Estrogen receptor expression in an endometrial stromal sarcoma after tamoxifen therapy

INTRODUCTION: Several cases of low-grade endometrial stromal sarcomas in women with breast cancer have been reported to be associated with tamoxifen therapy. Estrogen receptor expression has been used to characterize the partial estrogenic action of tamoxifen on the endometrium and has been found in tamoxifen-associated endometrial pathologies. CASE: A low-grade endometrial stromal sarcoma in a woman with a history of breast cancer treated with adjuvant tamoxifen is presented. Steroid receptor studies performed on the tumor were negative for estrogen and positive for progesterone. CONCLUSION: The absence of estrogen receptor expression suggests that endometrial stromal sarcomas are not necessarily caused by the estrogenic properties of tamoxifen.     

Protein kinase C alpha expression is inversely related to ER status in endometrial carcinoma: possible role in AP-1-mediated proliferation of ER-negative endometrial cancer

OBJECTIVE: Tamoxifen is the most widely used antiestrogen to treat all stages of estrogen-receptor (ER)-positive breast cancers. However, tamoxifen acts as a partial estrogen in the uterus and is known to increase the risk of endometrial cancer by two- to threefold. Recent evidence indicates that there is a connection between tamoxifen resistance and activation of the activator protein-1 (AP-1) pathway. We have previously reported a possible role for overexpression of protein kinase C alpha (PKCalpha), an upstream activator of the AP-1 pathway, in hormone-independent breast cancer and antiestrogen-stimulated endometrial tumors. We hypothesize that alterations of the PKC isozyme profile of endometrial carcinomas are similar to that of hormone-independent breast cancer and determine whether specific PKC isozyme alterations correlated with known clinicopathological features of endometrial cancer. METHODS: The PKC isozyme profile of endometrial carcinomas from 42 patients who were not previously exposed to antiestrogens was examined by Western blot. The relationship between PKC isozyme expression and key prognostic factors for endometrial carcinoma including hormone receptor status, tumor grade, stage, size, and depth of myometrial invasion was examined using the Spearman's rho correlation coefficient. RESULTS: As previously found in breast cancers, PKCalpha and estrogen receptor alpha (ERalpha) expression are inversely related (r(s) = -0.35, P = 0.046). We report significant inverse correlations among ER/progesterone receptor (PR) expression and tumor grade (r(s) = -0.49, P = 0.001 and r(s) = -0.44, P = 0.004, respectively), ER, and depth of myometrial invasion (r(s) = -0.40, P = 0.009). There were no other significant correlations between PKC isozyme expression and other key prognostic factors examined. CONCLUSION: This study indicates that, similar to what was previously observed in breast cancer, PKCalpha and ER expression is inversely related in endometrial cancer. PKCalpha expression may be a useful prognostic indicator in endometrial cancers. A model is offered which describes the putative role of PKCalpha overexpression in activation of the AP-1 pathway and increased proliferation of ER negative endometrial cancers.     

Gene expression profiling of tamoxifen-associated uterine cancers: evidence for two molecular classes of endometrial carcinoma

OBJECTIVE: Endometrial cancers associated with tamoxifen exposure potentially represent a unique resource for investigating the molecular mechanisms of estrogen-induced tumorigenesis. The purpose of this study was to test the hypothesis that tamoxifen-associated endometrial carcinomas have a distinct gene expression profile compared to matched cases not associated with this exposure. METHODS: Microarray-based expression profiling was performed on a series of tamoxifen-associated (N = 10) and matched sporadic cases (N = 29) of endometrial carcinoma. RESULTS: Supervised class comparison revealed no statistically significant difference between the two groups (P = 0.48). However, unsupervised hierarchical clustering of the entire sample of tumors revealed two groups with extremely diverse molecular profiles that were independent of tamoxifen exposure. Of recognized clinicopathological factors, histologic grade correlated best with these two molecular classes. CONCLUSIONS: These data suggest that the molecular profile of tamoxifen-associated endometrial cancers is not different from that of endometrial carcinomas generally, and further, that there exist two highly distinct molecular subtypes of endometrial carcinoma.     

