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• W2012808741 abstract "Endometrial cancer has been generally categorized into two broad groups of tumors, type I (TI) and type II (TII), with distinct epidemiological/clinical features and genetic alterations. Because telomere attrition appears to trigger genomic instability in certain cancers, we explored the role of telomere dysfunction in endometrial cancer by analyzing telomeres and other markers of telomere status in both tumor types. We describe a new method, telomere chromogenic in situ hybridization, which permitted us to detect cells with short telomeres relative to control (stromal) cells within the same tissue section. Using this method, we found that both types of tumor cells had short telomeres. However, only TII tumors were significantly associated with critical telomere shortening in adjacent, morphologically normal epithelium, suggesting that telomere shortening contributes to the initiation of TII but not TI tumors. To explore this hypothesis, we analyzed mice with critically short telomeres and documented distinctive endometrial lesions that histologically resembled the in situ precursor of TII serous carcinomas; these lesions have not been observed previously in TI mouse models of endometrial cancer. Based on this and previous studies, we propose a model in which telomere attrition contributes to the initiation of TII and progression of TI endometrial cancers. Endometrial cancer has been generally categorized into two broad groups of tumors, type I (TI) and type II (TII), with distinct epidemiological/clinical features and genetic alterations. Because telomere attrition appears to trigger genomic instability in certain cancers, we explored the role of telomere dysfunction in endometrial cancer by analyzing telomeres and other markers of telomere status in both tumor types. We describe a new method, telomere chromogenic in situ hybridization, which permitted us to detect cells with short telomeres relative to control (stromal) cells within the same tissue section. Using this method, we found that both types of tumor cells had short telomeres. However, only TII tumors were significantly associated with critical telomere shortening in adjacent, morphologically normal epithelium, suggesting that telomere shortening contributes to the initiation of TII but not TI tumors. To explore this hypothesis, we analyzed mice with critically short telomeres and documented distinctive endometrial lesions that histologically resembled the in situ precursor of TII serous carcinomas; these lesions have not been observed previously in TI mouse models of endometrial cancer. Based on this and previous studies, we propose a model in which telomere attrition contributes to the initiation of TII and progression of TI endometrial cancers. Endometrial cancer is the most common cancer of the female reproductive tract.1Jemal A Siegel R Ward E Murray T Xu J Thun MJ Cancer statistics, 2007.CA Cancer J Clin. 2007; 57: 43-66Crossref PubMed Scopus (7472) Google Scholar Although all endometrial cancers are believed to arise from a single cell type—the columnar epithelium that lines the inner surface of the uterus—endometrial cancers are subclassified into two classes of tumors with divergent epidemiological, clinical, histopathological, and molecular features.2Bokhman JV Two pathogenetic types of endometrial carcinoma.Gynecol Oncol. 1983; 15: 10-17Abstract Full Text PDF PubMed Scopus (1833) Google Scholar, 3Ellenson LH Wu TC Focus on endometrial and cervical cancer.Cancer Cell. 2004; 5: 533-538Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Type I (TI) endometrial cancers are strongly associated with estrogen-related risk factors such as obesity and unopposed estrogen therapy, and have a relatively good prognosis. In contrast, type II (TII) cancers have no association with estrogen-related risk factors, a much higher median age of onset, and a poor prognosis. These tumors are also histopathologically distinct, with TI being comprised of tumors with so-called “endometrioid” histology (and variants thereof such as endometrioid adenocarcinomas with squamous or mucinous differentiation), whereas TII tumors include uterine serous adenocarcinomas.4Clement PB Young RH Endometrioid carcinoma of the uterine corpus: a review of its pathology with emphasis on recent advances and problematic aspects.Adv Anat Pathol. 