RASSF1A

WKP

Definition: RASSF1A tumor suppressor functions as a regulator of the ordered proteolytic steps that organize mitosis. By controlling the stability of microtubules and the activity of the anaphase-promoting complex (APC), RASSF1A might provide a crucial link between mechanisms of tumor suppression and mitotic cell division.

BUB1B and RASSF1A genes play specific roles in the mitotic checkpoint, and their defects may cause chromosome instability or aneuploidy in mouse fibroblasts and human cancer cell lines; however, few studies have reported a correlation between defects in these genes and chromosome changes in human tumor samples.

Ras association domain-containing protein 1 is a protein that in humans is encoded by the RASSF1 gene. This gene encodes a protein similar to the RAS effector proteins.

Loss or altered expression of this gene has been associated with the pathogenesis of a variety of cancers, which suggests the tumor suppressor function of this gene.

The inactivation of this gene was found to be correlated with the hypermethylation of its CpG-island promoter region.

The encoded protein was found to interact with DNA repair protein XPA. The protein was also shown to inhibit the accumulation of cyclin D1, and thus induce cell cycle arrest. Seven alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.

Interactions

RASSF1 has been shown to interact with MAP1B, RASSF5, CNKSR1, HRAS, Death associated protein 6 and MAP1S.

Pathology

 Frequent promoter hypermethylation of RASSF1A and CASP8 in neuroblastoma (17064406)

 Combination of serum RASSF1A methylation and AFP is a promising non-invasive biomarker for HCC patient with chronic HBV infection. (26238200)

• Hypermethylation of the promoter region of the RAS association domain family 1A gene (RASSF1A) occurs widely in hepatocellular carcinoma (HCC) tissues.
• While the diagnostic performance of the use of RASSF1A methylation as a serum or plasma marker in patients with HCC has varied largely in the literature,
• Serum RASSF1A methylation demonstrated a satisfactory value for in the diagnosis of HBV related HCC, and could predict clinical progression and prognosis.
• It suggested that the combination of serum RASSF1A methylation and AFP level may be a promising non-invasive biomarker for the discrimination of patients with HCC from those with CHB.

Minimal residual disease (MRD) in neuroblastoma (NB)

 PCR-based detection of minimal residual disease (MRD) in neuroblastoma (NB) is presently based on NB-specific transcripts. However, the expression of these targets varies between patients and upon treatment, and only PHOX2B is truly specific.

 RASSF1a is methylated (RASSF1a(M)) in NB, and it has been investigated whether it can serve as a specific and stable DNA MRD marker.

 RASSF1a(M) is a novel, highly specific DNA marker for MRD detection in NB, equal to PHOX2B in specificity and sensitivity, and better suitable for MRD quantification.

 It has been proposed to include RASSF1a(M) in further prospective MRD studies in NB alongside RNA MRD markers. In addition, this assay might also be applicable for detection of circulating tumor cells in patients with other cancers withRASSF1a(M) such as breast or lung cancer.

Open references

 Combination of serum RASSF1A methylation and AFP is a promising non-invasive biomarker for HCC patient with chronic HBV infection. Dong X, He H, Zhang W, Yu D, Wang X, Chen Y. Diagn Pathol. 2015 Aug 4;10:133. doi : 10.1186/s13000-015-0317-x PMID: 26238200 (Free)

References

 Haruta M, Matsumoto Y, Izumi H, Watanabe N, Fukuzawa M, Matsuura S, Kaneko Y. Combined BubR1 protein down-regulation and RASSF1A hypermethylation in Wilms tumors with diverse cytogenetic changes. Mol Carcinog. 2008 Feb 19; PMID: 18286482

 Lazcoz P, Munoz J, Nistal M, Pestana A, Encio I, Castresana JS. Frequent promoter hypermethylation of RASSF1A and CASP8 in neuroblastoma. BMC Cancer. 2006 Oct 25;6:254. PMID: 17064406

 Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MW et al. ; A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet. 2007 Feb 11; PMID: 17293864

 Agathanggelou A, Cooper WN, Latif F. Role of the Ras-association domain family 1 tumor suppressor gene in human cancers. Cancer Res. 2005 May 1;65(9):3497-508. PMID: 15867337

 Jackson PK. Linking tumor suppression, DNA damage and the anaphase-promoting complex. Trends Cell Biol. 2004 Jul;14(7):331-4. PMID: 15246424

 Harada K, Toyooka S, Maitra A, Maruyama R, Toyooka KO, Timmons CF, Tomlinson GE, Mastrangelo D, Hay RJ, Minna JD, Gazdar AF. Aberrant promoter methylation and silencing of the RASSF1A gene in pediatric tumors and cell lines. Oncogene. 2002 Jun 20;21(27):4345-9. PMID: 12082624