Recent studies demonstrated that a single guanine insertion polymorphism in a matrix metalloprotease‐1 promoter created an Ets binding site and affected the elevation of the transcriptional level of matrix metalloproteinase‐1 (MMP‐1). Furthermore, in tumor cell lines derived from melanoma and breast cancer, the incidence of the 2G/2G genotype was significantly higher than that in the normal population. To evaluate the contribution of this polymorphism in endometrial carcinomas, we genotyped 100 endometrial carcinomas and then analyzed immunoexpression of MMP‐1 in these carcinomas. We found that endometrial carcinoma patients showed a significantly higher rate of 1G/2G or 2G/2G genotype than control individuals, and that tumors containing the 2G allele(a) expressed MMP‐1 protein more frequently than those with 1G/1G genotype. Therefore, the single nucleotide polymorphism at the MMP‐1 promoter affected the expression level of the MMP‐1 protein, which may result in the association with more aggressive character in endometrial carcinoma. Our result suggests that the presence of 2G polymorphism at the MMP‐1 promoter may be one of the risk factors for the development and/or progression of endometrial carcinoma.

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To investigate the putative role of BRCA1, a gene involved in hereditary breast and ovarian cancer, in sporadic ovarian tumors among Japanese women, we examined 76 unselected primary ovarian cancers for mutations in the coding region of BRCA1 using the single-strand conformation polymorphism technique. Although no somatic mutations were detected in any of the tumors, constitutional mutations were identified in four cases: two frameshifts, one nonsense mutation and one intronic base substitution 32 bp downstream of exon 22; RT-PCR experiments revealed that the single-base substitution in the intron seemed to increase the transcript lacking exon 22. All four cases were judged to involve truncation of the gene product. The evidence reported here supports a rather limited role of BRCA1 in ovarian carcinogenesis in the Japanese population.

To investigate the contribution of the β‐catenin gene to the development of ovarian carcinomas, mutational analysis of exon 3 of the β‐catenin gene was conducted. We analyzed 61 primary ovarian carcinomas, consisting of 49 non‐endometrioid‐type and 12 endometrioid‐type tumors, for genetic alteration of the β‐catenin gene. Five carcinomas showed β‐catenin mutations (S37C, T41I, T41A), including 4 (33%) of 12 endometrioid‐type tumors and 1 (14%) of 7 mucinous‐type tumors. All of these mutations altered at the serine/threonine residues that are potential sites of GSK3‐β phosphorylation. We detected no carcinomas with interstitial deletion involving exon 3 of β‐catenin. Furthermore, we immunohistochemically studied 27 of the 61 ovarian carcinomas. Both nuclear and cytoplasmic β‐catenin expressions were demonstrated in 4 of the 27 ovarian carcinomas for which tissue samples were available for examination. All 4 cases exhibited mutations in exon 3 of β‐catenin, including a mucinous carcinoma. Our results suggested that β‐catenin gene mutation at potential GSK3‐β phosphorylation sites results in accumulation of β‐catenin protein within the cells and its translocation to nuclei. Accumulated β‐catenin protein may be involved in the development of endometrioid‐type ovarian carcinomas, and some mucinous‐type ovarian carcinomas.

Microsatellite instability, monitored by replication error (RER), bas been observed in both sporadic and hereditary types of endometrial carcinoma. In the hereditary tumors, this instability is considered to be caused by a germline defect in the DNA mismatch‐repair system. We previously reported that nearly one‐quarter of sporadic endometrial carcinomas examined revealed an RER‐positive phenotype at multiple microsatellite loci. To investigate the role of genetic alterations of DNA mismatch‐repair genes in sporadic endometrial carcinomas, we screened 18 RER(+) endometrial carcinomas for mutations of hMLH1 and hMSH2. Although we found no germline mutations, we detected two somatic mutations of hMLH1 in a single endometrial cancer; these two mutations had occurred on different alleles, suggesting that two separate mutational events had affected both copies of hMLH1 in this particular tumor. These data implied that mutations of hMLH1 or hMSH2 play limited roles in the development of sporadic endometrial carcinomas, and that the tumors with genetic instability might have alterations of other mismatch‐repair genes, such as hPMS1 and hPMS2, or of unknown genes related to the mismatch‐repair system.

Endometrial and ovarian carcinomas are common among women belonging to hereditary nonpolyposis colorectal carcinoma (HNPCC) families; tumors developing in them are characterized by genetic instability due to an inherited dysfunction of the DNA-mismatch-repair system. To clarify the role of similar genetic factors in sporadic forms of gynecological tumors, we examined 77 endometrial and 68 ovarian carcinomas for replication error (RER) at five microsatellite loci. RER-positive phenotypes at two or more microsatellite loci were observed in 18 of the endometrial carcinomas, but in only two of the ovarian carcinomas. Among the patients with endometrial carcinomas, the frequency of RER tended to be higher in those under age 50 than in those over age 60. Furthermore, RER was significantly more frequent in poorly differentiated than in well-differentiated tumors (P = 0.008, Fisher's exact test). These data suggest that genetic factors characterized by RER are likely to play an important role in some endometrial carcinomas, particularly those of early onset and/or of the poorly differentiated type.

Recently, an activating mutation of the SRC gene has been implicated in about one-tenth of advanced colon cancers. The SRC 531 mutation results in truncation of SRC directly C-terminal to the regulatory Tyr 530 and appears to activate the Tyr 530. To investigate whether mutation of SRC plays an important role in the development and progression of gynecological tumors, we performed mutational analysis of the entire coding region of SRC in 70 ovarian carcinomas, 68 endometrial carcinomas and 3 endometrial stromal sarcomas by means of polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) followed by nucleotide sequencing and restriction fragment length polymorphism (RFLP) analysis. We found one truncated mutation at codon 531 (Gln to Stop) in an endometrial carcinoma. However, we found no mutation of this gene in ovarian carcinoma or endometrial stromal sarcoma. Our results suggest that mutation of SRC may be implicated in a small proportion of endometrial carcinomas.

Predisposing germline mutations in the BRCA1 gene were identified recently in families with 17q‐linked breast and ovarian cancers. Using single‐strand conformation polymorphism (SSCP) analysis, we examined primary breast cancers for mutations in coding exons of BRCA1 in a panel of 103 patients, of whom all either represented early‐onset cases (< 35 of age), were members of multiply‐affected families, and/or had developed bilateral breast cancers. Mutations were detected in tumors from four patients, all of whom had developed breast cancers bilaterally: a frame‐shift due to a 2‐bp deletion at codon 797; a nonsense mutation at codon 1214; and two missense mutations, one at codon 271 leading to Val → Met substitution, and the other at codon 1150 leading to Pro → Ser substitution. In each case the same mutation was present in constitutional DNA. The mean age of onset was 49 years among the Japanese carriers of BRCA1 mutations identified in this study, in contrast to the mean age of 35 observed among carriers of BRCA1 mutations in a similar U.S. study (Futreal et al., 1994). The evidence reported here supports a rather limited role of BRCA1 in breast carcinogenesis. © 1996 Wiley‐Liss, Inc.