2002; 9: 145-184Crossref PubMed Scopus (161) Google Scholar, 5Clement PB Young RH Non-endometrioid carcinomas of the uterine corpus: a review of their pathology with emphasis on recent advances and problematic aspects.Adv Anat Pathol. 2004; 11: 117-142Crossref PubMed Scopus (109) Google Scholar TI and TII tumors also have distinct genetic and molecular profiles. Microsatellite instability and defects in DNA mismatch repair are common in TI, but rare in TII tumors.6Goodfellow PJ Buttin BM Herzog TJ Rader JS Gibb RK Swisher E Look K Walls KC Fan MY Mutch DG Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers.Proc Natl Acad Sci USA. 2003; 100: 5908-5913Crossref PubMed Scopus (194) Google Scholar, 7Wang H Douglas W Lia M Edelmann W Kucherlapati R Podsypanina K Parsons R Ellenson LH DNA mismatch repair deficiency accelerates endometrial tumorigenesis in Pten heterozygous mice.Am J Pathol. 2002; 160: 1481-1486Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 8Black D Soslow RA Levine DA Tornos C Chen SC Hummer AJ Bogomolniy F Olvera N Barakat RR Boyd J Clinicopathologic significance of defective DNA mismatch repair in endometrial carcinoma.J Clin Oncol. 2006; 24: 1745-1753Crossref PubMed Scopus (144) Google Scholar Furthermore, TI and TII cancers have reciprocal mutational spectra. Mutations in PTEN, KRAS, and the CTNNB1 locus that encodes β-catenin are frequent in TI, but rare in TII tumors, which in contrast have a very high rate of P53 mutations.3Ellenson LH Wu TC Focus on endometrial and cervical cancer.Cancer Cell. 2004; 5: 533-538Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 9Schlosshauer PW Pirog EC Levine RL Ellenson LH Mutational analysis of the CTNNB1 and APC genes in uterine endometrioid carcinoma.Mod Pathol. 2000; 13: 1066-1071Crossref PubMed Scopus (88) Google Scholar Finally, TI tumors have relatively minor chromosomal abnormalities, whereas TII tumors exhibit abnormal, complex karyotypes characterized by hyperploidy and abnormal chromosomes with numerous end-to-end fusions.10Ellenson LH The molecular biology of endometrial tumorigenesis: does it have a message?.Int J Gynecol Pathol. 2000; 19: 310-313Crossref PubMed Scopus (11) Google Scholar, 11Hecht JL Mutter GL Molecular and pathologic aspects of endometrial carcinogenesis.J Clin Oncol. 2006; 24: 4783-4791Crossref PubMed Scopus (432) Google Scholar, 12Bardi G Pandis N Schousboe K Holund B Heim S Near-diploid karyotypes with recurrent chromosome abnormalities characterize early-stage endometrial cancer.Cancer Genet Cytogenet. 1995; 80: 110-114Abstract Full Text PDF PubMed Scopus (23) Google Scholar, 13Faruqi SA Satyaswaroop PG LiVolsi VA Deger RB Noumoff JS Establishment and characterization of a poorly differentiated lethal human endometrial carcinoma cell line (NOU-1) with karyotype 46, XX.Cancer Genet Cytogenet. 2002; 138: 44-49Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Genomic instability is one of the hallmarks of cancer,14Hanahan D Weinberg RA The hallmarks of cancer.Cell. 2000; 100: 57-70Abstract Full Text Full Text PDF PubMed Scopus (22416) Google Scholar and there is growing evidence that telomere attrition triggers genomic instability in epithelial carcinogenesis.15Artandi SE DePinho RA A critical role for telomeres in suppressing and facilitating carcinogenesis.Curr Opin Genet Dev. 2000; 10: 39-46Crossref PubMed Scopus (248) Google Scholar The telomerase holoenzyme that maintains telomeres consists of RNA catalytic and reverse transcriptase subunits (hTERC and hTERT, respectively), and because of the lack of hTERT expression in most adult somatic cells, telomeres progressively shorten with age, particularly in those tissue compartments or cell types that are highly proliferative and thus have an increased replicative history. Eventually, telomere attrition leads to naked chromosome ends repaired by nonhomologous end-joining, in turn leading to dicentric chromosomes that cannot be resolved at mitosis. This results in additional double-stranded DNA breaks (DSBs) similarly repaired by nonhomologous end-joining, thereby initiating a vicious cycle of chromosome bridging, fusion, and breakage.16DePinho RA Wong KK The age of cancer: telomeres, checkpoints, and longevity.J Clin Invest. 