DOG1, discovered on GIST-1),TMEM16A, gene FLJ10261, TMEM16A,and ORAOV2 (overexpressed in oral carcinoma)

DOG1 is a protein of unknown function which is selectively expressed in gastrointestinal stromal tumour. The DNA sequence of DOG1 predicts eight transmembrane regions, suggesting that the protein may act as an ion channe and it has been identified wit. a calcium dependent,receptor-activated chloride channel protein, also known as anoctamin 1. The gene is located at 11q13. DOG1.1 and DOG1.3 are both mouse monoclonal antibodies against the DOG1 protein.

Immunohistochemical expression

Cajal cells of the myenteric plexus stain with DOG1.1.
Mast cells stain with polyclonal anti-DOG13, but not with DOG1.12 or clone K94.
Epithelium of breast, prostate, salivary gland, liver, stomach, testis, pancreas, and gallbladder3,4.
Transitional epithelium of the bladder4.
Sweat glands but not other components of skin4.
DOG1 antiserum reacted with a number of tumour cores in a carcinoma array3.

The following tissues do NOT stain for DOG-1:

Connective tissue, smooth muscle and neural tissue of the gastrointestinal tract4.
Brain, thymus, tonsil, placenta, testis or postmenopausal ovary4.

Gastrointestinal Stromal Tumour		c-KIT
Gastrointestinal Stromal Tumour		positive	negative	total
DOG1 clone K9	positive	9604	264	9864
	negative	274	274	544
	total	9874	534	10404

GISTs by site:

Reference 4		DOG clone K9				c-kit
Reference 4		0	+< 10% of tumour cells	++10% to 30% of tumour cells	+++> 30% of tumour cells	0	+< 10% of tumour cells	++10% to 30% of tumour cells	+++> 30% of tumour cells
Oesophagus
Stomach	spindle cell sclerosing	2/36	1/36		33/36	1/36		3/36	33/36
	spindle cell palisading vacuolated		1/116	2/116	113/116
	spindle cell hypercellular	3/47		1/47	43/47	2/47	1/47	1/47	43/47
	spindle cell sarcomatous	3/68	1/68	2/68	62/68	3/68	2/68	6/68	57/68
	epithelioid sclerosing	11/115	6/115	8/115	90/115	13/115	10/115	22/115	70/115
	epithelioid discohesive	4/44	5/44	14/44	21/44	11/44	7/44	9/44	17/44
	epithelioid hypercellular	2/31	1/31	2/31	26/31	4/31	1/31	3/31	23/31
	epithelioid sarcomatous			1/9	8/9		1/9		8/9
	epithelioid/spindle and mixed	5/71	2/71	5/71	59/71	6/71	2/71	12/71	51/71
	total		17/537	37/537	445/537		24/537	60/537	413/537
Small intestine		14/372		6/372	352/372	9/372		3/372	360/372
Duodenum		4/57			53/57			1/57	56/57
Colon and rectum		5/64			59/64	4/64	1/64	4/64	55/64
Omentum		4/38			34/38	1/38	2/38	2/38	33/38
Abdomen NOS		7/90	1/90	3/90	79/90	8/90	3/90	8/90	71/90
Gastric paediatric		1/12			11/12	4/12			8/12
duodenal/small intestinal associated with neurofibromatosis					16/16				16/16
Total		65/1168	18/1168	45/1168	1040/1168	62/1168	30/1168	78/1168	998/1168

