Mutational Analysis of the<i>PTEN</i>Gene in Endometrial Carcinoma and Hyperplasia

Sun, Han; Enomoto, Takayuki; Fujita, Masami; Wada, Hiroko; Yoshino, Kiyoshi; Ozaki, Keiichiro; Nakamura, Takafumi; Murata, Yuji

doi:10.1309/7jx6-b9u9-3p0r-eqny

Cited by 103 publications

(78 citation statements)

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“…32,33,[38][39][40]42 However, there exists some controversy over exactly how they participate in that process.…”

Section: Discussionmentioning

confidence: 99%

“…Normal tissue DNA from the same patient or from 2 unrelated individuals was used as a control in the SSCP experiments. The 9 exons and intronic splice sites of the PTEN gene were amplified using 11 primer pairs previously described 30,33 with the exception that the sequence 5 0 -ACATCA ATATTTGAAATAGAAA-3 0 was used as the reverse primer for the amplification of exon 2. PCR amplifications were performed in 10 ll reaction volume containing 20 ng of DNA, 300 nM of each primer, 125 lM of deoxynucleotide triphosphates, 0.2 lCi of [a32P]dCTP, 13 commercial Appied Biosystems buffer, 1.5 mM MgCl 2 and 0.5 U AmpliTaq DNA polymerase (Applied Biosystems, Foster City, CA).…”

Section: Pten Gene Mutation Analysismentioning

confidence: 99%

“…PCR amplifications were performed in 10 ll reaction volume containing 20 ng of DNA, 300 nM of each primer, 125 lM of deoxynucleotide triphosphates, 0.2 lCi of [a32P]dCTP, 13 commercial Appied Biosystems buffer, 1.5 mM MgCl 2 and 0.5 U AmpliTaq DNA polymerase (Applied Biosystems, Foster City, CA). This was carried out under conditions similar to those already published, 30,33 with a few minor modifications. PCR products were diluted 1:1 with loading buffer, denatured at 95°C for 4 min and cooled on ice.…”

Section: Pten Gene Mutation Analysismentioning

confidence: 99%

“…21,22 It has been suggested that PTEN gene inactivation, mainly due to mutation and/ or LOH, plays a pivotal role in tumor progression of glioblastoma multiforme 23 and some other sporadic tumors. 24 Somatic MSI and PTEN gene mutations are frequently observed in sporadic endometrial cancer (EC), ranging from 9 to 44% [25][26][27][28][29] and from 25 to 83%, 27,[30][31][32][33][34][35] respectively. Both are associated with endometrioid histology and diploidy, 36,37 and have also been detected in endometrial hyperplasia, indicating that they are early occurrences in the tumorigenic process.…”

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confidence: 99%

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The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer

