Gene, genetics and genetic medicines in gastroenterology: Current status and its future

Table 10 Genes which regulates response to targeted therapy[101-125]

Disorder	Gene/mutation	Role	Treatment/clinical implication	Ref.
Colorectal cancer	KRAS (codon 12/13)	Predicts resistance to anti-EGFR therapy	Avoid cetuximab/panitumumab in mutant cases	Zhu et al[101]
Colorectal cancer	NRAS mutations	Similar to KRAS	Also predicts non-response to EGFR inhibitors	Hu et al[102]
CRC, cholangiocarcinoma	BRAF V600E	Poor prognosis, targetable	Consider BRAF + MEK inhibitors	Rizzo et al[103]
Gastric, colorectal cancer	HER2 (ERBB2) amplification	Targetable mutation	Responds to trastuzumab, pertuzumab	Bang et al[104]
CRC, gastric, biliary	MSI-H/dMMR	Biomarker for immunotherapy. Poor response to chemotherapy in stage 2 tumor	Eligible for checkpoint inhibitors (e.g., pembrolizumab)	Le et al[105]
HCC	CTNNB1 (β-catenin)	Resistance to immunotherapy	Poor response to immunotherapy	Shah et al[106]
	EZH2	Resistance to immunotherapy	Negatively express PD-L1	Xiao et al[107]
Crohn’s disease (IBD)	SNP rs396991GG of gene FCGR3A, rs976881-AA + GA (TNFRSF1B), SNPs in loci DENND1B (rs2488397) and aryl hydrocarbon receptor (rs1077773) s1813443-CC and rs1568885-TT (CNTN5) from the immunoglobulin superfamily	Resistance to biologics	Poor response to immunotherapy	Curci et al[108]; Yoon et al[109]; Ye and McGovern[110]
	Polymorphisms in ATG16 L1 (C11orf30; rs7927894CC, CCNY; rs12777960CC) (rs10210302)		Clinical response to adalimumab	Koder et al[111]
Crohn’s disease (IBD)	Polymorphisms in NOD2		Loss of response to anti-TNF	Juanola et al[112]
UC	Polymorphisms in IL-23R		Early response to infliximab	Jürgens et al[65]; Golan et al[113]
Crohn’s disease	ATG16 L1, IRGM	Autophagy pathway genes	Predict disease course and microbiome interaction	Rioux et al[114]
	Polymorphisms in FcγRIIIa, HLA-DRB1, HLA-DQA1 05		Development of ADA against infliximab and adalimumab	Salvador-Martín et al[115]; Billiet et al[116]
	Polymorphisms in FAS, FASL, and CASP9 (apoptotic pharmacogenetic index)		Clinical response to infliximab and adalimumab	Hlavaty et al[117]
	Gene protein tyrosine phosphatase non-receptor type 2 (rs7234029AG + GG, CASP9)		Non-response to anti-TNF and ustekinumab	Hlavaty et al[117]
HCC	EZH2		Negatively regulate PD-L1 expression. Less response to PD-L1 agonist	Meng et al[118]
	TOP2A, PRC1		Resistance to chemotherapy	Meng et al[118]; Wang et al[119]
IBS	TJP1, TPH1, SERT (SLC6A4)	Serotonin signaling, barrier dysfunction	May guide use of 5-HT3 antagonists or SSRIs	Camilleri et al[120]; Kerckhoffs et al[121]
Hereditary pancreatitis	SPINK1, PRSS1, CTRC	Trypsin regulation defects	May influence early interventions and surveillance	Panchoo et al[122]
Autoimmune hepatitis	HLA-DRB103, 04	Susceptibility and severity	May predict treatment response to steroids/immunosuppressants
Gastric, pancreatic, cholangiocarcinoma	ARID1A mutations	Epigenetic dysregulation	May predict response to EZH2 inhibitors or immunotherapy
Pancreatic cancer	KRAS		Anti EGFR treatment in effective	Fotopoulos et al[123]
	hENT1		Good response to gemcitabine therapy
	DCK		Increase active form of gemcitabine and increase survival
	DPD		Low DPD level associated with increase survival
	hMLLH1/2		Pancreatic cancer with MSI associated with less response to 5-FU
	TS		Lower level of TS associated with better response to capecitabine and 5-FU
	WOXX		Decreased expression interferes with gemcitabine sensitivity
	SMAD4 (DPC4)		Poor response to chemotherapy
GBC	ARID1A		Potential sensitivity to EZH2 inhibitors or immunotherapy	Wardell et al[124]
	CDKN2A loss/mutation		Resistant to chemotherapy	Nakamura et al[125]

CRC: Colorectal cancer; HCC: Hepatocellular carcinoma; IBD: Inflammatory bowel disease; UC: Ulcerative colitis; IBS: Irritable bowel syndrome; GBC: Gallbladder cancer; MSI-H: Microsatellite instability-high; dMMR: Deficient mismatch repair; SNP: Single nucleotide polymorphism; EGFR: Epidermal growth factor receptor; MEK: Mitogen-activated protein kinase; PD-L1: Programmed death-ligand 1; ADA: Anti-drug antibody; TNF: Tumor necrosis factor; SSRIs: Selective serotonin reuptake inhibitors; 5-HT3: 5-hydroxytryptamine type 3 (serotonin receptor); DPD: Dihydro pyrimidine dehydrogenase; 5-FU: 5-fluorouracil.