Chromosomal deletions and K‐ras gene mutations in human endometrial carcinomas

Imamura, Toshitaka; Arima, Takahiro; Kato, Hidenori; Miyamoto, Shingo; Sasazuki, Takehiko; Wake, Norio

doi:10.1002/ijc.2910510110

Cited by 63 publications

(42 citation statements)

References 23 publications

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“…There is controversy about the frequency of allelic deletion at the TP53 locus in sporadic ECs [14,15,16,17,18,19,20,21,22,23]. This may be explained by the limited number of polymorphic markers studied (only one or two), the small number of cases tested, and/or the inclusion of different subtypes of ECs.…”

Section: Discussionmentioning

confidence: 89%

“…Allelic loss at chromosome 17p13.1 (where the TP53 gene is located) has been reported to occur in positive ECs, with frequencies reaching 44% [14,15,16,17,18,19,20,21,22,23]. It is worth pointing out that TP53 gene point mutations correlated significantly with allelic loss in uterine corpus cancers (p = 0.024), absence of estrogen (p = 0.045) and progesterone (p = 0.001) receptors, DNA non-diploid status (p = 0.002) and high S-phase fraction values (p = 0.002) [19].…”

Section: Introductionmentioning

confidence: 99%

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Allelic Loss at TP53 Is Not Related to p53 Protein Overexpression in Primary Human Endometrial Carcinomas

Semczuk

Marzec²,

Skomra³

et al. 2005

Oncology

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We examined loss of heterozygosity (LOH) at the TP53 gene in primary human endometrial carcinomas (EC), and investigated the relationship between allelic loss, p53 protein overexpression, pRb-1 pathway alterations and MIB-1 proliferative activity. Applying the non-isotopic PCR-RFLP/VNTR-silver staining techniques, we investigated TP53 LOH in 46 tumors at four polymorphic loci. Out of 42 informative carcinomas, LOH was found in 19% of the cases studied. In general, there was no significant relationship between LOH and the clinical and pathological variables of cancer, including patient age, clinical stage, histological grade or depth of myometrial invasion. Interestingly, none of 7 tumors associated with hyperplasia revealed allelic imbalance, whereas 8 of 27 (30%) tumors without hyperplasia exhibited LOH (p = 0.312; Fisher’s exact test). Overexpression of nuclear p53 was not correlated with allelic loss at TP53 (p = 0.336, Fisher’s exact test). It is worth pointing out that p53 immunoreactivity was significantly related to proliferative activity of cancer (R = 0.42, p = 0.0037; Spearman’s rank correlation test). A tendency towards a poorer outcome was reported in EC patients displaying TP53 LOH during short-time follow-up (p = 0.093; log-rank test). None of the tumors simultaneously showed LOH at TP53 and RB1 genes(R = –0.211, p = 0.16; Spearman’s rank correlation test). p16^INK4A alterations (LOH and gene deletion) occurred concomitantly, with 3 tumors showing the TP53 allelic loss, whereas the cyclin D1/cdk4 complex was overexpressed in a case with TP53 LOH. Altogether, losses at TP53 were not associated with p53 nuclear overexpression, but may affect a subset of EC patients characterized by an unfavorable prognosis at short-time follow-up. Allelic loss at TP53 seems to arise independently of LOH at the RB1 gene in carcinomas of the uterine corpus in humans. Disruptions at p16^INK4A and/or cdk4/cyclin D1 concomitantly occurring with TP53 LOH may participate in the development of a subset of endometrioid-type ECs.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Allelic Loss at TP53 Is Not Related to p53 Protein Overexpression in Primary Human Endometrial Carcinomas

Semczuk

Marzec²,

Skomra³

et al. 2005

Oncology

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“…K-RAS and c-ERBB2/neu). 1,[5][6][7][8][9] However, the molecular genetic events underlying endometrial cancer tumorigenesis are still poorly understood.…”

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confidence: 99%

Analysis of chromosome 10 aberrations in rat endometrial cancer—evidence for a tumor suppressor locus distal to Tp53

