MUTATIONAL ACTIVATION OF RAS AND GSP ONCOGENES IN DIFFERENTIATED THYROID-CANCER AND THEIR BIOLOGICAL IMPLICATIONS

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 < 0.001) and in patients > 50 years of age (16 of 18 mutation positive), when compared to younger patients (6 of 14 mutation positive) (p < 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 < 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.