Cancer Research Annual Meeting 2010 2010 Workshops
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
[Cancer Research 59, 462-466, January 1, 1999]
© 1999 American Association for Cancer Research
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gurin, C. C.
Right arrow Articles by Boyd, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gurin, C. C.
Right arrow Articles by Boyd, J.
[Cancer Research 59, 462-466, January 15, 1999]
© 1999 American Association for Cancer Research

Molecular Biology and Genetics

Causes and Consequences of Microsatellite Instability in Endometrial Carcinoma1

Cheryl C. Gurin, Mark G. Federici, Lan Kang and Jeff Boyd2

Gynecology and Breast Research Laboratory, Department of Surgery [C. C. G., M. G. F., L. K., J. B.], and Department of Human Genetics [J. B.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Genetic instability of microsatellite repeat sequences [microsatellite instability (MI)] is commonly seen in tumors associated with the hereditary nonpolyposis colorectal cancer syndrome and is a result of inactivating mutations in any of several genes involved in a particular pathway of DNA mismatch repair. Sporadic (i.e., nonhereditary) manifestations of several tumor types, including colorectal, gastric, and endometrial carcinomas, also exhibit MI in a significant fraction of cases. Many MI sporadic colorectal carcinomas are associated with somatic mutations of mismatch repair genes, and several genes with coding region microsatellites are frequently mutated as a result in these cancers. The molecular causes and consequences of MI in sporadic endometrial carcinomas remain obscure, however. The aims of this study were: (a) to identify a series of sporadic endometrial carcinomas with clear evidence of MI; (b) to determine the extent to which somatic alterations in mismatch repair genes are associated with this MI; and (c) to establish whether the genes containing coding region microsatellite repeats that are known to be disrupted in MI+ gastrointestinal cancers are also disrupted in MI+ endometrial carcinomas. Matched pairs of normal and tumor DNA from 57 consecutive cases of endometrial carcinoma were examined for evidence of MI using a consensus panel of microsatellite markers. Fourteen cases (25%) displayed unequivocal evidence of MI, consistent with previously published estimates of the incidence of MI+ sporadic endometrial carcinoma. These cases were subjected to a mutation screen of the coding regions and exon-intron boundaries of the mismatch repair genes MSH2 and MLH1. Although several polymorphisms were detected, no clearly deleterious mutations were found in either of these genes. Notably, however, hypermethylation of the MLH1 promoter region was identified in 10 of 14 (71%) MI+ cases. Somatic mutations in coding region microsatellite repeats in the TGFßIIR, IGFIIR, BAX, E2F4, MSH3, MSH6, BRCA1, and BRCA2 genes were generally rare. Four MI+ tumors (29%) contained somatic mutations in the PTEN gene, only one of which was likely the result of MI. These data indicate that somatic mutational inactivation of known mismatch repair genes does not account for the great majority of sporadic endometrial carcinomas with MI and that a significant fraction of these cases may instead be causally associated with hypermethylation of the MLH1 promoter. Furthermore, genes with coding region microsatellites that are frequently mutated in MI+ gastrointestinal cancers are rarely mutated in MI+ endometrial cancers, implying the existence of alternative molecular targets for the tumorigenic effects of MI in this tumor type.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Progress in elucidating the molecular genetic basis of the HNPCC3 syndrome has established that an inherited mutation in one of several genes encoding components of a family of DNA mismatch repair proteins confers predisposition to colorectal and other cancers. The great majority of HNPCC kindreds for which a specific genetic alteration has been identified are linked to one of two genes, MSH2 or MLH1 (1) . Following somatic inactivation of the homologous wild-type allele, the resulting defect in postreplicative DNA mismatch repair leads to MI, believed to represent the molecular phenomenon responsible for tumorigenesis in the affected tissue(s) (2 , 3) . Sporadic, i.e., nonhereditary, manifestations of several HNPCC component tumor types also exhibit MI in a substantial fraction of cases, especially colorectal (4, 5, 6) , gastric (7, 8, 9, 10) , and endometrial (11, 12, 13, 14) carcinomas. The underlying molecular genetic defect in sporadic MI+ colorectal cancers appears to be somatic mutational inactivation of either MSH2 or MLH1 in some cases (15, 16, 17) , perhaps in as many as 65% (18) of cases, with hypermethylation of the MLH1 promoter and attenuation of MLH1 expression evident in some cases (19) . In contrast, the molecular basis for MI in sporadic endometrial cancers remains obscure, with somatic mutations in MSH2 or MLH1 having been described in only four MI+ endometrial cancers to date (20, 21, 22) .