Nordlander

Karlsson

et al. 2007

Intl Journal of Cancer

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We have recently shown in the BDII rat model of human endometrial adenocarcinoma (EAC), rat chromosome 10 (RNO10) is frequently involved in chromosomal aberrations. In the present study, we investigated the association between RNO10 deletions, allelic imbalance (AI) at RNO10q24 and Tp53 mutation in 27 rat EAC tumors. We detected chromosomal breakage accompanied by loss of proximal and/or gain of distal parts of RNO10 in approximately 2/3 of the tumors. This finding is suggestive of a tumor suppressor activity encoded from the proximal RNO10. Given the fact that Tp53 is located at RNO10q24-q25, we then performed Tp53 mutation analysis. However, we could not find a strong correlation between AI/deletions at RNO10q24 and Tp53 mutation. Instead, the observed patterns for AI, chromosomal breaks and deletions suggest that major selection was directed against a region located close to, but distal of Tp53. In different human malignancies a similar situation of AI at chromosome band 17p13.3 (HSA17p13.3) unassociated with TP53 mutation has been observed. Although RNO10 is largely homologous to HSA17, the conservation with respect to gene order among them is not extensive. We utilized publicly available draft DNA sequences to study intrachromosomal rearrangement during the divergence between HSA17 and RNO10. By using reciprocal comparison of rat and human genome data, we could substantially narrow down the candidate tumor suppressor region in rat from 3 Mb to a chromosomal segment of about 0.5 Mb in size. These results provide scientific groundwork for identification of the putative tumor suppressor gene(s) at 17p13.3 in human tumors. ' 2006 Wiley-Liss, Inc.Key words: BDII; endometrial adenocarcinoma; RNO10; 17p13.3; allelic imbalance; Tp53 mutation; tumor suppressor gene Endometrial cancer is the most frequently diagnosed female genital tract malignancy in the western world. 1 Endometrial adenocarcinoma (EAC) is the prevalent subtype, accounting for approximately 75% of the reported cases. 2 It has been clearly demonstrated that an inherited genetic predisposition plays a critical role in the development of many cases of EAC, as the risk for a woman to develop EAC is tripled when there is an affected firstdegree relative. 3,4 Molecular genetic analysis of uterine tumor biopsies have revealed alterations in a number of chromosomal regions harboring transforming genes, including tumor suppressor genes (e.g. TP53, PTEN and hMLH1) and oncogenes (e.g. K-RAS and c-ERBB2/neu). 1,5-9 However, the molecular genetic events underlying endometrial cancer tumorigenesis are still poorly understood.Females of the inbred BDII rat strain are genetically prone to spontaneously occurring hormone-related endometrial carcinoma, providing a suitable experimental model system for genetic analysis of inherited EAC in humans. 10,11 Cytogenetic and comparative genome hybridization (CGH) analyses of the tumors pointed to common deletions in the proximal part of rat chromosome 10 (RNO10) in the tumor material. 12 According to Knudson's two-hit theo...

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“…Altogether, 10 of 72 (14%) tumors displayed TP53 point mutations and LOH, whereas a total of 33 (36%) EC women showed point mutations, LOH, or both genetic alterations simultaneously [32]. The overall number of allelic losses appears to increase with advanced tumor stage, thereby indicating the significant association between LOH accumulation and the progression of the disease [28]. Analysis of Southern blot hybridization using probes YNZ22 (D17S5) and MCT35.1 (D17S31) revealed allelic loss in 5 tumors: 2 clear-cell carcinomas (stages IA and IB due to the International Federation of Gynecology and Obstetrics, FIGO), 1 endometrioid-type uterine adenocarcinoma (stage IIB), and 2 advanced-stage (both at IVB stages of the disease) endometrioid-type ECs [28].…”

Section: Loh Tp53 and Clinicopathological Features Of Ecmentioning

confidence: 99%

“…Allelic loss at TP53 locus has been reported in tumors originating from genital tract organs, including ovarian [20,21,22,23], cervical [24,25,26] and endometrial [6,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44] carcinomas. Table 1 summarizes data presenting the prevalence of allelic loss at the TP53 locus in primary human ECs (divided into two subtypes).…”

Section: Introductionmentioning

confidence: 99%

Prevalence of Allelic Loss at TP53 in Endometrial Carcinomas

Semczuk

Schneider‐Stock²,

Szewczuk³

2010

Oncology

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Alterations within the TP53 tumor suppressor belong to the most common genetic features reported in various human neoplasms, including endometrial cancer. In this article, the prevalence of allelic loss at the TP53 locus in primary human endometrial carcinomas (ECs) is discussed. Furthermore, we reviewed the role of allelic imbalance at 17p13.1 in metastatic human ECs on the basis of a literature review and on recently published data ascertained by our laboratory staff.

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Chromosomal deletions and K‐ras gene mutations in human endometrial carcinomas

Cited by 63 publications

References 23 publications

Allelic Loss at <i>TP53</i> Is Not Related to p53 Protein Overexpression in Primary Human Endometrial Carcinomas

Allelic Loss at <i>TP53</i> Is Not Related to p53 Protein Overexpression in Primary Human Endometrial Carcinomas

Analysis of chromosome 10 aberrations in rat endometrial cancer—evidence for a tumor suppressor locus distal to Tp53

Prevalence of Allelic Loss at <i>TP53</i> in Endometrial Carcinomas

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