Endometrial adenocarcinoma: Genetic analysis suggesting heritable site-specific uterine cancer

Sandles, Lisa G.; Shulman, L.P.; Elias, Sherman; Photopulos, Guy J.; Smiley, Linda; Posten, William; Simpson, Joe Leigh

doi:10.1016/0090-8258(92)90101-n

Cited by 53 publications

(29 citation statements)

References 10 publications

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“…Similarly, among the translocation chromosomes, 14 contained the Thra but not the Tp53 gene, and the remaining two exhibited one or two Tp53 signals but none from Thra. The conclusion is that these RNO10-derived marker chromosomes occurring in 18 EAC tumors had resulted from 4 Deviation from expected number of copies based on the tumor cell ploidy.-5 N -no break in RNO10; D -break leading to deletion chromosome; T -break leading to translocation chromosome. Note that only breaks between Tp53 and Thra1 were considered.…”

Section: Rno10 Aberrations Revealed By Chromosome Paint and Dual-colomentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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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Section: Rno10 Aberrations Revealed By Chromosome Paint and Dual-colomentioning

confidence: 99%

mentioning

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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“…Endometrial carcinoma (EC) is the prevalent subtype, accounting for w75% of the reported cases (Cavanagh et al 1999). Most of the ECs are sporadic, but an inherited genetic predisposition has been demonstrated in about 5% of cases, as the risk for a woman to develop EC is tripled when there is an affected first-degree relative (Sandles et al 1992, Gruber & Thompson 1996, Sandles 1998. Based on the biology and clinical features, two different pathways are distinguished for tumorigenesis of sporadic EC, w80% are designated as type I, including those with endometrioid histology, mostly of low grade, occur between the ages of 20-54 years old, follow the estrogen-related pathway, and have a favorable outcome.…”

Section: Introductionmentioning

confidence: 99%

Molecular classification of spontaneous endometrial adenocarcinomas in BDII rats

Samuelson

Hedberg²,

Nilsson³

et al. 2009

Endocrine-Related Cancer

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Female rats of the BDII/Han inbred strain are prone to spontaneously develop endometrial carcinomas (EC) that in cell biology and pathogenesis are very similar to those of human. Human EC are classified into two major groups: Type I displays endometroid histology, is hormone-dependent, and characterized by frequent microsatellite instability and PTEN, K-RAS, and CTNNB1 (b-Catenin) mutations; Type II shows non-endometrioid histology, is hormone-unrelated, displays recurrent TP53 mutation, CDKN2A (P16) inactivation, over-expression of ERBB2 (Her2/neu), and reduced CDH1 (Cadherin 1 or E-Cadherin) expression. However, many human EC have overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II. The EC developed in BDII rats can be related to type I tumors, since they are hormone-related and histologically from endometrioid type. Here, we combined gene sequencing (Pten, Ifr1, and Ctnnb1) and real-time gene expression analysis (Pten, Cdh1, P16, Erbb2, Ctnnb1, Tp53, and Irf1) to further characterize molecular alterations in this tumor model with respect to different subtypes of EC in humans. No mutation in Pten and Ctnnb1 was detected, whereas three tumors displayed sequence aberrations of the Irf1 gene. Significant down regulation of Pten, Cdh1, p16, Erbb2, and Ctnnb1 gene products was found in the tumors. In conclusion, our data suggest that molecular features of spontaneous EC in BDII rats can be related to higher-grade human type I tumors and thus, this model represents an excellent experimental tool for research on this malignancy in human.

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“…Family history may also be a risk factor as familial clustering of endometrial cancers has been reported (5). Sandles and co-investigators (5) suggested that two 'genetic models' may be implicated in the development of endometrial adenocarcinoma: the cancer family syndrome (Lynch II or hereditary nonpolyposis colorectal cancer syndrome) and a predisposition for endometrial adenocarcinoma alone.…”

Section: Introductionmentioning

confidence: 99%

Expression of erbB-1 and erbB-2 genes in normal and pathological human endometrium

Bryś

Semczuk²,

Rechberger³

et al. 2007

Oncol Rep

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Abstract. Overexpression of the erbB-1 (EGFR, epidermal growth factor receptor) and erbB-2 (HER2/neu) proteins contributes to the aggressive behavior of malignant tumors originating from the endometrium. We currently examined whether the trend of these proteins to overexpression is a direct effect of their gene transcriptional activities. Expression of the erbB-1/erbB-2 genes was measured applying the quantitative RT-PCR technique in 25 uterine carcinomas, 12 normal endometria, a carcinosarcoma and a case of botryoid sarcoma of the uterine cervix. We showed that erbB-1 mRNA was overexpressed in 48% (12/25) and erbB-2 mRNA was overexpressed in 8% (2/25) of the analysed tumors. The level of expression appeared to be significantly higher in the malignant tumors as compared to the benign ones for erbB-1 and for erbB-2 (p=0.0001 and p=0.008, respectively). A significant correlation between erbB-1 overexpression and tumor differentiation was found (Spearman rank correlation test, p<0.001). Concomitant erbB-1 and erbB-2 overexpression was detected only in 1 out of 25 (4%) uterine neoplasms. erbB-1 was overexpressed in a sarcoma botryoides of the uterine cervix. Our data suggest that erbB-1/erbB-2 overexpression is a direct effect of higher than normal transcriptional activity of the encoding genes in a subset of human endometrial carcinomas.

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Endometrial adenocarcinoma: Genetic analysis suggesting heritable site-specific uterine cancer

Cited by 53 publications

References 10 publications

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

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

Molecular classification of spontaneous endometrial adenocarcinomas in BDII rats

Expression of erbB-1 and erbB-2 genes in normal and pathological human endometrium

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