18q22.3

CYB5,MCB5,METAG

Breast cancer

The effects of cytochrome b5 on breast cancer remain unclear. A proteomic approach addressed by Neubauer and collaborators found differences in the cytochrome b5 levels of sensitive to tamoxifen (ER+/PR+) and less sensitive (ER+/PR-) mammary tumor specimens. The ER+/PR+ samples exhibited decreased levels of cytochrome b5 and this lead the group to suggest that the differential susceptibility against tamoxifen might, in part be explained, as a result of aberrant cytochrome b5-dependent metabolism.

Pancreatic cancer

CYB5A has been recently identified as a prognostic factor for Pancreatic Cancer Adenocarcinoma (PDAC). Giovannetti and collaborators performed comparative genomic hybridization studies in resected patients and found a significant correlation between decreased survival and the loss of the cytoband 18q22.3, where CYB5A is located. Analysis of mRNA and protein levels of other cohorts revealed the prognostic value of CYB5A: decreased CYB5A expression levels were associated with shorter survival. In vivo orthotopic models with patient-derived CYB5A+ cells showed a significant reduction in tumor size coupled with increased survival compared to the controls. Interestingly, additional gain- and loss-of function studies performed by the group revealed a novel role of CYB5A, namely, autophagy induction.

Hepatocellular carcinoma (HCC)

Lee and collaborators addressed a proteomic approach in order to identify novel biomarkers in resected tumor and adjacent non-malignant tissue samples of 80 HCC patients. This study revealed that CYB5A significantly correlated with serum AFP, a biomarker commonly used for HCC surveillance. Moreover they suggested that its decreased levels might be a result of the disruption of the membrane-bound polysome attachment, which is required for cytochrome b5 type A synthesis.

Lung squamous cell carcinoma

Sriram and colleagues analyzed 62 primary lung SCCs (28 with recurrence and 34 with no evidence of recurrence) using a whole-genome aCGH microarray to identify genomic copy number alterations specific to tumors. They identified CYB5A among prognostic genes that had lower copy number in the lung SCC of patients who recurred (Sriram et al., 2012). Moreover, they demonstrated association of the reduced copy number and mRNA expression of SOCS6 with disease recurrence in SCC patients.

Ovarian cancer

Cortesi et al., performed a comparative proteomic study on biopsies from six consecutive patients with endometrioid or serous ovarian carcinoma who had not been previously treated with chemotherapy prior to surgical resection, in order to recognize potential biomarkers. They identified CYB5A among the proteins separated by 2-DE electrophoresis and detected by MS analysis.

Colorectal tumors

Agostini and collaborators evaluated the value of ten markers including CYB5A (D18S58) in 44 CRC patients, who underwent surgery using a multiplex PCR assay for a rapid and proper classification of tumor microsatellite instability (MSI)-H, MSI-L and MSS. They revealed that a complete panel of these markers could allow the accurate evaluation of tumor MSI status in CRC patients, supporting further investigations on the prognostic value of CYB5A and other markers in management of CRC patients.

Gastric Cancer

Nair and colleagues carried out gene expression analysis in Singapore and UK Gastric cancer datasets using GeneSpring. This study showed the upregulation of CYB5A in the Singapores Population (Nair et al., 2014).

Rheumatoid arthritis (RA)

RA is characterized by decreased androgens levels and CYB5A acts as a cofactor of one of the two enzymes responsible for de novo androgens synthesis, cytochrome P450 17A1 (17,20-lyase). For this reason, Stark and collaborators analyzed the presence of Single Nucleotide Polymorphisms (SNPs) in the CYB5A gene in two published RA Genome Wide Association Study (GWAS) datasets. Subsequently, cytochrome b5 expression analyses as well as androgen production after steroid conversion were evaluated in candidate SNPs from a RA case-control study. Among the most important findings was the identification of a SNP in CYB5A, designated as rs1790834, which was associated to decreased risk of RA. The group suggested that rs1790834 might exert its protective effects by increasing the capacity of androgen synthesis.

Type 2 diabetes and adiposity

Huang and colleagues performed whole exome sequencing in order to identify potential functional coding variants affecting metabolic processes associated with increased risk of type 2 diabetes. Their analyses revealed a SNP in CYB5A, designated as rs7238987, which was significantly associated with pre-diabetic traits such as Percentage Body Fat (PFAT) and Body Mass Index (BMI). All together, the group identified a potential new locus for adiposity and higher risk of type 2 diabetes. Nevertheless, functional studies validating these results are still lacking.

Cushing Syndrome

The effects of cytochrome b5 on cytochrome P450 17A1 have been shown by distinct research groups. Since Cushings syndrome is characterized by abnormalities in the production of cortisol and adrenal androgens, the expression levels and activity of cytochrome b5 in this condition have also been evaluated. Sakai and colleagues performed in vitro biochemical assays on adrenocortical adenoma tissue from Cushins syndrome patients and found high levels of cytochrome b5, which correlated with higher 17,20-lyase activity. Moreover, an immunohistochemical study performed by Yanase and collaborators revealed high cytochrome b5 levels in all adrenocortical layers in adrenal glands, with a particularly intense immunoreactivity in the zona reticularis, providing evidence for the functional association between cytochrome b5 type A and the production of adrenal androgens.