PTEN mutations in endometrial carcinomas: A molecular and clinicopathologic analysis of 38 cases

Bussaglia, Elena; Río, E. Del; Matías‐Guiu, Xavier; Prat, Jaime

doi:10.1016/s0046-8177(00)80244-0

Cited by 158 publications

(108 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…16,20 -27 Although most of the PTEN mutations occurred in the predominant endometrioid tumor type, three of the five nonendometrioid tumors (two mixed UPSC/endometrioid, one UPSC) also contained PTEN mutation, which may seem contradictory to previous reports associating PTEN mutations with better prognostic factors (including endometrioid type) in endometrial carcinoma. 22,24,26 However, in agreement with others, we found a significant correlation between PTEN mutations and MSI phenotype. Because one of the three PTEN-mutated nonendometrioid tumors was highly MSI (four microsatellite loci), and a second (although stated as MSS) did show instability for mononucleotide markers, this indicates the role of PTEN alterations in the MSI pathway of tumorigenesis irrespective of histology status.…”

Section: Discussionsupporting

confidence: 92%

Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis

Koul

Wïllén

Bendahl

et al. 2002

Cancer

View full text Add to dashboard Cite

BACKGROUNDEndometrial carcinomas seem to carry a different prognosis depending on the presence or absence of concomitant complex atypical hyperplasia (hyperplasia). The molecular genetic profile of these two pathogenetic types, based on the genes reportedly mutated in these cancers, remains to be defined. Although microsatellite inability is reported in approximately 25% of endometrial carcinomas, its relation with the 2 pathogenetic types is not investigated.METHODSTo elucidate their underlying genetic changes, we analyzed 53 sporadic endometrial tumors, including 19 with and 34 without hyperplasia, for microsatellite instability (MSI), DNA ploidy (by flow cytometry), and for mutations in different genes.RESULTSMicrosatellite instability was present in 21%, DNA nondiploidy in 15%, and mutations in the PTEN, KRAS, CTNNB1/β‐catenin, TP53, and CDKN2A genes were detected in 32, 11, 13, 17, and 0% of the tumors, respectively. Microsatellite instability and mutations in these genes were present in tumors both with and without complex atypical hyperplasia. All cases with complex atypical hyperplasia were early stage (I–II) endometrioid tumors and associated with long progression free disease (P = 0.0004). Furthermore, most tumors with hyperplasia had low World Health Organization or International Federation of Gynecology and Obstetrics grade, had less myometrial invasion, and showed expression of estrogen receptors. All MSI tumors were diploid and had a significantly higher rate of PTEN mutations, but similar rates of KRAS, β‐catenin, and TP53 mutations compared with microsatellite stable tumors. TP53 mutations more often were found in nondiploid tumors but never in tumors with PTEN, KRAS, or β‐catenin mutations, and all PTEN mutations occurred in diploid tumors.CONCLUSIONSThus, PTEN, KRAS, β‐catenin, and TP53 mutations occurred in tumors both with and without hyperplasia, but PTEN and TP53 mutations were more common in tumors without hyperplasia. However, none of these genes seems to clearly distinguish tumors with and without hyperplasia, suggesting that other factors may be involved. Conversely, alterations in the PTEN and TP53 genes seem to define distinct subgroups of endometrial carcinoma, the former associated with diploidy and MSI, the latter with macroscopic chromosomal instability. Cancer 2002;94:2369–79. © 2002 American Cancer Society.DOI 10.1002/cncr.10498

show abstract

Section: Discussionsupporting

confidence: 92%

Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis

Koul

Wïllén

Bendahl

et al. 2002

Cancer

View full text Add to dashboard Cite

show abstract

“…25,26 PTEN was mutated or deleted homozygously in glioma, endometrial, and breast carcinoma tumors. [27][28][29] It was reported that PTEN mutations were identified in small cell carcinomas, but not in non-small-cell carcinomas. 30,31 We found that the frequency of the loss of expression of PTEN was higher in high-grade neuroendocrine carcinoma than in classic large cell carcinoma or carcinoid tumor, and the differences were significant; however, the difference was not significant between large cell neuroendocrine carcinoma and small cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis

