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NF1 gene loss of heterozygosity and expression analysis in sporadic colon cancer
T Cacev1, S Radosević, R Spaventi
1Division of Molecular Medicine, Ruder Bosković Institute, Bijenicka c 54, HR-10000 Zagreb, Croatia. tcacev@irb.hr
Background And Aims:
Colon cancer tumorigenesis is a multistep process of mutation accumulation in a number of oncogenes and tumour suppressor genes. NF1 gene protein, neurofibromin, acts as a tumour suppressor by turning the active form of Ras into an inactive form. This molecular switch has an important role in the control of the cell cycle and differentiation, and changes in Ras activity are present in many different cancers. This is the first study to investigate the role of NF1 in sporadic colon cancer.
Methods:
We investigated loss of heterozygosity (LOH) at the NF1 locus. Real time reverse transcription-polymerase chain reaction was used to determine NF1 mRNA expression in tumours and corresponding normal tissue. Expression of neurofibromin was analysed by immunohistochemistry. Relative ratio of NF1 mRNA type I and II isoform expression was also examined.
Results:
LOH of the NF1 gene was detected in 20.7% of heterozygous samples. NF1 mRNA expression was significantly increased in tumour tissue compared with corresponding normal tissue (p = 0.04291). There was a statistically significant increase in NF1 type I isoform expression (p = 0.0005) in tumour tissue compared with corresponding normal colon tissue. NF1 isoform type II was predominantly expressed in normal tissue while the NF1 isoform type I prevailed in tumour samples. The transition from dominant expression of isoform type II in normal mucous tissue 15 cm away from the tumour to dominant expression of isoform type I in tumour tissue itself was detected. Total neurofibromin expression increased as tumours were more advanced but expression of wild-type neurofibromin remained the same.
Conclusions:
Our findings suggest that the NF1 gene may play a role in the development and progression of colon cancer and the NF1 gene may be a potential tumour marker and a new potential target for colon cancer therapy.
Insights
The NF1 gene, neurofibromin, may play a role in colon cancer development. Increased NF1 mRNA expression and a shift in isoform dominance were observed in tumor tissues, suggesting its potential as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Colon cancer tumorigenesis involves accumulating mutations in oncogenes and tumor suppressor genes.
- Neurofibromin (NF1) protein functions as a tumor suppressor by inactivating Ras.
- Altered Ras activity is implicated in various cancers, making NF1 a gene of interest.
Purpose of the Study:
- To investigate the role of the NF1 gene in sporadic colon cancer.
- To analyze NF1 gene alterations, mRNA expression, and protein expression in colon tumors.
Main Methods:
- Loss of heterozygosity (LOH) analysis at the NF1 locus.
- Real-time reverse transcription-polymerase chain reaction (RT-PCR) for NF1 mRNA expression.
- Immunohistochemistry for neurofibromin expression and isoform analysis (Type I and II).
Main Results:
- LOH of the NF1 gene was found in 20.7% of heterozygous samples.
- NF1 mRNA expression was significantly increased in tumor tissue compared to normal tissue (p=0.04291).
- NF1 type I isoform expression increased significantly (p=0.0005) in tumors, while type II dominated in normal tissue. Total neurofibromin increased with tumor advancement.
Conclusions:
- The NF1 gene may contribute to colon cancer development and progression.
- NF1 alterations and expression patterns suggest its potential as a colon cancer biomarker.
- The NF1 gene represents a potential therapeutic target for colon cancer treatment.
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