Endometriosis is characterized by ectopic endometrial-like epithelium and stroma, of which molecular characteristics remain to be fully elucidated. We sequenced 107 ovarian endometriotic and 82 normal uterine endometrial epithelium samples isolated by laser microdissection. In both endometriotic and normal epithelium samples, numerous somatic mutations were identified within genes frequently mutated in endometriosis-associated ovarian cancers. KRAS is frequently mutated in endometriotic epithelium, with a higher mutant allele frequency (MAF) accompanied by arm-level allelic imbalances. Analyses of MAF, combined with multiregional sequencing, illuminated spatiotemporal evolution of the endometriosis and uterine endometrium genomes. We sequenced 109 single endometrial glands and found that each gland carried distinct cancer-associated mutations, demonstrating the heterogeneity of the genomic architecture of endometrial epithelium. Remarkable increases in MAF of mutations in cancer-associated genes in endometriotic epithelium suggest retrograde flow of endometrial cells already harboring cancer-associated mutations, with selective advantages at ectopic sites, leading to the development of endometriosis.

The E-cadherin promoter frequently undergoes hypermethylation in human gastric cancers, particularly those of the undifferentiated-scattered histologic subtype. E-cadherin promoter hypermethylation is associated with decreased expression and may occur early in gastric carcinogenesis.

In an attempt to elucidate various histological features of gastric cancers, seven human gastric adenocarcinomas were studied in vitro and in nude mice. Growth pattern of each cultured cell line in vitro corresponded well to the histological type of parent tumor. The cell lines, MKN7, MKN74, and MKN28 derived from differentiated carcinomas showed morphological characteristics of intestinal differentiation in cell polarity and microvilli with core-filaments in vitro as well as in nude mice. However, they gradually diminished the characteristics in course of time. The cell lines, MKN 45 and OKAJIMA, derived from undifferentiated carcinomas, had natures of not only ordinary gastric mucosa but also intestinal metaplastic mucosa. They seem to have multipotentiality for differentiation, and preserved well the natures for long periods of culture. The KWS-I cell line composed of undifferentiated cells in vitro displayed the potential for differentiation in nude mice. However, the differentiation of KATO-I11 cells derived from a signet-ring cell carcinoma was suppressed in nude mice. The common abnormality of chromosome was not found, and the growth rate in vitro was not dependent on the histological type of parent tumor. ACTA PATHOL. JPN. 36: 65-83, 1986. I n t reductionBecause of the high incidence of gastric carcinoma in Japan and its various histological features, deep interest has been taken in its carcinogenesis, histogenesis, growth pattern, and cell differentiation. The cultivation of human cancer cells has been expected to be one of the methods for making these subjects clearer.Cell lines of human gastric carcinoma over fifteen at least have been established till now in Japan. However, little attention has been given to comparing these cell lines with each other and with each parent tumor.The present study was undertaken to compare seven cell lines derived from human gastric carcinomas with each other in respects of biology and morphology in vitro and in nude mice. long term culture were inspected. Furthermore, stable and unstable natures of parent tumor cells through Materials and MethodsCell lines ; Seven cultured cell lines derived from gastric adenocarcinomas including a signetring cell carcinoma were used in this study ( Table 1). The cell line MKN7 was derived from a well differentiated tubular adenocarcinoma. Two cell lines, MKN74 and MKN28, were derived from moderately differentiated tubular adenocarcinomas. The MKN45 cell line was derived from a poorly differentiated adenocarcinoma of medullary type. The KWS-I cell line, kindly donated by Dr. M. Sekiguchi ), was derived from a poorly differentiated adenocarcinoma with focal scirrhous pattern. The KATO-I11 cell line, kindly donated by Dr. M. Sekiguchi, was derived from a signetring cell carcinoma. The culture courses, drug-M phosphate buffer (pH 7.4) for 30 minutes. Tissue cubes were fixed in 2.5% glutaraldehyde 0.1 M phosphate buffer (pH 7.4) for 1 hour. Both of them were postfixed in 1% osmium tetraoxide for 1 hour, and embedded in Epon-812. Ultrathin s...

Clear cell tumors of the ovary are frequently associated with ovarian endometriosis. Clinicopathologically, it has been suggested that clear cell tumors develop from endometriosis, but there has been little molecular evidence supporting this speculation. Microarray analysis revealed recently that hepatocyte nuclear factor1beta (HNF-1beta) was significantly upregulated in clear cell carcinoma of the ovary. In the present study, we examined 30 clear cell tumors (26 malignant, three borderline, and one benign) and 40 endometriotic cysts to clarify if differentiation into the clear cell lineage already begins in ovarian endometriosis. All of the 30 clear cell tumors, including borderline and benign ones, showed immunohistochemical expression of HNF-1beta in the nucleus, while other types of ovarian epithelial tumors (endometrioid, serous, mucinous, and Brenner tumors) rarely expressed it. Among 30 clear cell tumors, 17 (56%) cases were associated with endometriosis, and endometriotic epithelium was identified in 12 cases. In nine of the 12 cases, distinct nuclear immunostaining for HNF-1beta was detected in the endometriotic epithelium, as well as in the clear cell tumor. HNF-1beta expression was observed either in atypical endometriosis (four cases), or in endometriosis of a reactive nature (five cases). Furthermore, 16 of 40 (40%) endometriotic cysts without a neoplasm also expressed HNF-1beta, and the expression was almost exclusively observed in the epithelium showing inflammatory atypia. Our results indicate that HNF-1beta is an excellent molecular marker for ovarian clear cell tumors, including benign, borderline and malignant lesions. Early differentiation into the clear cell lineage takes place in ovarian endometriosis, not only in atypical endometriosis, but also in endometriosis with degenerative and regenerative changes, and this is probably responsible for the frequent occurrence of clear cell carcinoma in ovarian endometriosis. Keywords: ovary; clear cell tumor; endometriosis; hepatocyte nuclear factor-1beta; histogenesis Among malignant epithelial tumors of the ovary, clear cell carcinomas, as well as endometrioid adenocarcinomas, are most frequently associated with ovarian endometriosis. The frequency of endometriosis is reportedly between 21 and 54% in large series of clear cell carcinomas. [1][2][3][4][5] In addition, an atypical glandular change in endometriosis, the socalled atypical endometriosis, is often present associated with clear cell carcinomas, while it is rare in endometriosis without a neoplasm. 2,6,7 Thus, many clinicopathological studies have strongly suggested a malignant transformation of endometriosis to clear cell carcinomas, but little molecular evidence exists to support the notion that endometriosis is the precursor of clear cell carcinomas. A molecular genetic study showed that ovarian endometriosis and its adjacent carcinoma shared a common allelotype; however, few clear cell carcinomas were subjected to this study. 8 Recently, a study using an oligonucleotide array technique...

We investigated whether inhibition of nuclear factor-B (NF B) increases the efficacy of paclitaxel in in vitro