2003; 111: S9-S14PubMed Google Scholar This model accounts for many heretofore unexplained aspects of cancer, such as the exponential increase in the incidence of most epithelial cancers with advancing age, and observations that carcinomas tend to be aneuploid with highly abnormal chromosomes that result from multiple nonreciprocal translocations. The TP53 protein plays an essential and central role in sensing the genomic damage triggered by telomere attrition. By promoting apoptosis or senescence in the context of critically shortened telomeres, TP53 mediates many of the aging and cancer-prone phenotypes seen in short telomere hTERC-deficient mice bred for several generations.15Artandi SE DePinho RA A critical role for telomeres in suppressing and facilitating carcinogenesis.Curr Opin Genet Dev. 2000; 10: 39-46Crossref PubMed Scopus (248) Google Scholar Inactivation of the p53 gene ameliorates the aging phenotypes seen in mice with short telomeres, but also greatly increases the incidence of spontaneous cancers, particularly carcinomas.15Artandi SE DePinho RA A critical role for telomeres in suppressing and facilitating carcinogenesis.Curr Opin Genet Dev. 2000; 10: 39-46Crossref PubMed Scopus (248) Google Scholar, 17Artandi SE Chang S Lee SL Alson S Gottlieb GJ Chin L DePinho RA Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice.Nature. 2000; 406: 641-645Crossref PubMed Scopus (933) Google Scholar Thus, telomere attrition and p53 inactivation (be it by direct mutation or other indirect mechanisms such as MDM2 amplification) appear to potently synergize to promote epithelial carcinogenesis. These observations taken together suggest that telomere attrition might be an important molecular event driving endometrial carcinogenesis. In particular, this may help explain the striking association of TII tumors with advanced age and p53 inactivation. To explore this hypothesis, we have evaluated telomere lengths in situ using a novel chromogenic method (Telo-CISH), and also analyzed another molecular marker (pH2AX) associated with double-stranded breaks (DSBs) and telomere attrition. Both TI and TII tumors exhibited telomere shortening; however, only TII tumors were associated with telomere shortening in adjacent normal epithelium, and they more frequently exhibited pH2AX foci, a marker of DSBs, consistent with the notion that telomere shortening drives the initiation of TII tumors. Furthermore, we demonstrate that telomere attrition in mice (which normally have longer telomeres than humans) promotes the formation of distinct TII-like precursor lesions unlike those seen in other mouse models of endometrial cancer, all of which to date result in TI-like cancers or precancers. Our findings suggest that telomere attrition contributes differentially to TI and TII endometrial cancers. Use of archival human tumor samples was approved by the University of Texas Southwestern Medical Center Institutional Review Board. Cases with mixed histology (eg, mixed endometrioid/serous) or of subtypes whose assignation as TI versus TII is less established (eg, clear cell), were excluded. Standard histological criteria were used.4Clement PB Young RH Endometrioid carcinoma of the uterine corpus: a review of its pathology with emphasis on recent advances and problematic aspects.Adv Anat Pathol. 2002; 9: 145-184Crossref PubMed Scopus (161) Google Scholar, 5Clement PB Young RH Non-endometrioid carcinomas of the uterine corpus: a review of their pathology with emphasis on recent advances and problematic aspects.Adv Anat Pathol. 