		Cabazitaxel	Null	OS	⁽⁷⁹⁾
SLCO2B1	rs1077858	ADT	G	PFS	⁽³⁰⁾
		ADT	G	OS	⁽³¹⁾
		Abiraterone	G	MRD	⁽⁷²⁾
	rs1789693	ADT	T	PFS	⁽³⁰⁾
		Abiraterone	T	MRD	⁽⁷²⁾
	rs34550074	Abiraterone	T	MRD	⁽⁷²⁾
	rs12422149	ADT	A	CSS	⁽²⁹⁾
		ADT	G	PFS	⁽³⁰⁾
		ADT	G	PFS	⁽³²⁾
		ADT	G	PFS	⁽³¹⁾
		Abiraterone	G	PFS	⁽⁷³⁾
YB-1	rs10493112	Abiraterone	A	PFS	⁽⁷⁴⁾
	rs12030724	ADT	A	PFS	⁽³⁹⁾
		ADT	A	PFS, OS	⁽⁴⁰⁾
ESR1	rs1062577	ADT	A	OS	⁽¹²⁾
	rs2234693	Docetaxel	C	PFS	⁽⁸⁰⁾
	rs9340799	Docetaxel+Thalidomide	G	PFS	⁽⁸⁰⁾

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Table 5. Genetic Polymorphisms Associated with the Outcome of Taxane Treatment for Castration-Resistant Prostate Cancer.

From: Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer

Gene name	Function	rs number	Polymorphism types	Treatment	Validation	Reference
CYP1B1	Drug metabolizing enzyme	rs1056836	cSNP	Docetaxel	Validated	^{(82), (83)}
ABCB1	Drug excretion pump	rs1128503, rs2032582, rs1045642	cSNP	Docetaxel+Thalidomide		⁽⁸⁴⁾
ABCB11	Drug excretion pump	rs7602171	iSNP	Docetaxel+Thalidomide		⁽⁸⁵⁾
ABCG2	Drug excretion pump	rs2231142	cSNP	Docetaxel+Vinorelbine/Estramustine phosphate		⁽⁸⁶⁾
ESR1	Steroid receptor	rs2234693, rs9340799	iSNP	Docetaxel+Thalidomide		⁽⁸⁰⁾
GSTP1	Antioxidant	rs1138272	cSNP	Docetaxel+Thalidomide		⁽⁸⁵⁾
SLC5A6	Transporter	rs1395	cSNP	Docetaxel+Thalidomide		⁽⁸⁵⁾
VEGFA	Angiogenesis	rs1570360	rSNP	Docetaxel, Celecoxib+Cyclophosphamide		⁽⁸⁷⁾

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Table 6. Druggable Targets in Androgen Metabolism and Their Inhibitors.

From: Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer

Target enzyme	Inhibitor	Developmental status
CYP17	Abiraterone	Approved
	Orteronel (TAK-700)	Phase III (terminated)
	Galeterone	Phase II (terminated)
3β-HSD	Trilostane	Phase II (terminated)/on market for Cushing's syndrome
AKR1C3	Indometacin	Phase II/on market as NSAIDs
	N-(indolylcarbonyl)-piperidines	Phase I
5α-reductase (types I and II)	Dutasteride	Phase II (terminated)/on market for benign prostatic hyperplasia
5α-reductase (type II)	Finasteride	On market for androgenetic alopecia

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