Molecular carcinogenesis of endometrial cancer

In 1983, Bokhman proposed a dualistic model of endometrial tumorigenesis based on the clinical observations and clinicopathologic correlations. The majority of endometrial cancers (approximately 70-80%), designated as type I carcinomas, follow the estrogen-related pathway. Histologically, most of the type I tumors seem to arise in the background of hyperplastic endometrium, show an endometrioid differentiation, and are of low grade. Clinically, they are overall characterized by a favorable behavior. Another 10-20% of endometrial cancers, designated as type II carcinomas, follow the estrogen-unrelated pathway and arise in the background of atrophic endometrium. Type II tumors usually occur at an older age, approximately 5-10 years later than type I tumors. They are typically high-grade carcinomas of nonendometrioid differentiation, most frequently serous, less frequently clear cell. Type II carcinomas behave as an aggressive clinical course and poor prognosis. This dualistic model was subsequently supported by the molecular studies, approximately a decade later. At present, endometrioid and serous carcinoma, which represent the major phenotypes of types I and II endometrial carcinomas, respectively, are characterized by distinctive types of genetic instability and molecular alterations. In endometrioid (type I) carcinoma, four major genetic changes are responsible for the tumorigenesis, i.e. silencing of PTEN tumor suppressor gene, presence of microsatellite instability due to alterations of the mismatch repair genes, mutation of K-ras protooncogene, and alteration of beta-catenin gene. On the other hand, p53 mutation and overexpression of Her2/neu oncogene are two major genetic alterations in serous and clear cell (type II) carcinomas. However, like in any model, there is evidence for exceptions. Many endometrial carcinomas are in the gray zone with overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II endometrial cancers. Finally, a small group of endometrial carcinoma is noted to be hereditary. It is known as the most common extracolonic malignancy in hereditary nonpolyposis colorectal cancer (Lynch syndrome), an autosomal dominantly inherited disorder of cancer susceptibility. Inactivation of the mismatch repair genes MSH2 and MSH6 seems to play a central role in the tumorigenesis.     

Microsatellite instability in mitochondrial genome of common female cancers

Abstract.   Wang Y, Liu VWS, Tsang PCK, Chiu PM, Cheung ANY, Khoo US, Nagley P, Ngan HYS. Microsatellite instability in mitochondrial genome of common female cancers. Int J Gynecol Cancer 2006; 16(Suppl. 1): 259–266.
To investigate the occurrence of mitochondrial genome instability in primary cervical, endometrial, ovarian, and breast carcinomas, we analyzed 12 microsatellite regions in mitochondrial DNA (mtDNA) of tumor tissues and their matched normal controls. Four of the 12 microsatellite markers starting at nucleotide position (np) 303, 514, 956, and 16184, respectively, exhibited instability as indicated by the change in length of short base-repetitive sequences of mtDNA in cancer tissue relative to that in control normal tissue from the same patient. About 25.4% of cervical cancers, 48.4% of endometrial cancers, 21.9% of ovarian cancers, and 29.4% of breast cancers carried one or more mitochondrial microsatellite instability (mtMSI). mtMSI was frequently detected in the D-loop region but rarely occurred in the coding region. A relatively long C tract interrupted by a T residue is the mtMSI hot spot in all four types of cancer studied. Different tumors have different mtMSI profiles. In particular, the frequency of mtMSI in endometrial cancer was significantly higher than in the other three types of cancer. Furthermore, carriers of a germ-line T to C polymorphism at np 16189 could be more susceptible to breast cancer development in light of the higher frequency detected in cancer patients than in normal individuals.     

Evaluation of germline PTEN mutations in endometrial cancer patients

BACKGROUND AND OBJECTIVE: Cowden Syndrome is a rare autosomal dominant disorder characterized by multiple hamartomas, increased risks of breast and thyroid cancers, and possibly endometrial carcinoma. Susceptibility to Cowden syndrome is conferred by germline mutation of the PTEN tumor suppressor gene, and somatic mutations of PTEN are common in sporadic endometrial carcinomas. The aim of this study was to test whether a substantial proportion of endometrial cancers are associated with germline mutations of the PTEN gene, not necessarily in association with clinically overt Cowden syndrome. METHODS: A retrospective cohort of 240 consecutive patients with pathologically confirmed endometrial carcinoma diagnosed at our institution from 1999 to 2002 was ascertained for study. Genomic DNA was isolated from peripheral blood lymphocytes and the entire PTEN coding region and exon-intron junctions were screened for mutations by single strand conformation polymorphism analysis. Potential variants were subjected to direct sequence analysis. RESULTS: No clearly deleterious PTEN sequence variant was identified in this screened cohort of endometrial cancer patients. One patient harbored a 5-bp deletion in the intronic region adjacent to the splice acceptor site of PTEN exon 4, but this variant has been previously classified as a rare polymorphism. CONCLUSIONS: Although these data do not preclude the possibility of an increased risk of endometrial cancer in association with the Cowden syndrome, they indicate that germline PTEN mutations do not account for a significant proportion of genetic attributable risk for endometrial carcinoma.     