2004; 11: 117-142Crossref PubMed Scopus (109) Google Scholar Tissue blocks were selected that contained both malignant and morphologically normal epithelium. Telo-CISH was performed using a custom-synthesized digoxigenin conjugated telomere probe Dig-OO-(C3TA2)3 (Biosynthesis, Lewisville, TX), where OO represents a Fmoc-AEEA-OH (8-amino-3,6-dioxaoctonic acid) linker. Probe was solubilized in dH20, aliquoted, and stored at −20°C. Five-μm tissue sections were deparaffinized in xylene and hydrated in an ethanol series. Slides were boiled gently in 10 mmol/L sodium citrate for 10 minutes and treated with 0.5% pepsin (pH 2) for 10 minutes. The duration of pepsin treatment should be optimized for each tissue because overdigestion results in tissue loss, and underdigestion results in decreased signal. Denaturation was performed by covering the tissue section with hybridization buffer, placing coverslips, and incubating the slide at 95°C for 5 minutes. Hybridization was performed overnight at 37°C in hybridization buffer [70% formamide, 10 mmol/L Tris pH 7.5, and 8.5 mmol/L MgSO4 with 10% blocking agent (catalog no. 1096176; Roche, Nutley, NJ) prepared in 0.1 g/ml of maleic acid buffer (catalog no. 1585762, Roche)] with 4 μg of probe per ml of hybridization buffer. Denaturation and hybridization steps were performed in a digital, temperature-controlled hybridization unit (catalog no. 240000; Boekel Scientific, Feasterville, PA). Slides were washed in 0.1× standard saline citrate at 55°C for 30 minutes × 2, then blocked in phosphate-buffered saline (PBS) and 2% bovine serum albumin for 30 minutes at room temperature. Polyclonal rabbit anti-digoxigenin/horseradish peroxidase (1:1000; DAKO, Carpinteria, CA) was applied in PBS and 2% bovine serum albumin for 1 hour at room temperature. Slides were washed with Tris-buffered saline plus 0.1% Tween for 5 minutes × 4 and signal was detected with freshly prepared liquid diaminobenzidine (DAKO). Slides were incubated in diaminobenzidine at room temperature for ∼1 hour, lightly counterstained with hematoxylin, and mounted in Permount (Fisher Scientific, Pittsburgh, PA). Visualization of signals was performed with standard bright-field optics using a ×100 (oil immersion) objective. Telomere length Southern analysis was performed using the TeloTAGGG kit (Roche Applied Science) per the manufacturer's instructions. Normal matched DNA samples were obtained from tissues not involved by tumor such as ovary, fallopian tube, or cervix. For IHC, 5-μm sections were deparaffinized in xylene and hydrated in a graded ethanol series. Slides were then boiled in 10 mmol/L sodium citrate for antigen retrieval and allowed to cool slowly at room temperature for 20 minutes. Endogenous peroxidases were blocked with 3% H2O2 in dH2O for 30 minutes. Slides were incubated with primary antibodies against p53 (1:100, catalog no. RM-9105; LabVision, Fremont, CA) and pH2AX (phosphorylated at serine 319) (1:1000, catalog no. 613401; Biolegend, San Diego, CA). Detection was performed using horseradish peroxidase-conjugated secondary antibodies with the Impress detection system (Vector Laboratories, Burlingame, CA). Slides were counterstained with hematoxylin and mounted in Permount. Cases with <5% positive cells (dot-like nuclear pattern) were scored as pH2AX-negative. CISH was performed using a chromosome 7 centromeric probe (Invitrogen, Carlsbad, CA), with signal detection performed with the CISH detection kit (Invitrogen) per the manufacturer's instructions. Slides were counterstained with hematoxylin and mounted in Permount. Cases were scored in a blinded manner as follows: no aneuploidy, no cells with >2 signals; mild aneuploidy, 3 or more signals in ≤5% of cells; moderate aneuploidy, 3 or more signals in 5 to 20% of cells; and severe aneuploidy, 3 or more signals in >20% of cells. This study was approved by an institutional animal care and use committee. Mice were housed in a barrier facility. G0i and G5i mice of mixed genetic background (C57/B6, 129, FVB/n) were generated as described.18Hemann MT Strong MA Hao LY Greider CW The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability.Cell. 2001; 107: 67-77Abstract Full Text Full Text PDF PubMed Scopus (916) Google Scholar In brief, G4 mTerc−/− mice were crossed to G0 mTerc +/+ or −/− mice to generate the G5i and G0i cohorts and sibling controls. Archived blocks from age-matched TI (n = 14) and TII tumors (n = 15) were obtained; the median age was 65.1years for both groups. The selected TI tumors exhibited classic, well-differentiated endometrioid histology whereas TII cases were serous carcinomas (see Figure 1 for representative histologies). To validate these cases, p53 IHC was performed. Most TII endometrial cancers express high levels of p53 protein, presumably because of the functional inactivation of p53, which suppresses the Mdm2-dependent feedback loop that normally targets p53 for degradation.19Lax SF Kurman RJ A dualistic model for endometrial carcinogenesis based on immunohistochemical and molecular genetic analyses.Verh Dtsch Ges Pathol. 