The frequency of p53, k-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma

Abstract

BACKGROUND The two most common types of uterine endometrial carcinoma, endometrioid (UEC) and serous (USC), differ in their histopathologic appearance 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‐ras and p53 mutations and microsatellite instability (MI) between UEC and USC by analyzing all 3 molecular genetic changes in one set of tumors. Furthermore, the distribution of these molecular genetic alterations was determined among UECs of different histopathologic grade. The authors analyzed 58 UECs with known MI status for K‐ras and p53 mutations. The K‐ras and p53 genes 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) in 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 direct sequencing of exons 5–8. UECs and USCs with p53 mutations showed strong immunoreactivity 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 frequency of both K‐ras and p53 mutations and MI was significantly different between UEC and USC (P < 0.001). In UECs, MI and K‐ras mutations occurred in low grade as well as in high grade tumors, whereas p53 mutations were present almost exclusively in high grade tumors. CONCLUSIONS The results of this study suggest that different molecular genetic 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 hypothesis that UEC and USC are separate entities and suggest that different molecular genetic alterations may be responsible for their distinct morphology and biologic behavior. Cancer 2000;88:814–24. © 2000 American Cancer Society.

Molecular genetic pathways in various types of endometrial carcinoma: from a phenotypical to a molecular-based classification

“…p53 mutations were found in a subset of approximately 10-20% of endometrioid carcinomas, which were mostly grade 3 [44,66,67]. Grade 1 carcinomas and atypical hyperplasia seem to lack mutant p53, and, in grade 2 carcinomas, p53 mutations seem to occur rarely [44]. p53 mutations are almost always associated with aneuploidy and do not seem to concur with PTEN mutations in the same tumor [39].…”

“…Reduced membranous staining and heterogeneous staining, respectively, for e-cadherin, which is associated either with mutation or methylation, is found in about 5-50% of endometrioid carcinomas [28]. p53 mutations were found in a subset of approximately 10-20% of endometrioid carcinomas, which were mostly grade 3 [44,66,67]. Grade 1 carcinomas and atypical hyperplasia seem to lack mutant p53, and, in grade 2 carcinomas, p53 mutations seem to occur rarely [44].…”

“…Sherman and Kurman [84], approximately a decade later. During the recent years, the dualistic model was supported by molecular genetic analyses performed by different groups [14,44,51].…”

“…Only a few studies have included small numbers of endometrioid carcinomas with various types of cellular differentiation [14,44,77]. The available data, thus, have to be interpreted with caution.…”

“…The available data, thus, have to be interpreted with caution. The data presented in Table 2 and Table 3 are drawn from our own previous analysis [44]. There is evidence that these tumors are genetically related to usual endometrioid carcinoma, since the frequencies of molecular alterations are similar if compared by histological grade.…”