Bilbao

Rodríguez

Ramírez

et al. 2006

Intl Journal of Cancer

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Microsatellite instability (MSI) and mutations in the PTEN gene are among the molecular alterations involved in endometrial carcinogenesis. There is conflicting information regarding to their role in this type of tumor. For this reason, we have studied both molecular lesions in a large population-based series of 205 patients with sporadic endometrial cancer. MSI was found in 41 (20.0%) of the tumors and PTEN mutations were found in 74 (36.1%). There were differences in genotype between tumors with and without MSI. Tumors with MSI showed both a higher frequency of PTEN mutations (58.5% vs. 30.4%) (p 5 0.002, Fisher's exact test) and a higher number of insertions or deletions (I/D) of one nucleotide within the mononucleotide tracts of the PTEN gene (45.8% vs. 11.4% out of all I/D, p 5 0.005). Conversely, G:C to A:T transitions in CpG dinucleotides were found mostly in microsatellite stable tumors (57.7% vs. 18.2% out of all single-base substitutions, p 5 0.037). Overall, 67.6% of tumors with mutated PTEN exhibited multiple mutations or allelic imbalance (AI). Multiple PTEN mutations in the same tumor were more frequent in tumors with MSI (60% vs. 25.7%); by contrast the presence of AI accompanying PTEN mutation was higher in microsatellite stable tumors (74.3% vs. 40%) (p 5 0.028). In addition, patients with both genetic alterations were diagnosed at more advanced stage of progression (54.2% for MSI vs. 20.0% for MSS, p 5 0.006), and exhibited a worse prognosis (hazard ratio [95% confidence interval]: 3.0 [1.1-13.1], p 5 0.034, log-rank test) than patients with only the PTEN gene mutated. Our data suggest that the DNA mismatch repair system status influences: (i) both the frequency and the mutational spectrum of PTEN; (ii) the nature of one of the hits that inactivate this tumor-suppressor gene; and (iii) the clinical condition and behavior of the patients. ' 2006 Wiley-Liss, Inc.Key words: microsatellite instability; PTEN mutation; endometrial cancer Microsatellite instability (MSI) is caused by defects in the DNA mismatch repair (MMR) system, either by mutations or by epigenetic events leading to gene silencing. 1,2 Tumors with MSI are characterized by a massive instability in simple repeated sequences and mutations in many cancer-related genes, particularly those with simple repeated sequences in their coding regions. [3][4][5][6][7] Tumors with MSI display a strong microsatellite mutator phenotype (MMP), which underlies a mutational pathway for gastrointestinal cancer that differs in genotype and phenotype from cancers with microsatellite stability (MSS).The MMP pathway for colon cancer possesses several peculiar characteristics in genotype. These tumors show a paradoxically low incidence of mutations affecting the prototypical cancer genes for colon cancer, namely the APC and p53 tumor suppressor genes and the K-ras oncogene. 3,[8][9][10][11] This low mutational incidence is also accompanied by a decreased incidence of loss of heterozygosity (LOH), 1,3,12 which is reflected at the cytogenetic level in freque...

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“…32,33,[38][39][40]42 However, there exists some controversy over exactly how they participate in that process.…”

Section: Discussionmentioning

confidence: 99%

Section: Pten Gene Mutation Analysismentioning

confidence: 99%

Section: Pten Gene Mutation Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer

Bilbao

Rodríguez

Ramírez

et al. 2006

Intl Journal of Cancer

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“…Endometrial carcinoma is the most common invasive malignant neoplasm of the female genital tract, with an estimated 46,470 diagnosed cases and 8,120 deaths in 2011 in the United States (Cancer Statistics, 2011). Two major types of endometrial carcinoma include type I or endometrioid endometrial carcinoma (EEC) and type II including uterine serous and clear cell carcinomas (Sun et al, 2001;Fader et al, 2009). Cancer is one of the leading causes of death in the world (Zhao et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

The Polymorphism of Hypoxia-inducible Factor-1a Gene in Endometrial Cancer

Kafshdooz¹,

Tabrizi²,

Mohaddes³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Background: Endometral carcinoma is the most common malignant tumor of the female genital tract and the fourth most common cancer in women after breast, colorectal and lung cancers Hypoxia-inducible factor -1 (HIF-1) is a key transcription factor that regulates cellular response to hypoxia HIF-1 plays important roles in the development and progression of cancer through activation of various genes that are involved in crucial aspects of cancer biology, including angiogenesis, energy metabolism, vasomotor function, erythropoiesis, and cell survival. In this study, we aimed to investigate the association between HIF-1 1772 C/T polymorphisms and endometrial cancer. Materials and Methods: 75 patients with endometrial carcinoma and 75 patients whose underwent hysterectomy for non tumoral indication selected for evaluation of HIF-1 1772 C/T polymorphisms by PCR-RFLP and sequencing. Results: For the 1772 C/T polymorphism, the analysis showed that the T allele and genotype TT were significantly associated with endometrial cancer risk. Conclusions: Our results suggest that the C1772T polymorphism of the HIF-1a may be associated with endometrial cancers.

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

Koul

Wïllén

Bendahl

et al. 2002

Cancer

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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

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Mutational Analysis of thePTENGene in Endometrial Carcinoma and Hyperplasia

Cited by 103 publications

References 20 publications

The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer

The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer

The Polymorphism of Hypoxia-inducible Factor-1a Gene in Endometrial Cancer

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

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