1997; 81: 228-232PubMed Google Scholar, 20Wu X Bayle JH Olson D Levine AJ The p53-mdm-2 autoregulatory feedback loop.Genes Dev. 1993; 7: 1126-1132Crossref PubMed Scopus (1642) Google Scholar As expected, the majority of TII tumors showed strong p53 expression, whereas most TI tumors did not (13 of 14 versus 1 of 15; P = 2 × 10−6, Fisher's exact test), confirming that our TI and TII tumor sets differ significantly with respect to p53 status and thus represent distinct biological entities (Figure 1). To explore the hypothesis that telomere shortening contributes to endometrial carcinogenesis, we sought to assess telomere lengths in situ. Peptide nucleic acid (PNA)-fluorescence in situ hybridization (FISH), which uses fluorescently-labeled PNA probes, has been used to analyze telomere lengths in human tissue sections.21van Heek NT Meeker AK Kern SE Yeo CJ Lillemoe KD Cameron JL Offerhaus GJ Hicks JL Wilentz RE Goggins MG De Marzo AM Hruban RH Maitra A Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia.Am J Pathol. 2002; 161: 1541-1547Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar, 22Meeker AK Hicks JL Platz EA March GE Bennett CJ Delannoy MJ De Marzo AM Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis.Cancer Res. 2002; 62: 6405-6409PubMed Google Scholar, 23Meeker AK Gage WR Hicks JL Simon I Coffman JR Platz EA March GE De Marzo AM Telomere length assessment in human archival tissues: combined telomere fluorescence in situ hybridization and immunostaining.Am J Pathol. 2002; 160: 1259-1268Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 24Meeker AK Hicks JL Gabrielson E Strauss WM De Marzo AM Argani P Telomere shortening occurs in subsets of normal breast epithelium as well as in situ and invasive carcinoma.Am J Pathol. 2004; 164: 925-935Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar However, one limitation of this technique is that tissue architecture is not well visualized in dark-field microscopy, making it difficult to reliably distinguish between normal and malignant endometrial epithelium. To overcome this limitation, we adapted the PNA-FISH technique and developed a chromogenic method, which we have termed Telo-CISH (telomere chromogenic in situ hybridization). A telomeric PNA probe conjugated to digoxigenin was synthesized and hybridized to tissue sections, followed by incubation with an anti-digoxigenin antibody/horseradish peroxidase conjugate. Detection with the chromogen diaminobenzidine resulted in telomeric signals that were permanent and could be visualized via conventional bright-field microscopy, greatly facilitating observation of telomere signals in the context of the underlying tissue architecture. The signals were nuclear and dot-like, consistent with specific telomere detection (Figure 2). To determine whether Telo-CISH could be used as a qualitative assay for telomere length, we compared signals in three different samples processed identically. Laboratory mouse strains have average telomere lengths >30 kb, whereas human telomeres are much shorter, in the range of 5 to 10 kb.25Friedrich U Griese E Schwab M Fritz P Thon K Klotz U Telomere length in different tissues of elderly patients.Mech Ageing Dev. 2000; 119: 89-99Crossref PubMed Scopus (275) Google Scholar, 26Hemann MT Greider CW Wild-derived inbred mouse strains have short telomeres.Nucleic Acids Res. 2000; 28: 4474-4478Crossref PubMed Scopus (182) Google Scholar Normal human tissues gave rise to readily detectable telomeric signals, but, as expected, mouse tissues produced much more intense signals (Figure 2A). Intraluminal cells in prostatic intraepithelial neoplasia showed virtually absent telomeric signals, consistent with previous PNA-FISH studies documenting severe telomere attrition in prostatic intraepithelial neoplasia lesions (Figure 2A).22Meeker AK Hicks JL Platz EA March GE Bennett CJ Delannoy MJ De Marzo AM Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis.Cancer Res. 2002; 62: 6405-6409PubMed Google Scholar, 23Meeker AK Gage WR Hicks JL Simon I Coffman JR Platz EA March GE De Marzo AM Telomere length assessment in human archival tissues: combined telomere fluorescence in situ hybridization and immunostaining.Am J Pathol. 