High concordance of molecular tumor alterations between pre-operative curettage and hysterectomy specimens in patients with endometrial carcinoma

Objective

Molecular alterations in endometrial cancer have been shown to be prognostically significant but have not yet been implemented in the current clinical risk assessment. Few studies have investigated the reliability of molecular alterations in pre-operative specimens. Therefore, the objective was to determine whether molecular analysis of pre-operative endometrial cancer samples accurately reflects those alterations in the subsequent hysterectomy specimens.

Methods

Paired pre-operative and hysterectomy specimens of 48 patients diagnosed with endometrial carcinoma, 42 endometrioid (EEC) and 6 non-endometrioid (NEEC) carcinomas, were analyzed for immunohistochemical expression of p53, PTEN and β-catenin. Tumor DNA was isolated and analyzed for microsatellite instability (MSI), TP53 mutations and somatic hot spot mutations in 13 genes.

Results

In EEC patients, loss of PTEN, nuclear β-catenin and p53-mutant expression was found in 43%, 7% and 12%, respectively. No nuclear β-catenin was found in 5 of 6 NEEC patients, all serous cancers, whereas a p53-mutant expression was present in all serous cases. MSI was found in 19.5%, all EEC. Concordance for PTEN, β-catenin, p53 expression and MSI status was found in 79%, 92%, 79% and 93.5%, respectively. We detected 65 hot spot mutations in 39/48 (81%) tumors. Overall concordance of the GynCarta multigene analysis was 99.8%.

Conclusions

The results confirm the reliability of immunohistochemical and DNA-based techniques in the evaluation of molecular alterations in pre-operative endometrial specimens and high concordance rates with the definitive hysterectomy specimens. The resulting molecular signature provides initial pre-operative diagnostic information on the status of oncogenic pathways, which may contribute to individualized treatment strategies.     

Endometrial carcinoma in tamoxifen-treated breast cancer patient: clinicopathological, immunohistochemical, and genetic analysis.

Endometrial polyps and endometrial neoplasms are a recognized complication of chronic tamoxifen treatment. This study describes an endometrial carcinoma that developed in a woman receiving low-dose tamoxifen treatment for breast cancer. Little is known about steroid receptor status, somatic alterations in oncogenes and tumor suppressor genes, and inherited susceptibility in endometrial carcinomas associated with tamoxifen use. In the present case, the endometrial carcinoma was negative for estrogen receptors and weakly positive for progesterone receptors. In addition, analysis of K-ras, c-erbB2/neu, cyclin D1, and p53 status revealed a codon 12 point mutation in the K-ras oncogene. The patient was determined not to be a carrier of germ-line mutations in cytochrome P-450 1A1 (CYP1A1), an estrogen-metabolizing gene previously associated with enhanced endometrial cancer risk, but she was a carrier of a methylenetetrahydrofolate reductase gene variant related with putative alterations in DNA methylation.     

Favorable survival associated with microsatellite instability in endometrioid endometrial cancers

OBJECTIVE: To determine whether microsatellite instability in endometrioid endometrial cancer is associated with favorable survival. METHODS: Microsatellite instability analysis was performed in 131 patients with endometrioid endometrial cancer using three polymorphic markers in paired cancer and normal DNA. Logistic regression and multivariable analyses calculated the relation between microsatellite instability, clinical features, and survival. RESULTS: Microsatellite instability was detected in 29 of 131 (22%) endometrioid endometrial cancers. There was no correlation between microsatellite instability and age, race, grade, stage, or depth of myometrial invasion. Microsatellite instability was associated with better survival in univariate and multivariable analyses after controlling for confounding influences (P =.03). The 5-year survival rate of those with microsatellite instability was 77% (95% confidence interval 55%, 90%) compared with only 48% (95% confidence interval 39%, 57%) in other cases. Microsatellite instability was associated with other molecular features that predict favorable outcome including PTEN mutation (P =.002) and the absence of p53 overexpression (P =.01). CONCLUSION: Microsatellite instability is a molecular alteration associated with favorable outcome in endometrioid endometrial cancers, even when accounting for other prognostic factors. This association might be explained by the finding that the pathway of molecular carcinogenesis characterized by loss of DNA mismatch repair favors alteration of genes that result in a less virulent clinical phenotype.     

