Mutations of the <i>β‐Catenin</i> Gene in Endometrial Carcinomas

Kobayashi, Kazutoyo; Sagae, Satoru; Nishioka, Yoshihiro; Tokino, Takashi; Kudo, Ryuichi

doi:10.1111/j.1349-7006.1999.tb00665.x

Cited by 87 publications

(67 citation statements)

References 11 publications

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“…In this study, we identified mutations in exon 3 of the β-catenin gene in 16 (22.9%) of 70 endometrial carcinomas, in line with previous studies (Fukuchi et al, 1998;Kobayashi et al, 1999;Mirabelli-Primdahl et al, 1999). Although our mutation analysis was limited, it has been reported that mutations outside exon 3 of the β-catenin gene was infrequent, despite the entire coding sequence was analysed (Ilyas et al, 1997).…”

Section: Discussionsupporting

confidence: 90%

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β- Catenin mutations and aberrant nuclear expression during endometrial tumorigenesis

et al. 2001

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SummaryTo clarify the possible role of aberrant β-catenin expression during endometrial tumorigenesis, a total of 199 cases of endometrial carcinomas (endometrioid type), as well as 37 cases of simple/complex and 32 of atypical hyperplasias, was consecutively investigated for immunohistochemistry, along with 141 normal endometrial samples distant from carcinomas. Of 199 carcinoma cases, 73 tumours as well as 44 normal samples were also analysed using a combination of RT-PCR and Southern blot hybridization, Western blot, and mutation gene assays. Cell membrane β-catenin immunoreactivity showed a stepwise decrease from normal, through atypical hyperplasia, to grade 3 carcinomas. In contrast, the nuclear accumulation in atypical hyperplasias and grade 1 or 2 tumours was higher than in simple/complex hyperplasias. Mutations in exon 3 of the β-catenin gene involving codons 33, 34, 37, 41, and 45 were observed in 16 (22.9%) of 70 endometrial carcinomas, as well as 3 (12.5%) of 24 atypical hyperplasias, the results being significantly related to low membrane and high nuclear immunoreactivity but not relative mRNA expression levels, suggesting that the gene mutations may be closely associated with changes in subcellular distribution. In addition to significant association between β-catenin mutation and low grade histological malignancy (P = 0.048), the mutations were detected in none of 15 and 13 (26%) of 50 tumours with or without lymph node metastasis, the difference being significant (P = 0.027). These findings suggest that β-catenin abnormalities may play an important role in a relatively early event during the endometrial hyperplasia-carcinoma sequence.

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Section: Discussionsupporting

confidence: 90%

“…In endometrial carcinomas, the alterations have been considered to be related to an early clinical stage with well differentiated histology or early onset of endometrial carcinomas (Fukuchi et al, 1998;Kobayashi et al, 1999). In addition to histological malignancy, we also found a significant correlation with no lymph node metastasis.…”

Section: Discussionsupporting

confidence: 68%

β- Catenin mutations and aberrant nuclear expression during endometrial tumorigenesis

et al. 2001

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“…[12][13][14]22,23 Abnormalities of b-catenin have also been shown in a significant proportion of endometrial neoplasms. 3,5 Mutations have been recorded in 13-31% cases and appear more common in lowgrade endometrioid adenocarcinomas, [31][32][33][34][35][36] whereas an abnormal immunolocalization in the form of reduced membrane staining with diffuse cytoplasmic and/or nuclear staining has been recorded in 25-76% cases. [34][35][36][37][38][39] Most b-catenin mutations lead to decreased protein degradation and are associated with altered (usually nuclear) immunoreactivity.…”

