6q27

RNASE6PL,bA514O12.3

Ovarian cancer

Loss of expression or downregulation of RNASET2 occurs in a significant fraction of human ovarian cancer cell lines and primary ovarian tumours. Moreover, the genomic region (chromosome 6q27) where the RNASET2 genes maps has been reported to be frequently deleted or otherwise rearranged in a high fraction of ovarian cancer samples. However, no mutation in the RNASET2 gene have been described so far in human ovarian cancer samples. Therefore, this gene seems to be involved in tumor suppression mainly by means of its downregulation at the transcript/protein level in this cancer type. When overexpressed by gene transfer experiments in human ovarian cancer cell lines displaying a low level of endogenous mRNA, RNASET2 strongly suppresses the tumorigenic and metastatic potential of these cell lines in a murine xenogratf model in vivo. The same observation was reported following a complementary experiment, i.e. by knocking-down RNASET2 expression in a poorly aggressive ovarian cancer cell line expressing high levels of endogenous RNASET2.
In both in vivo models, RNASET2-mediated tumor suppression was associated with a marked recruitment of cells from the monocyte/macrophage lineage in the tumor mass. Further experiments have demonstrated a direct chemotactic role for cells from the monocyte/macrophage carried out by the RNASET2 protein. Very recently, downregulation of RNASET2 expression has been associated with resistance to cis-platin and carboplatin in ovarian cancer cells and tissues.

Malignant melanoma

Besides ovarian carcinoma, the chromosome region 6q27 (where the RNASET2 genes maps) has been reported to be frequently deleted or rearranged in malignant melanoma. Downregulation of RNASET2 has also been reported in cell lines representing this cancer type. Overexpression of RNASET2 in the human melanoma-derived SK-MEL28 cell line was associated with a significant suppression of tumor growth in vivo (in a xenograft model with immunocompromised mice), but not in vitro, supporting the notion of RNASET2 as a tumor-antagonizing gene whose oncosuppressive action is carried out asimmetrically, i.e. only in the context of a complex tissue architecture where a significant cross-talk between cancer cells and the stromal compartment take place. Moreover, the T2 RNase protein encoded from the Aspergillus niger ortholog gene has been shown to inhibit human melanoma cell growth and metastasis in a xenograft model. The underlying oncosuppressive mechanism in this model was the inhibition of tumor angiogenesis by means of competitive inhibition with angiogenin.

Colorectal cancer

In an HT29 human colon cancer-derived xenograft experimental model, human recombinant RNASET2 was shown to greatly suppress tumor growth in vivo independent from its catalytic activity. Tumor angiogenesis was mainly affected by recombinant RNASET2 injection in this cancer model.

More recently, screening of a protein microarray with sera from anaplastic large cell lymphoma (ALCL) patients identified RNASET2 as an ALK-negative ALCL-associated antigen.

Cystic leukoencephalopathy

Several loss-of function mutations have been reported in probands affected by cystic leukoencephalopathy, an autosomal recessive disorder whose clinical and radiological phenotype is indistinguishable with respect to the pattern of brain abnormalities observed in people suffering from congenital cytomegalovirus infection. Affected people develop several neurologic abnormalities in the early post-natal period, including psychomotor defects, seizures and sensorineural hearing impairment, characterized by a diagnostic MRI pattern.

Six independent mutations in the RNASET2 gene have been reported in both familial and sporadic cases affected by cystic leukoencephalopathy. All mutations are predicted to result in a loss of function phenotype.

The C184R mutant RNASET2 protein expressed from the 550T>C allele showed defective intracellular trafficking, likely due to impaired protein folding or stability.

Autoimmune disorders

Genome-wide association studies have recently implicated the RNASET2 locus in the susceptibility for a few autoimmune disorder, such as vitiligo, Crohns disease and Graves disease.