Effect of selective estrogen receptor modulators on estrogen-sensitive tissues

Selective estrogen receptor modulators (SERMs) act exclusively through estrogen receptors and possess tissue-specific agonistic or antagonistic properties. The effects of all referred SERMs in bone and cardiovascular system are estrogenic, namely they inhibit postmenopausal bone loss and favorably influence plasma lipoproteins and some coagulation factors. The aim of this paper is to review the effects of SERMs on estrogen-dependent breast tissues and on the endometrium. There are two types of SERMs in clinical use, based on their chemical structure: the triphenylethylenes and the benzothiophenes. The prototype of the SERMs with triphenylethylene structure is tamoxifen. Tamoxifen, like all other SERMs, is an estrogen antagonist in the breast and is widely used for adjuvant treatment of breast cancer. A recent study suggests that tamoxifen also may prevent breast cancer in patients at risk. Because of the partial estrogenic activity of tamoxifen in the endometrium, its clinical use is associated with uterine hypertrophy and an increased risk of endometrial cancer. Other triphenylethylene SERMs, droloxifene, toremifene, and idoxifene, also show efficacy in the treatment of breast cancer, in a manner similar to tamoxifen. A better toxicology profile and a decreased endometrial estrogen agonism may be advantages of the new triphenylethylene SERMs. Raloxifene is a SERM with a chemical structure different from triphenylethylenes. Raloxifene, a benzothiophene, possesses an estrogen-antagonistic effect in the breast similar to triphenylethylenes. Clinical studies on postmenopausal osteoporotic women on raloxifene as compared with placebo show a significant decrease in the rate of newly diagnosed breast cancers. In clinical studies, in contrast to tamoxifen, no stimulatory effect in the endometrium could be observed with raloxifene.     

Absence of PTEN repeat tract mutation in endometrial cancers with microsatellite instability

OBJECTIVE: PTEN, a tumor suppressor gene shown to be frequently mutated in endometrial cancers, has been suggested to be a target of microsatellite instability (MSI)-driven mutagenesis. We set out to investigate the relationship between MSI and PTEN mutation in a large series of primary endometrial carcinomas. METHODS: Thirty-nine MSI-positive endometrial cancers were evaluated by single-strand conformational variant analysis and direct sequencing to screen all nine PTEN exons for mutation. RESULTS: Fifteen specimens (38%) demonstrated 16 PTEN mutations. We observed only one alteration in the poly-adenine repeat of exon 8 that is suggested to be a target for mutation in endometrial cancers with MSI. Seven of 16 (44%) mutations in our series were deletions of >/=3 bp, a class of mutation not usually associated with tumors with defective DNA mismatch repair. To determine the significance of this high frequency of deletion, 26 additional endometrial cancers without MSI were matched with the 39 MSI-positive cancers for the prognostic factors of tumor histology, stage, grade, and patient race. The MSI-positive tumors had a significantly higher frequency of deletions involving >/=3 bp when compared with the MSI-negative group (5/11 versus 0/10, P = 0.035). CONCLUSIONS: Repeat tract mutation in PTEN is an uncommon event in MSI-positive cancers. Deletion of >/=3 bp in this gene is more common in MSI-positive cancers when compared with tumors without MSI.     

Molecular differences between RER+ and RER– sporadic endometrial carcinomas in a large population-based series

Studies, to date, have suggested that there are distinct molecular differences between microsatellite stable (RER(-)) and unstable (RER(+)) solid tumors, such as colorectal carcinoma. We investigated a range of molecular events including mutation frequency of K-ras, microsatellite instability within the coding region of TGF-beta RII, BAX, and IGF-IIR, loss of expression of p53, hMLH1, hMSH2, hMSH6, and PTEN, and methylation of hMLH1, hMSH2, and PTEN within a large population-based series of sporadic endometrial carcinomas to establish whether there are distinct differences between replication error repair (RER(+)) and RER(-) cases. RER(+) endometrial carcinomas tended to be diploid with normal p53 expression, compared with RER(-) cases. Mutations in TGF-beta RII, IGF-IIR, and BAX were rare, but there was a strong association between mutation and RER(+) status. Methylation and loss of hMLH1 expression were significantly more common in RER(+) cases, as was methylation of PTEN. K-ras mutations were equally frequent in RER(+) and RER(-) cases. Despite the absence of distinct clinicopathological differences between RER(+) and RER(-) cases in this series of sporadic endometrial carcinomas, our results confirm that there are molecular differences between RER(+) and RER(-) cases, but the molecular events occurring in RER(+) endometrial carcinomas differ from those seen in RER(+) colorectal carcinomas.     