Section: Endometrial Carcinoma Invasionmentioning

confidence: 99%

Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands

et al. 2009

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Endometrial adenocarcinomas may show a distinctive pattern of invasion characterized by the presence of microcystic, elongated and fragmented glands, often most evident along the advancing tumor margin. Earlier, we have shown that these changes appear restricted to low-grade endometrioid carcinomas, many of which show focal mucinous differentiation and lymphovascular space invasion. However, the molecular alterations associated with this morphological alteration are not known. In this study, we have examined immunoreactivity for the cell cycle regulatory proteins cyclin D1, p16 and b-catenin in 22 endometrial carcinomas, specifically comparing the results in conventional tumor areas and in foci in which the glands exhibited microcystic, elongated and fragmented appearances. The conventional neoplastic glands exhibited cyclin D1 and p16 expression in most cases, with 450% tumor cells positive in 8 cases and 11 tumors, respectively. Membranous expression of b-catenin was usually preserved, with variable cytoplasmic and nuclear staining. Cyclin D1 and b-catenin predominantly stained cells at the peripheral or basal aspect of the conventional glands, whereas p16 was more uniformly expressed centrally. Tumor foci composed of microcystic, fragmented and elongated glands showed strong expression of cyclin D1 and p16, sometimes in contrast to unstained contiguous or adjacent conventional neoplastic elements, and there was also loss or fragmentation of membranous b-catenin staining. Intravascular tumor cells also expressed cyclin D1 and p16 and therefore the immunostains often highlighted subtle foci of lymphovascular invasion. The heterogenous expression of cell cycle regulatory proteins within endometrial adenocarcinoma illustrates the importance of assessing microanatomical variations in immunoreactivity, particularly at the advancing margin of tumors. The upregulation of cyclin D1 and p16, together with loss of membranous b-catenin expression in microcystic, fragmented and elongated glands, is similar to epithelial-mesenchymal transitions observed in other malignancies and suggests that this pattern of invasion represents an active rather than a degenerative cellular process. Modern Pathology (2009) 22, 725-733; doi:10.1038/modpathol.2009 published online 6 March 2009 Keywords: endometrial; carcinoma; invasion; MELF; epithelial-mesenchymal transition; immunohistochemistry Endometrial carcinomas can be divided into two major groups on the basis of clinicopathological, immunohistological and molecular features. 1,2 The more common (type 1) subgroup accounts for 80-85% of cases and mainly comprises endometrioid adenocarcinomas of low-to-intermediate grade. These tumors typically occur in perimenopausal and younger postmenopausal patients, often arise in hyperestrogenic states and are associated with atypical endometrial hyperplasia/endometrial intraepithelial neoplasia. Frequently, type 1 carcinomas are confined to the uterine corpus at the time of diagnosis (stage 1), and the prognosis in such patients is generally ...

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“…Deregulation of the cadherin/catenin complex has been implicated in cancer development, progression, differentiation, invasion, and metastatic potential in several malignancies. [17][18][19][20] Deregulation of b-catenin has been described to be caused by oncogenic mutation of the b-catenin gene (CTNNB1), mutations in the APC gene, or alterations of the Wnt signal transduction pathway. 21,22 Recent studies have estimated that the mutation frequency of b-catenin in ovarian endometrioid carcinoma ranges from 16 to 54%.…”

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confidence: 99%

Low membranous expression of β-catenin and high mitotic count predict poor prognosis in endometrioid carcinoma of the ovary

et al. 2010

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Mutations in the b-catenin gene are common in ovarian endometrioid carcinoma. Few studies have addressed the association of b-catenin expression with tumor characteristics and patient outcome, yielding controversial results. The purpose of this study was to retrospectively assess the expression of b-catenin in ovarian endometrioid carcinoma and correlate its expression with the Gynecologic Oncology Group's (GOG) grading system, clinicopathological characteristics, and patient survival. A total of 49 patients with primary ovarian endometrioid carcinoma were included in this study. A four-tier score grading system was used for the membranous staining (negative, weak, moderate, and strong) and the percentage of positive cells for the nuclear staining of b-catenin. The status of five morphometric parameters, nuclear morphology (uniform or pleomorphic), mitotic count, glandular pattern, degree of squamous differentiation, and status of papillary pattern, was assessed. We found that a low membranous expression of b-catenin and a high mitotic count (415 per 10 high-power fields) were significantly associated with poor prognosis and early recurrence of ovarian endometrioid carcinoma. In addition, cases with nuclear expression of b-catenin showed an intermediate overall survival risk and late disease recurrence. Young age at the time of diagnosis, advanced disease stage, and suboptimal debulking were among the clinical factors predicting poor survival and early disease recurrence. The presence of squamous differentiation, a papillary pattern or nuclear pleomorphism did not show any correlation with overall survival or disease-free survival. Low membranous expression of b-catenin and high mitotic count are poor prognostic indicators in patients with ovarian endometrioid carcinoma, whereas the GOG grading system showed no prognostic value. Our data suggest that there is a need to define a better grading system for ovarian endometrioid carcinoma. Molecular markers such as b-catenin and mitotic count could aid in defining this grading system.

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Mutations of the β‐Catenin Gene in Endometrial Carcinomas

Cited by 87 publications

References 11 publications

β- Catenin mutations and aberrant nuclear expression during endometrial tumorigenesis

β- Catenin mutations and aberrant nuclear expression during endometrial tumorigenesis

Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands

Low membranous expression of β-catenin and high mitotic count predict poor prognosis in endometrioid carcinoma of the ovary

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