Global gene expression landscape of gallbladder cancer and advances in targeted therapeutic strategies

Table 1 Summarization of most significant dysregulated genes in the genesis of GBC and their geographic heterogeneity

Category of gene	Gene name	Criteria of genetic dysregulation	Geographic heterogeneity in proportion of dysregulated expression amongst studied GBC samples
Oncogenes	EGFR	Overexpression	8.1% in Japan - 93.3% in North India
	ERBB2	Overexpression	12.8% in Chile - 56.6% in North India
	CCND1 (encoding cyclin D1)	Overexpression	5.6% in South Korea - 68.3% in China
	BCL2	Overexpression	7.7% in South Korea - 18.4% in Japan
	BRIC5 (encoding survivin)	Overexpression	58% in India - 76.5% in Turkey
	MYC	Amplification	3.7% in Japan - 86.7% in Brazil
	MET	Overexpression	5.6% in Japan - 74% in South Korea
Tumor supressor genes	FHIT	Downregulation	45% in Japan - 94% in Chile
	CDKN2A	Downregulation	20% in South Korea - 88% in North India
	Mutated TP53	Overexpression	56% in North India - 71% in Spain
Angiogenesis factors	PTGS2 (encoding COX-2)	Overexpression	59% in Slovenia - 80% in South Korea
	VEGFA	Overexpression	48% in India - 81% in Chile
Cell-adhesion molecule	CDH1 (encoding E-cadherins)	Downregulation	26% in Chile - 67% in North India
Cancer stem cell gene	POU5F1 (encoding Oct4)	Overexpression	59% in China - 64.5% in North India
Immunoinhibitory molecule	CD274 (encoding PD-L1)	Overexpression	10.9% in Croatia - 40% in Japan

GBC: Gallbladder cancer.

Table 2 Overview of top differentially expressed genes in gallbladder cancer from sequencing studies

Number of samples	Comparison	List of significantly upregulated genes in GBC	List of significantly downregulated genes in GBC	Geographic and ethnic background	Ref.	Technique employed
3 pairs	Gallbladder wall of gallbladder adenoma and GBC (common) vs gallbladder wall of gallstones	EDN1, MS4A8, ALB, MSLN, CTSV, BAG1, LOC100507412, MCOLN3, ZKSCAN1	TBX3, TSK, SCD, NOVA1, PFKFB3	China	Ge et al[106], 2021	Microarray
3 pairs	GBC tissue vs gallbladder adenoma tissue	CEACAM5, OLFM4, TFAP2A, CDH17, VAV3, CD55, CPS1, KRT17, SERPINB5, HEPH, ALB, HMGS2, CHP2, TFF1, TRIM31, SULF1, HOXB6, GUCY1A3, C15orf48, HIST1H2AI		China	Ge et al[106], 2021	Microarray
3 pairs	GBC tissue vs para-cancerous tissue	KLK6, TNNT1, DUOXA1, CEACAM7, SLC44A5, CDC45	CNTN1, CPVL, PTGER3, ADRB3, LYVE1, DES, KLRG1, NRK, AOAH, PRKCB, TAGAP, GREM2, KLRD1, KCNMA1, PCDH18, KCTD12, FBLN1, CHRM2, FGF7	China	Wang et al[107], 2017	Microarray
16 samples	12 advanced GBC tissues vs 4 chronic cholecystitis tissues	Skp2, BUB1, MAD2 L1, ESPL1, E2F1, CHEK1, CDK2, CCNB1, CDC20, CDC2, PKMYT1, RBL1, CDC45, STAT1, TNF, SOD2, MCM4, POLE, RCF-4, PASK, ECT2, KIF20, CENPF, TPX2	SMOC2, WNT10B, FGF2, CCND2, TGF-β3, COX7A1, CKMT2.	India	Kumar et al[108], 2020	Microarray
11 samples	8 GBC vs 3 normal gallbladder tissues	SERPINB3, DUSP1, FOXJ1, CHP1, KLK5, HOXB13, HOXB9, MAGEB2, KLK1, HOXC11, HOXC10, HOXC9, CLCA4, OLFM4, PI3, MUC17, SERPINB7, LEMD1, FAM71E2, TRIM29, TRIM31, CDC45, CDH3	DCAF12 L, PPAN-P2RY11, ZNF275, GIMAP1-5, MT1M, APOA1, PGLYRP2, SHBG, CYP1A1, GOLGA6A, BMP10, HEPN1, TTC36, FAM99B, HEPACAM, RTP3, CYP3A43, SHBG, PLGLA, GDF2, FGF21, PAQR9, CREB3 L3, FETUB, FCN2, CPN1, PRODH2, PKLR, SERPINA11, SERPINA1, ARID3C	United States	Zuo et al[109], 2016	RNA seq
2 pairs	2 GBC vs 2 adjacent non-tumorous tissues	OLFM4, BIRC5, TK1, PI3, TNNT1, CLIC3, MMP9, TRIM29, SERPINA1	DPT, SMOC2, GLP2R, LMOD1, FBLN5, WNT2B	China	Gu et al[110], 2015	RNA seq
10 samples	10 GBC tissues vs normal gallbladder tissues from SRA database	MSLNL, FOXJ1, HMGA2, KRT17, MYEOV, LYPD2, REG4, TMEM238, TRIM31, NOTUM, LRFN4	IGCSF10, GCG, NLGN4Y, PAH, CCKAR, CHRM2, CRISP3, FGF19, GLYATL2, ADIPOQ, DMBT1, CHRDL1	India	Dixit et al[40], 2022	RNA seq