Failure of megestrol acetate to reverse tamoxifen induced endometrial neoplasia: two case reports

Abstract. Rose PG, Brandewie EV, Abdul-Karim FW. Failure of megestrol acetate to reverse tamoxifen induced endometrial neoplasia: two case reports.
Tamoxifen's agonist effect on the endometrium has been associated with an increased incidence of endometrial carcinoma. It has been suggested that this agonist effect may be averted by the concomitant use of a progestational agent. We report two patients with breast cancer receiving tamoxifen who developed endometrial carcinoma and atypical endometrial hyperplasia, respectively. In one patient, this occurred despite the use of concomitant megestrol acetate. In the other patient, tamoxifen-associated endometrial hyperplasia persisted and progressed despite cessation of tamoxifen and initiation of megestrol acetate therapy. These cases may have implications for strategies to avert tamoxifen induced endometrial neoplasia.     

Dualistic model of molecular pathogenesis in endometrial carcinoma

Sporadic endometrial carcinoma can be divided into two biologically and clinically distinctive subtypes of which one is estrogen-related (type I), the other estrogen-unrelated (type II). Type I carcinomas occur at younger age, express estrogen (ER) and progesterone receptors (PR), are frequently associated with endometrial hyperplasia and show a good prognosis. Type II carcinomas occur at older age, are negative for ER and PR, arise in the background of atrophic endometrium and show poor prognosis. Histologically, endometrioid carcinomas correspond to type I carcinomas whereas serous carcinoma is the prototype of type II carcinomas. Endometrioid and serous carcinomas are significantly different with respect to their molecular changes. Endometrioid carcinomas frequently show microsatellite instability (MIN), PTEN and K-ras mutation but infrequently p53 mutations, loss of p16 expression and her2/neu amplification, respectively. In contrast, serous carcinomas show a high frequency of p53 mutations and often loss of p16 expression whereas MIN and PTEN and K-ras mutations are uncommon. Familial endometrial carcinoma associated with HNPCC occur about two decades earlier than sporadic carcinomas, show endometrioid histology and are frequently MIN positiv due to germline mutations of mismatch repair genes (mostly MLH1 and MSH2). During the progression of endometrioid carcinoma PTEN mutations and MIN are considered early changes since they are present in a high frequency in atypical endometrial hyperplasia whereas p53 mutations, loss of p16 expression and her2/neu amplification are considered late events since they are predominantly found in poorly differentiated tumors. In contrast, p53 mutations are considered an early event in the pathogenesis of serous carcinoma occurring already in its putative precursor endometrial intraepithelial carcinoma (EIC). The future research will focus, besides the discovery of new relevant genes, on the interaction of known genes as well as their clinical relevance.     

Molecular analysis of endometrial hyperplasia in HNPCC-suspicious patients may predict progression to endometrial carcinoma.