et al. 2006

View full text Add to dashboard Cite

The distinction between pulmonary large cell neuroendocrine carcinoma and small cell carcinoma is difficult in some cases. Some propose that these carcinomas should be classified as one high-grade neuroendocrine carcinoma. We examined biological features of small cell carcinoma (n ¼ 23), large cell neuroendocrine carcinoma (n ¼ 17), and classic large cell carcinoma (n ¼ 12). The average ratio of nuclear diameter of the tumor cells to that of lymphocytes for small cell carcinoma was smaller than that for large cell neuroendocrine carcinoma (Po0.0001). The frequencies of the expressions of CD56, mASH1, TTF-1, and p16 were higher and that of NeuroD was lower in small cell carcinoma than in large cell neuroendocrine carcinoma. The frequency of loss of heterozygosity at 3p was higher in high-grade neuroendocrine carcinomas than in classic large cell carcinoma (P ¼ 0.0002). Allelic losses at D5S422 (5q33) were more frequent in small cell carcinoma than in large cell neuroendocrine carcinoma (P ¼ 0.0091). Mean fractional regional loss indices of the tumors were 0.38, 0.65, and 0.72 for patients with classic large cell carcinoma, large cell neuroendocrine carcinoma, and small cell carcinoma, respectively (P ¼ 0.0003). Five-year overall survivals of patients with classic large cell carcinoma, large cell neuroendocrine carcinoma and small cell carcinoma in stage I were 67, 73, 60%, respectively. Patients with NeuroD expression had better survivals, and those with p63 expression had poorer survivals in large cell neuroendocrine carcinoma. Patients with TTF-1 expression had poorer survivals in small cell carcinoma. Our data suggest that large cell neuroendocrine carcinoma and small cell carcinoma are different morphologically, phenotypically, and genetically, although there are some overlapping features. Although further studies are needed to analyze the biological behavior of high-grade neuroendocrine carcinomas including sensitivity to chemotherapy, the pathological distinction of large cell neuroendocrine carcinoma from small cell carcinoma may be necessary to treat the patients with neuroendocrine tumors.

show abstract

“…Nonendometrioid endometrial carcinomas exhibit alterations of p53, 4 STK15, 3 p16, E-cadherin, 5 and C-erbB2, as well as loss of heterozygosity on several chromosomes. 6 In contrast, endometrioid endometrial carcinomas show microsatellite instability, 7 and mutations in the PTEN, 8 KRAS, 9 and CTNNB-1 genes. [10][11][12] Oncogenic activation of tyrosine kinases is a common mechanism of carcinogenesis.…”

mentioning

confidence: 99%

FGFR2 alterations in endometrial carcinoma

et al. 2011

View full text Add to dashboard Cite

Fibroblast growth factor receptor 2 (FGFR2) is a tyrosine kinase receptor involved in many biological processes such as embryogenesis, adult tissue homeostasis and cell proliferation. Mutations in FGFR2 have been reported in up to 10-12% of endometrial carcinomas identical to those found in congenital craniofacial disorders. Inhibition of FGFR2 could be a new therapeutic target in endometrial carcinoma. FGFR2 immunostaining was assessed in three tissue microarrays: one constructed from paraffin-embedded blocks of 60 samples of normal endometrium in different phases of menstrual cycle, and two tissue microarrays containing endometrial carcinoma samples (95 and 62 cases). FGFR2 expression was correlated with stage, histological type and grade as well as with immunostaining of PTEN, RASSF1A, estrogen and progesterone receptors, KI67, Cyclin D1, STAT-3 and SPRY2. FGFR2 mutations were assessed by PCR and direct sequencing, with DNA obtained from 31 paraffin-embedded endometrial carcinoma samples. In normal endometrium, FGFR2 expression was higher in the secretory than in the proliferative phase (P ¼ 0.001), with an inverse correlation with Ki67 (P ¼ 0.00032), suggesting a tumor-suppressor role for FGFR2 in normal endometrium. Cytoplasmic expression of FGFR2 was higher in endometrial carcinoma when compared with the atrophic endometrium from the same patients (P ¼ 0.0283), but was lower in comparison with normal endometrium from women in the menstrual cycle. Interestingly, nuclear staining was observed in some cases, and it was less frequent in endometrial carcinoma when compared with the adjacent atrophic endometrium (P ¼ 0.0465). There were no statistical differences when comparing superficial and myoinvasive endometrial carcinoma samples. Endometrioid endometrial carcinomas showed higher expression of FGFR2 than nonendometrioid endometrial carcinomas (fold change 2.56; P ¼ 0.0015). Grade III endometrioid endometrial carcinomas showed decreased FGFR2 expression when compared with grade II endometrioid endometrial carcinomas (P ¼ 0.0055). No differences were found regarding pathological stage. Two missense mutations of FGFR2 gene were detected in exons 6 and 11 (S252W and N549K, respectively; 6.45%). Results support the hypothesis that FGFR2 has a dual role in the endometrium, by inhibiting cell proliferation in normal endometrium during the menstrual cycle, but acting as an oncogene in endometrial carcinoma.

show abstract

PTEN mutations in endometrial carcinomas: A molecular and clinicopathologic analysis of 38 cases

Cited by 158 publications

References 36 publications

Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis

Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis

Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis

FGFR2 alterations in endometrial carcinoma

Contact Info

Product

Resources

About