		polyclonal anti-DOG1	DOG1.1	DOG1.3	K9	CD117	CD34
GIST	KIT-mutation positive GIST		200/2181, 23/252	197/2231		180/2211	142/2241
	PDGFRA-mutation positive GIST		23/291, 2/112	12/291		3/321	9/331
	Wild-type GIST		33/371, 4/72	31/371		29/351	20/381
	CD117 positive GIST		26/262
	CD117 negative GIST		10/282
	GIST associated with neurofibromatosis		16/162
	paediatric GIST		9/112
	total	136/1393	370/4251			317/4281	254/4301
Leiomyoma			0/221			0/211	0/221
Leiomyoma, intramural, in the GI-tract					0/254
Leiomyoma, of muscularis mucosae of colon/rectum					0/94
Leiomyoma, uterine type, abdomen and retroperitoneum					5/424
Leiomyomatosis peritonealis disseminata					4/174
Leiomyosarcoma		1/403	1/3261		0/684	3/3311	5/3341
Solitary fibrous tumour					0/8including 7 from the abdomen4
Undifferentiated sarcoma			0/791		0/26small intestine, colon/rectum4	1/871	9/851
MPNST			0/851		0/84	0/861	11/831
Neurofibroma			0/531			0/551	38/551
Schwannoma		0/33			0/33Schwannoma, stomach or colon4
Glomus tumour					0/144
Synovial sarcoma		1/203	1/391		6/37including 2 from the stomach4	0/441	1/441
Desmoid fibromatosis		0/173	0/351		0/204	0/321	0/311
Solitary fibrous tumour			0/201			0/211	12/201
DFSP			0/201			0/201	15/171
Dedifferentiated liposarcoma			0/91		0/184	0/101	3/81
Melanoma, metastatic to GI-tract					0/674
Desmoplastic melanoma			1/101			1/101	1/101
Inflammatory pseudotumour			0/41			0/51	0/51
Angiosarcoma			0/141			1/111	7/111
Osteosarcoma			0/141			0/141	0/141
Endometrial stromal sarcoma			0/131			0/121	0/131
Rhabdomyosarcoma			0/121			0/131	0/131
Epithelioid haemangioendothelioma			0/121			3/121	4/121
Well-differentiated liposarcoma			0/111			0/91	0/81
Extraskeletal myxoid chondrosarcoma			0/111			6/111	0/111
Low-grade fibromyxoid sarcoma			0/111			0/111	0/111
Fibroadenoma			0/111			0/111	9/111
Myxoid liposarcoma			0/101			0/101	0/91
Ewing/PNET		1/93	0/101		0/114	1/101	0/91
Clear cell sarcoma			0/71			1/71	0/71
DSRCT			0/61		0/74	1/71	0/71
Pleomorphic liposarcoma			0/31			0/31	0/31
Epithelioid sarcoma			0/31			0/31	1/31
Fibrosarcoma		1/43	0/31			0/31	0/31
Chondrosarcoma			0/31			0/31	0/31
PEComa, abdominal					0/34
Alveolar soft part sarcoma			0/21			2/21	0/21
Endometrial stromal sarcoma					0/84
Phyllodes tumour			0/21			0/21	0/21
Total for all sarcomas other than GISTs			3/9351
Hepatocellular carcinoma			1/41	Supplementary data on staining of non-sarcomatous tumours is available on line (subscription required)
Salivary gland	Basal cell adenoma		1/11
Salivary gland	Adenoid cystic carcinoma		1/71
Pulmonary adenocarcinoma			1/81
Gastric adenocarcinoma, intestinal type					8/294
Gastric adenocarcinoma, signet ring cell-type/diffuse					3/134
Colonic adenocarcinoma					1/204
Squamous cell carcinoma of oesophagus					9/154
Undifferentiated sarcomatoid carcinoma of small intestine					0/214
Cholangiocarcinoma of liver					1/64
Carcinoid, small intestine					0/64
Extramedullary myeloid tumour, soft tissues, and skin					0/54
Inflammatory fibroid polyp, small intestine					0/654
Inflammatory myofibroblastic tumour, GI-tract					0/154
Kaposi sarcoma, soft tissue, and skin					0/194
Mastocytoma, skin					0/34
Neuroblastoma					0/74
Seminoma, testicular					0/164
Total for all tumours other than GIST		4/4603			5/5624

Diagnostic utility

Diagnosis of gastrointestinal stromal tumour. Consistent DOG1-negativity of many regularly or potentially KIT-positive tumors, such as metastatic melanoma, seminoma, Ewing sarcoma, and extramedullary myeloid tumor, makes this marker a valuable adjunct in the differential diagnosis of GIST. 2.6% of KIT-positive GISTs of the GI tract (especially small intestinal ones) are negative for DOG1, indicating the need to use both KIT and DOG1 antibodies in problem cases4.

References

1 Espinosa I, Lee CH, Kim MK, et al. A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors. Am J Surg Pathol 2008; 32:210-8 Further information available on line

2 Liegl B, Hornick JL, Corless CL, et al. Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors, including unusual subtypes. Am J Surg Pathol 2009; 33:437-46

3 West RB, Corless CL, Chen X, et al. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol 2004; 165:107-13 FULL TEXT

4 Miettinen M, Wang ZF, Lasota J. DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors: a study of 1840 cases. Am J Surg Pathol. 2009 Sep;33(9):1401-8.

This page last revised 1.10.2009.