Women predisposed to hereditary nonpolyposis colorectal cancer are at high risk of developing endometrial carcinoma at a young age. Hereditary nonpolyposis colorectal cancer-associated endometrial carcinomas are of the endometrioid type, usually arise from complex atypical hyperplasia, and often show microsatellite instability. To identify occult hereditary nonpolyposis colorectal cancer individuals among endometrial carcinoma patients, we examined complex atypical hyperplasias and endometrial carcinomas of 60 women < or =50 years of age (mean age: 35.7 years) using microsatellite instability, immunohistochemistry, and DNA sequence analysis. Three patient groups were recruited: group 1, patients with complex atypical hyperplasia exclusively (n = 27); group 2, patients with complex atypical hyperplasia and synchronous or metachronous endometrial carcinoma (n = 15); group 3, patients with endometrial carcinoma only (n = 18). Overall, 13 of 33 endometrial carcinomas (39%) displayed high-level microsatellite instability. None of the complex atypical hyperplasias in group 1 had high-level microsatellite instability or loss of hMLH1/hMSH2 protein expression. In group 2 patients, 33% of complex atypical hyperplasias and 53% of endometrial carcinomas had high-level microsatellite instability. Loss of hMSH2 protein expression was found in six endometrial carcinoma patients, five of them with verified hMSH2 germline mutations, including four patients with high-level microsatellite instability in complex atypical hyperplasia. Among group 3 patients, 28% of endometrial carcinomas displayed high-level microsatellite instability; three of those five endometrial carcinomas were from patients with multiple extrauterine hereditary nonpolyposis colorectal cancer-associated tumors. We conclude that young women (< or =50 years of age) with concurrent complex atypical hyperplasia and multiple hereditary nonpolyposis colorectal cancer-associated carcinomas are at risk of developing high-level microsatellite instability endometrial carcinoma. Combined microsatellite instability and immunohistochemistry analysis allows the identification of a high proportion of hereditary nonpolyposis colorectal cancer patients among young women with endometrial carcinoma and complex atypical hyperplasia. All complex atypical hyperplasias with high-level microsatellite instability progressed to endometrial carcinoma. Only one third of the complex atypical hyperplasias with microsatellite stability progressed to high-level microsatellite instability endometrial carcinoma, while seven complex atypical hyperplasias progressed to microsatellite stability endometrial carcinoma. Microsatellite analysis of complex atypical hyperplasia in young patients may therefore be a useful prognostic marker for predicting possible progression to high-level microsatellite instability endometrial carcinomas.     

PTEN mutation, expression and LOH at its locus in ovarian carcinomas. Relation to TP53, K-RAS and BRCA1 mutations

OBJECTIVE: We aimed to evaluate frequency of PTEN mutation, LOH and expression in ovarian tumors. In search for a molecular pathway, we confronted PTEN gene mutations with TP53, K-RAS and BRCA1 gene status in the same tumors. We also evaluated clinical significance of PTEN expression in a subgroup of patients uniformly treated with platinum-based regimens. METHODS: Molecular analysis was performed on 105 ovarian tumors (100 carcinomas) with the use of the SSCP and sequencing. Seventy-six tumors were analyzed for LOH at 10q23 locus with the use of six polymorphic markers. Immunohistochemical PTEN expression was done on paraffin-embedded material. Multivariate and univariate analysis was performed with the STATA program. RESULTS: PTEN mutations occurred in 5/100 (5%) of all carcinomas and in 3/15 (20%) of endometrioid carcinomas (EC). Low-grade EC that developed in borderline tumors had PTEN and/or K-RAS mutation (4/5, 80%), while high-grade EC had TP53 mutations only. There was a reverse association between PTEN and TP53 mutations (P = 0.005). LOH at PTEN locus was found in 60% of endometrioid and in 28% of serous and clear cell carcinomas. PTEN expression did not associate with PTEN mutations or LOH. Strong PTEN expression diminished risk of death in a TP53 positive group only (HR = 0.35, P = 0.029). CONCLUSION: Our results suggest that PTEN mutations may play a role in a development of low-grade endometrioid tumors. PTEN haploinsufficiency caused by LOH or epigenetic events may possibly contribute to development of other histological types and may be an adverse prognostic factor.     

Estrogen receptor polymorphisms in tamoxifen-treated women with breast cancer.

In postmenopausal women with estrogen receptor (ER)-positive breast cancer, long-term tamoxifen administration has proved beneficial after surgical treatment and subsequent chemotherapy. One of the major adverse effects of tamoxifen is the development of endometrial pathology (polyps, endometrial hyperplasia and endometrial cancer). PvuII and XbaI polymorphisms of the estrogen receptor-alpha gene (ERalpha) and RsaI and AluI polymorphisms of the estrogen receptor-beta gene (ERbeta) have been associated with breast cancer. Thus the present study aimed to identify whether ER gene polymorphisms are associated with breast cancer stage or endometrial responsiveness to long-term tamoxifen treatment in 87 postmenopausal, tamoxifen-treated women with ER-positive breast cancer. The mean age of the patients was 58.7 +/- 4.7 years and the mean duration of tamoxifen treatment was 3.9 +/- 1.1 years. At diagnosis, the stage of breast cancer was determined as follows: 29 women (32%) at Stage I, 49 (58%) at Stage II and 9 (10%) at Stage III. The frequency distributions of the estrogen receptor polymorphisms in all women with breast cancer were not different from those predicted by the Hardy-Weinberg equilibrium hypothesis (p > 0.10). None of the ER polymorphisms studied was linked to either the presence of endometrial pathology or the stage of breast cancer.     

