The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma - Evidence of distinct molecular genetic pathways

BACKGROUND. The two most common types of uterine endometrial carcinoma, end ometrioid (UEC) and serous (USC), differ in their histopathologic appearanc e and biologic behavior. Recent studies suggest that these differences may be associated with distinct molecular genetic alterations. METHODS. In the current study, the authors compared the frequencies of K-ra s and p53 mutations and microsatellite instability (MI) between UEC and USC by analyzing all 3 molecular genetic changes in one set of tumors. Further more, the distribution of these molecular genetic alterations was determine d among UECs of different histopathologic grade. The authors analyzed 58 UE Cs with known MI status for K-ras and p53 mutations. The K-ras and p53 gene s were analyzed in 45 and 6 cases of USC, respectively. These results were combined with previous data on p53 mutations (21 cases) and MI (34 cases) i n USC. RESULTS. MI was present in 16 of 57 UECs (28%) but in none of 34 USCs. p53 mutations were found in 7 of 42 UECs (17%) and 25 of 27 USCs (93%) by direc t sequencing of exons 5-8. UECs and USCs with p53 mutations showed strong i mmunoreactivity for p53 in about 85% of the cases, whereas about 15% of the cases were immunonegative. K-ras mutations at codon 12 were found in 15 of 58 UECs (26%) and in only 1 of 45 USC (2%) by dot blot oligohybridization after polymerase chain reaction amplification of exon 1. Notably, the frequ ency of both K-ras and p53 mutations and MI was significantly different bet ween UEC and USC (P < 0.001). In UECs, MI and K-ras mutations occurred in l ow grade as well as in high grade tumors, whereas p53 mutations were presen t almost exclusively in high grade tumors. CONCLUSIONS. The results of this study suggest that different molecular gen etic pathways are involved in the pathogenesis of UEC and USC and that low grade UEC may progress to high grade UEC. These findings support the hypoth esis that UEC and USC are separate entities and suggest that different mole cular genetic alterations may be responsible for their distinct morphology and biologic behavior. (C) 2000 American Cancer Society.