Mutations of the Ki-ras oncogene in endometrial carcinoma Diane Ignar-Trowbridge, PhD,. John I. Risinger, MS: Georgette A. Dent, MD,c Matthew Kohler, MD/ Andrew Berchuck, MD/ John A. McLachlan, PhD,. and Jeff Boyd, Ph Db Research Triangle Park, Chapel Hill, and Durham, North Carolina OBJECTIVE: The purpose of this study was to assess the extent of involvement of the (as oncogene in endometrial carcinoma. STUDY DESIGN: Genomic deoxyribonucleic acid from 30 samples of endometrial carcinoma was examined for point mutations in codons 12, 13, and 61 from the Ha-ras, Ki-ras, and N-ras genes by means of the polymerase chain reaction, slot-blotting, and deoxyribonucleic acid sequencing procedures. RESULTS: An apparent somatic mutation of Ki-ras codon 12 in one of 10 paraffin-embedded tumors was confirmed by deoxyribonucleic acid sequence analysis. Two of 20 frozen endometrial carcinoma specimens were also shown to contain a point mutation in Ki-ras codon 12. No correlation between ras mutation and a number of histologic or clinical parameters was observed. CONCLUSIONS: These data suggest a potential role for Ki-ras codon 12 mutations in the development of some (10%) endometrial cancers. (AM J OSSTET GVNECOL 1992;167:227-32.) Key words: Endometrial carcinoma, oncogene, ras, polymerase chain reaction Carcinoma of the uterine endometrium is the most frequently diagnosed gynecologic malignancy in the United States, but few data on the molecular genetic features of this tumor exist. We believe that a series of genetic alterations involving both protooncogenes and tumor suppressor genes plays a role in the development of endometrial carcinomas as it does in other human cancers.' The variable nature of these genetic events can be noted in the clinical observation of two distinct forms of endometrial carcinoma. e . 3 Type I tumors are frequently associated with a history of unopposed es- trogen exposure or other hyperestrogenic condition such as obesity. They occur in perimenopausal women, are typically of low grade and good prognosis, and are often associated with or preceded by endometrial hy- perplasia. In contrast, type II tumors, which have a poorer prognosis, appear unrelated to estrogenic stim- ulation, manifest at a later age (>60), and are generally of higher grade and/ or uncommon histologic subtype. The clustering of endometrial carcinoma in certain families· and the occurrence in patients with multiple primary tumors (especially those of the colon),·7 suggest genetic transmission of endometrial cancer risk. From the Laboratory of Reproductive and Developmental Toxicology" and the Laboratory of Molecular Carcinogenesis,' National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, the Department of Pathology, University of North Carolina School of Medicine, Chapel Hill,' and the Department of Obstetrics and Gynecology. Duke University Medical Center, Durham. d Received for publication October 23,1991; 1,1992: accepted January 23,1992. Reprint requests: Jeff Boyd, PhD. National Institute of Environmen- tal Health Sciences! NIH, P.O. Box 12233, Research Triangle Park, NC 27709. 6/1 !36672 The potential role of protooncogenes in the cause of endometrial carcinoma has only recently been ad- dressed, unlike the etiologic factors of the more well- characterized female cancers of the breast, ovary, and uterine cervix. Amplification and/ or overexpression of the c-erbB2 protooncogene may occur in a subset of tumors, although the extent of this phenomenon is still unclear. s , 1O In addition, the inappropriate expression of colony stimulating factor-l and its receptor, the c-fms protooncogene, has been implicated as a potential au- touine growth stimulatory pathway in endometrial car- cinoma.'" .2 Activating point mutations in members of the ras gene family represent the most frequent oncogene ab- normality in human tumors.· 3 Several recent reports suggest that ras mutations may playa role in some en- dometrial carcinomas; specifically, a total of 6 of 12 human endometrial carcinoma cell lines in two studies lo ." and 13 of 41 primary tumors in three studies"·'6 exhibit point mutations in Ki-ras codon 12. In the three previous studies of primary tumor speci- mens, however, a relatively small number of cases were examined in each study (10, 12, and 19, respectively), and a majority of the mutations (11 of 13) were found in endometrial carcinomas from Japan'·' '6; the re- maining two were from Australia.' s Additional studies are needed to define the extent of involvement of the ras gene family in endometrial carcinomas from the United States, where the incidence of endometrial car- cinoma is the highest in the world and where a majority of tumors are of the type I variety, in contrast to Japan, where the incidence of endometrial carcinoma is the lowest in the world and where a significantly higher fraction of tumors are of the type II classification. 17 227