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Mutational activation of RAS and GSP oncogenes in differentiated thyroid cancer and their biological implications
P E Goretzki1, J Lyons, S Stacy-Phipps
1Department of Pharmacology, University of California, San Francisco.
Abstract:
Activating mutations of ras-genes (Kirsten-ras, Harvey-ras, N-ras) and genes encoding for the alpha subunit of G-proteins (Gs, Gi2, Gi3, Go, Gz) were assessed in 32 differentiated thyroid cancer (DTC) tissues from German (n = 22) and American (n = 10) patients. Gs-protein (GSP) and/or ras mutations were found in 69% of all tissues with a heterogeneous distribution pattern. An increased prevalence could be demonstrated in metastatic (8 of 9 mutation positive) when compared to localized disease (13 of 23 mutation positive) (p less than 0.001) and in patients greater than 50 years of age (16 of 18 mutation positive), when compared to younger patients (6 of 14 mutation positive) (p less than 0.001). No activating mutations were found on H-ras and K-ras genes nor on genes encoding for the alpha subunits of Gi2, Gi3, Go, and Gz. Differentiated thyroid cancer tissue from German patients revealed a higher prevalence for GSP mutations (73%) than did DTC from American patients (20%) (p less than 0.001). We demonstrated a high frequency of ras and GSP mutations in DTC and suggest that these mutations may contribute to our basic understanding of this disease and might initiate a new search for more rational and individualized therapeutic approaches in patients with DTC.
Insights
Activating mutations in Gs-protein (GSP) and ras genes are common in differentiated thyroid cancer (DTC). These genetic alterations are more prevalent in metastatic disease and older patients, suggesting potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Differentiated thyroid cancer (DTC) is a common endocrine malignancy.
- The role of specific gene mutations in DTC pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the prevalence of activating mutations in ras-genes and G-protein alpha subunits in DTC tissues.
- To correlate mutation status with clinical parameters such as disease stage and patient age.
Main Methods:
- Analysis of DNA from 32 differentiated thyroid cancer tissues (22 German, 10 American) for mutations in ras-genes (K-ras, H-ras, N-ras) and G-protein alpha subunits (Gs, Gi2, Gi3, Go, Gz).
- Mutation detection using established molecular techniques.
Main Results:
- Activating mutations in Gs-protein (GSP) and/or ras genes were found in 69% of DTC tissues.
- Mutations were significantly more frequent in metastatic disease (8/9) compared to localized disease (13/23) (p < 0.001).
- Higher prevalence of mutations was observed in patients >50 years old (16/18) versus younger patients (6/14) (p < 0.001).
- No mutations were detected in H-ras, K-ras, or Gi2, Gi3, Go, Gz genes.
- German patients showed a higher prevalence of GSP mutations (73%) than American patients (20%) (p < 0.001).
Conclusions:
- Activating ras and GSP mutations are frequent in differentiated thyroid cancer.
- These mutations may play a role in DTC development and progression.
- Findings suggest potential for targeted therapies in DTC based on mutation status.