GBC: Gallbladder cancer; RNA seq: RNA sequencing.

Table 3 Overview of targeted gene therapy in gallbladder cancer currently undergoing clinical trial

Agent	Target gene/pathway	Combined with	Patient characteristics	NCT number	Clinical trial location
Trastuzumab	Her2	Pembrolizumab + gemcitabine	Previously untreated Her2+ unresectable cholangiocarcinoma and GBC	NCT06178445	Germany
Trastuzumab		Tucatinib	Unresectable or metastatic Her2 overexpressed/amplified BTC, including GBC, cervical cancer, uterine cancer, and urothelial cancer	NCT04579380	Belgium, Germany, Italy, Japan, Korea, Netherlands, Poland, Spain, United Kingdom, United States
Zanidatamab		Cisplatin + gemcitabine	Locally advanced unresectable or metastatic BTC, including GBC	NCT06282575	Argentina, Belgium, Brazil, Canada, Chile, China, Finland, France, Germany, India, Israel, Italy, Japan, Korea, Portugal, Puerto Rico, Romania, Spain, Sweeden, United Kingdom, United States
Zanidatamab		Combination chemotherapy	Unresectable locally advanced or metastatic, recurring Her2+ BTC, including GBC and colorectal cancer	NCT03929666	United States, Canada, Chile, Korea
RC48-ADC		NA	Previously treated locally advanced or metastatic Her2+ BTC, including GBC, who have failed first-line chemotherapy	NCT04329429	China
Afatinib	EGFR	Gemcitabine + oxaliplatin	Resectable GBC patients	NCT04183712	China
Tivozanib	VEGFR/VEGF	Atezolizumab	Stage IV otherwise incurable cancer including: GBC, bile duct cancer, pancreatic adenocarcinoma, prostate cancer, ovarian cancer	NCT05000294	United States
Tivozanib		NA	Unresectable cholangiocarcinoma and GBC, previously treated by at least one type of chemotherapy	NCT04645160	United States
Bevacizumab		Gemcitabine + albumin-paclitaxel + sintilimab	Initially unresectable GBC	NCT05757336	China
Ivonescimab		NA	Previously treated GBC, who have failed first-line chemotherapy	NCT06529718	Belgium, France, United Kingdom
Surufatinib		Tislelizumab	First line of treatment for unsectable or metastatic BTC, including GBC.	NCT06134193	China
Envafolimab	PD-L1	Gemcitabine + cisplatin	First line of treatment for advanced BTC, including GBC	NCT06013943	China
Durvalumab		Gemcitabine hydrochloride + cisplatin + nab-paclitaxel	Locally advanced or metastatic GBC	NCT06591650	China
Durvalumab		Tremelimumab + capecitabine	A phase II study in BTC patients after curative surgery	NCT05239169	Germany
Camrelizumab		Gemcitabine + oxaliplatin	Unresectable GBC	NCT06423170	China
Everolimus	mTORC1	Standard chemotherapy	First line of treatment for metastatic or unresectable GBC	NCT05833815	India
Merestinib	MET	Cisplatin + gemcitabine	First line of treatment in advanced BTC, including GBC	NCT02711553	United States, Argentina, Australia, Austria, Belgium, China, Denmark, France, Germany, Hungary, Korea, Mexico, Spain, Sweeden, Turkey, United Kingdom

GBC: Gallbladder cancer; BTC: Biliary tract cancer; NCT: National clinical trial; NA: Not available; VEGF: Vascular endothelial growth factor; PD-L1: Programmed death-ligand 1.