Somatic mutations of the PTEN/NMAC1 gene associated with frequent chromosomal loss detected using comparative genomic hybridization in endometrial cancer

OBJECTIVES: We analyzed the mutational status of the transforming growth factor-beta type II receptor (TGF beta RII), BAX, and PTEN/MMAC1 genes as well as microsatellite instability (MI) in 29 consecutive cases of endometrial carcinoma operated on at the Cancer Institute Hospital (Tokyo, Japan). To identify chromosomal loss associated with significant somatic mutations, we conducted comparative genomic hybridization (CGH) analysis. METHODS: We conducted a direct sequence for mutational analysis of these genes. To examine copy number loss at the chromosomal regions bearing these genes, we used CGH analysis. CGH analysis may provides a genome-wide overview about tumor-associated genomic imbalances. RESULTS: Among nine tumors that showed the MI+ phenotype, four (44%) demonstrated a significant mutation with a definite amino acid change in the PTEN/MMAC1 gene. CGH analysis demonstrated that all four tumors (100%) showed chromosomal copy number loss around the locus of this gene, whereas four (57%) of seven tumors with PTEN/MMAC1 mutations showed chromosomal loss or double mutations in MI- carcinomas. The role of TGF beta RII and BAX genes is limited as a target gene of MI+ phenotype in endometrial cancer, because several mutations of these genes were detected but a chromosomal loss was demonstrated by CGH in only one tumor in MI+ endometrial cancers with mutation. CONCLUSIONS: This report reveals, by using CGH, that most MI+ endometrial cancers with PTEN/MMAC1 mutations as well as MI- tumors showed inactivation of both alleles of this gene, which strongly suggested the involvement of this gene in carcinogenesis.     

RAS/RAF mutation and defective DNA mismatch repair in endometrial cancers

OBJECTIVE: Defective DNA mismatch repair is a common genetic abnormality in both colon cancers and endometrial cancers. Cancers with defective DNA mismatch repair have the so-called mutator phenotype and accumulate genetic errors at an increased rate. An early mutational target in cells with defect DNA mismatch repair may be the RAS/RAF pathway. Colon cancers often have KRAS2 mutations and, if not KRAS2 mutations, may have BRAF mutations. This study investigated the spectrum and frequency of mutations in BRAF and KRAS2 in endometrial carcinomas on the basis of mismatch repair status. STUDY DESIGN: Four hundred forty-one patients with endometrial cancer were staged properly and graded and evaluated for mismatch repair status. These patients were then stratified to groups by the degree of microsatellite instability that was observed in their tumors. One hundred forty-six of the selected tumors were then evaluated for KRAS2 and BRAF mutations on the basis of their microsatellite instability. RESULTS: One hundred forty-six endometrioid endometrial cancers were evaluated for KRAS2 and BRAF mutations. Thirty-five cancers (24%) had activating KRAS2 mutations, but only a single BRAF mutation was identified in an microsatellite instability-positive cancer. Twenty-four of 81 microsatellite instability high cancers (29.6%) in which the MLH1 repair gene was methylated had KRAS2 mutations. When compared with the other groups, this finding approached statistical significance (P=.06). KRAS2 mutation status was associated with increasing age at diagnosis (P=.02). CONCLUSION: Despite many similarities between colon and endometrial cancers, the mechanism of the development of endometrial cancers appears to be different from colon cancers in that BRAF is not affected by a mismatch repair problem, because only KRAS2 mutations were seen. In addition, increasing age appears to lead to an increased likelihood that such a mutation will occur.     

Uterine mullerian adenosarcoma following adenomyoma in a woman on tamoxifen therapy.

The clinical and pathologic findings in a 53-year-old woman who developed a uterine adenosarcoma following an adenomyoma are described. During the interval between the diagnosis of adenomyoma and the subsequent diagnosis of adenosarcoma, the patient developed breast carcinoma and received adjuvant chemotherapy that included tamoxifen. The possible stimulatory effects of this drug upon the patient's pre-existing adenomyoma are discussed in view of reports of tamoxifen-associated endometrial carcinoma and uterine sarcomas developing in the setting of estrogen excess.