2002; 160: 1259-1268Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar Thus, Telo-CISH can be used for qualitative telomere length determinations in tissue sections and should be able to differentiate between cells with large differences in average telomere length within tissue sections. Epithelial cells in other neoplastic and preneoplastic lesions, including ductal carcinoma in situ of the breast, as well as invasive breast and prostate cancers, also exhibited decreased telomere signals by Telo-CISH (unpublished data). Telo-CISH was performed on tissue sections of all 29 TI and TII cases. A control normal endometrial sample showed approximately equivalent telomere signals in stroma and epithelium (Figure 2B), demonstrating that the digoxigenin-labeled telomere probe hybridized well to both epithelial and stromal cell nuclei. Telo-CISH revealed diverse patterns of telomere lengths in TI and TII tumors. In the majority of TI tumors, nonmalignant nonhyperplastic (morphologically normal) epithelium showed strong signals, whereas adjacent tumor epithelium showed dramatically decreased signals (Figure 2C). A small minority of TI cases showed decreased telomere signals in the tumor as well as adjacent nonmalignant epithelium (Figure 2D, Table 1). This argues that in most TI tumors, telomere shortening is not an initiating tumorigenic event but rather occurs secondarily as a consequence of hyperproliferation and the increased replicative history of the tumor cells. With TII tumors, these patterns were reversed, with a minority of cases showing decreased signals in malignant epithelium only (Figure 2E), but the majority showed significant telomere attrition even in epithelium that was morphologically entirely normal (Figure 2F) (TII neoplasms do not progress via intermediate hyperplasias, and the malignant and normal epithelium are readily distinguishable at lower magnification). In one TII tumor, morphologically normal cells did show short telomeres relative to stromal cells, but the tumor cells showed very strong telomere signals, even stronger than the stromal cells (Figure 2G). In this case, telomere attrition was likely followed by the reactivation of hTERT or another mechanism such as ALT that stabilizes telomeres.27Hahn WC Telomerase and cancer: where and when?.Clin Cancer Res. 2001; 7: 2953-2954PubMed Google ScholarTable 1Telo-CISH Study of Endometrial Cancer CasesTelomere signals in normal versus tumor epitheliumType IType IIDecreased in normal and tumor3/1411/15Decreased in tumor only11/143/15Decreased in normal, increased in tumor0/141/15Qualitative comparison of signals in morphologically normal epithelium and tumor relative to adjacent stroma were determined. Cases fell into three general categories as summarized. Open table in a new tab Qualitative comparison of signals in morphologically normal epithelium and tumor relative to adjacent stroma were determined. Cases fell into three general categories as summarized. As summarized in Table 1, only 3 of 14 TI tumors showed decreased telomere signals in morphologically normal epithelium, versus 11 of 15 TII tumors (P = 0.007, Fisher's exact test) These data demonstrate that telomere shortening is a general feature of TI and TII carcinogenesis, but more specifically, suggest that such telomere shortening is an important mechanism driving the initiation of TII tumors (see model presented in the Discussion). Telo-CISH permits direct comparisons of small numbers of cells visualized in situ, but does not readily provide a global view of telomere length in all cells in a biological sample. To confirm the somewhat unanticipated finding that a significant proportion of early TI tumors already have significant telomere shortening (given our initial hypothesis that telomere shortening drives TII tumorigenesis), we analyzed 20 TI tumors (predominantly grade I) where matched normal DNA was available, permitting the most accurate assessment of telomere shortening in individual endometrial tumors. Tumor DNA was