Cancer, immune disorders

Behcet's disease

Behcet's disease, also known as silk road disease, is a rare immune disease characterized by small blood vessel vasculitis, mucous membrane ulceration, and ocular defects. Affected systems include the gastrointestinal tract, pulmonary, musculoskeletal, cardiovascular, and nervous system. This disease is often fatal due to aneurysms or severe neurological defects. JAK1 has been proposed as a suceptibility gene for Behcet's disease. Three single nucleotide polymorphisms (SNPs) in the JAK1 gene were associated with a signficantly increased risk for the development of Behcet's disease in Han Chinese populations, including rs2780815, rs310241, and rs3790532. When found in an individual, these SNPs were estimated to convey a risk of developing Behcet's disease of 35%, 28%, and 27%, respectively.
 

Colorectal cancer (CRC); Acute myeloid leukemias (AML); Non-small cell lung cancer (NSCLC); Gynecologic cancer

JAK1 may be an oncoprotein (OP). Abnormal activity of STAT3 is implicated in the oncogenesis of several cancer types, including colorectal cancer and non-small cell lung cancer. JAK1 has been implicated in promoting the survival, invasion, and migration of colorectal cancer and non-small cell lung cancer cells due to over activation of STAT transcription factors resulting in the aberrant expression of certain downstream genes, such as Bcl-2, p21, p27, E-cadherin, VEGF, and MMPs. In addition, somatic mutations in the JAK1 gene have been observed in patients with acute myeloid leukemia (AML), including both T478S and V623A substitution mutations. The mutant JAK1 proteins displayed significantly enhanced activation of downstream STAT1 in response to type 1 interferon treatment, as well as increased activation of multiple dowstream intracellular signalling pathways. Truncating mutations of JAK1 have been observed in several cancer types, with 68% of the specimens coming from gynecologic cancers. Within the JAK1 gene sequence, mutations are clustered at the K142, P430, and K860 residues and induce frameshift mutations. Cancer cells with mutant truncated JAK1 protein are defective in IFN-gamma induced expression of LMP2 and TAP1, which inhibits the presentation of tumour antigens to be recognized by the immune system. Therefore, these truncating mutations are hypothesized to promote the ability of tumour cells to evade the immune system, enabling tumour survival.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Barrett's esophagus epithelial metaplasia (%CFC= +46, p<0.026); Bladder carcinomas (%CFC= +109, p<0.0001); Cervical cancer stage 2A (%CFC= +147, p<0.008); Cervical cancer stage 2B (%CFC= +124, p<0.103); Classical Hodgkin lymphomas (%CFC= -48, p<0.083); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= -91, p<0.0001); Oral squamous cell carcinomas (OSCC) (%CFC= +84, p<0.0006); Ovary adenocarcinomas (%CFC= -57, p<0.017); Pituitary adenomas (ACTH-secreting) (%CFC= +149); and Skin melanomas - malignant (%CFC= -47, p<0.0001). The COSMIC website notes an up-regulated expression score for JAK1 in diverse human cancers of 256, which is 0.6-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 156 for this protein kinase in human cancers was 2.6-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.09 % in 30277 diverse cancer specimens. This rate is only 20 % higher than the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.36 % in 1393 large intestine cancers tested; 0.32 % in 602 endometrium cancers tested; 0.22 % in 683 stomach cancers tested; 0.14 % in 805 skin cancers tested; 0.11 % in 5026 haematopoietic and lymphoid cancers tested; 0.1 % in 2069 lung cancers tested; 0.08 % in 1654 liver cancers tested; 0.07 % in 1709 breast cancers tested.

Most frequent mutations with the number of reports indicated in brackets: R724H (10); S703I (7); V658F (7).

Broad distribution of mutation sites with many point mutations, deletions, insertions and at least three complex mutations across the entire protein.