prepared from frozen tumors and analyzed by telomere length Southern analysis (Figure 3A), with the median telomere lengths determined by standard methods (Figure 3B). This confirmed significant telomere attrition in TI tumors (P = 0.0068, Fisher's exact test). Analysis of additional TI, TII, and endometrial cancer cell line DNA samples for which matched samples were not available (n = 9, 10, and 6, respectively) also demonstrated similar degrees of telomere attrition, as did, for comparison, ovarian papillary serous adenocarcinomas (n = 10) (Figure 3C). These findings confirm that telomere shortening is a general feature of both TI and TII endometrial cancers. The finding that significant telomere shortening is present in the morphologically normal epithelium adjacent to TII but not TI cancers suggests that telomere shortening can drive endometrial cancer initiation, serving as a mutagenic mechanism that actively promotes cancer via breakage-fusion-bridge cycles.16DePinho RA Wong KK The age of cancer: telomeres, checkpoints, and longevity.J Clin Invest. 2003; 111: S9-S14PubMed Google Scholar If so, then aneuploidy and DNA DSBs may be detectable in this premalignant adjacent epithelium. To explore this possibility, we performed ploidy analyses by CISH, which permits direct visualization and assessment of aneuploidy in the context of tissue morphology in routine sections. We used a centromeric probe for chromosome 7 because it is among the most common chromosomes showing aneuploidy in ovarian/uterine tumors,28Taetle R Aickin M Yang JM Panda L Emerson J Roe D Adair L Thompson F Liu Y Wisner L Davis JR Trent J Alberts DS Chromosome abnormalities in ovarian adenocarcinoma: I. Nonrandom chromosome abnormalities from 244 cases.Genes Chromosom Cancer. 1999; 25: 290-300Crossref PubMed Scopus (62) Google Scholar but other chromosomes could also in principle be used as general markers of aneuploidy. Although the use of a single centromeric probe likely underestimates the degree of aneuploidy, analysis of TI and TII tumors revealed significant differences. Most TI tumors showed very mild aneuploidy that was difficult to detect; in contrast, TII tumors showed moderate to severe aneuploidy that was readily apparent in tumor cells (see Materials and Methods for criteria), and this difference was statistically significant (P = 0.0028, Fisher's exact test) (Figure 4, A and B). Notably, in at least three TII cases, we observed clear evidence of aneuploidy in the adjacent, morphologically normal epithelium that was p53-negative (Figure 4C). This indicates that significant aneuploidy is present, at least in some cases, even in the morphologically normal epithelium that presumably represents an early precursor to the adjacent TII tumor, and further suggests that normal p53 function is the key tumor suppressive mechanism restricting the growth of such aneuploid cells. The histone H2AX, a member of the histone H2A family, is rapidly phosphorylated at serine 139 at sites of DSBs, where such phosphorylated H2AX (pH2AX, also known as γ-H2AX) is believed to recruit additional factors to effect DSB repair.29Rothkamm K Lobrich M Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses.Proc Natl Acad Sci USA. 2003; 100: 5057-5062Crossref PubMed Scopus (1329) Google Scholar We thus sought to define patterns of pH2AX expression in endometrial cancers. In some control specimens (proliferative, secretory, and atrophic endometrium, and in other normal tissues such as colon) nonspecific diffuse nuclear staining was observed (data not shown). The basis of this nonspecific staining has not been explored, but may relate to cross-reactivity with the unphosphorylated form of H2AX, or some other nuclear antigen. In any case, this nonspecific staining was readily distinguished from the dot-like pattern that signifies bona fide double DNA stranded-breaks, and only dot-like pH2AX expression was scored as positive. All TII cases (12 of 12, 100%) were pH2AX-positive, whereas only a minority (5 of 12, 42%) o" @default.
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• W2012808741 title "Differential Roles of Telomere Attrition in Type I and II Endometrial Carcinogenesis" @default.
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