In tumors affected by MI, the mechanism of tumorigenesis is believed to involve frameshift mutations of microsatellite repeats within coding regions of genes, the inactivation of which contributes to tumor development. Genes commonly affected through this mechanism in MI+ gastrointestinal cancers include TGFßRII (23 , 24) , IGFIIR (25) , BAX (26) , MSH3 and MSH6 (27) , E2F4 (28) , and BRCA1 and BRCA2 (29) . Limited analyses of MI+ endometrial cancers suggest that mutations of TGFßRII (30) and IGFIIR (31) may be much less common than in MI+ gastrointestinal cancers, but the other loci have yet to be examined in endometrial cancers. Of interest in this context is the recent demonstration that PTEN tumor suppressor gene mutations are found in 30–50% of all endometrial carcinomas (32, 33, 34) and are more common in MI+ than in MI- tumors (32 , 33) . PTEN mutations are rare in MI+ gastrointestinal cancers (33) , suggesting that PTEN may represent a mutational target of MI specific to endometrial tumorigenesis.

The purpose of this study was to perform a comprehensive analysis of the molecular genetic causes and consequences of MI in a series of sporadic endometrial carcinomas. The MI+ tumors were so classified using a panel of microsatellite markers developed together with a consensus recommendation for the definition of MI (35 , 36) . To determine the extent to which somatic mutations in known mismatch repair genes contribute to MI in sporadic endometrial cancers, complete mutational analyses were performed on the mismatch repair genes MSH2 and MLH1. The same tumors were then examined for evidence of somatic frameshift mutations presumed to result from defective mismatch repair and included analyses of coding region microsatellites within the genes TGFßIIR, IGF2R, BAX, E2F4, MSH3, MSH6, BRCA1, and BRCA2. A complete mutational analysis of the PTEN gene was also performed in all MI+ tumors.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tumor Acquisition and DNA Preparation.
This study was approved by the Institutional Review Board of the Memorial Sloan-Kettering Cancer Center. All tumors and corresponding normal tissues were from patients that underwent primary endometrial cancer surgery at this institution, prior to chemotherapy or radiation therapy, and were obtained as frozen specimens from the Department of Pathology. Pathological review was performed on every case to confirm a diagnosis of endometrial carcinoma. Genomic DNA was isolated using standard procedures (37) . All molecular genetic analyses were performed on the same DNA sample from each tumor.

MI Analysis.
The assessment of MI was based on the use of a panel of microsatellite markers developed by a multicenter consortium for diagnostic reliability and the standardization of criteria for definition of MI (35 , 36) . Tumors were classified as MI+ if at least three of five (60%) markers in the primary panel (BAT26, BAT40, APC, Mfd15, and D2S123) displayed evidence of mutant alleles in tumor DNA compared to corresponding normal tissue DNA. Reactions for PCR amplification were carried out in a volume of 20 µl containing 50 ng of genomic DNA, 1.5 mM MgCl2, 50 mM KCl, 10 mM Tris-HCl (pH 8.3), 200 µM each dNTP, 0.8 µM each primer, and 0.75 units of Taq polymerase (Perkin-Elmer Corp., Foster City, CA). One primer was end-labeled with [{gamma}-33P]ATP by polynucleotide kinase using the KinAce-It kit (Stratagene, La Jolla, CA) and column purified prior to PCR. Thirty PCR cycles were performed, consisting of 30 s at 94°C, 30 s at 55°C, and 30 s at 72°C, followed by a 7-min extension at 72°C. The PCR products were processed by diluting 1:1 in denaturing loading buffer (95% formamide, 10 mM NaOH, 0.05% xylene cyanol FF, and 0.05% bromphenol blue), heated at 90°C for 2 min, and 5 µl were electrophoresed in 6% polyacrylamide gels containing 8.3 M urea for 2–3 h at 70 W. The gels were fixed in 10% methanol-10% acetic acid, dried, and exposed to Hyperfilm MP autoradiography film (Amersham) for 3–24 h at room temperature.

Mismatch Repair Gene Mutation Analysis.
The complete coding regions and exon-intron junctions of MSH2 and MLH1 were screened for mutations in all MI+ tumors by SSCP analysis followed by sequence analysis of all potential variants. Intron-based primers for PCR amplification of the 16 exons of MSH2 and 19 exons of MLH1 were as described previously (38 , 39) . Each PCR was carried out in a volume of 20 µl containing: 50 ng of cDNA; 1.5.mM MgCl2; 50 mM KCl; 10 mM Tris-HCl (pH 8.3); 200 µM each dATP, dGTP, and dTTP; 20 µM dCTP; 1 µCi of [{alpha}-33P]dCTP (6,000 Ci/mmol, NEN); 0.8 µM each primer; and 1 unit of Taq polymerase (Perkin-Elmer Corp.). Amplification was performed in a Perkin-Elmer 9600 thermal cycler for 35 cycles consisting of 20 s at 94°C, 20 s at 55°C, and 30 s at 72°C. PCR products were diluted 1:10 in denaturing loading buffer[95% formamide, 10 mM EDTA (pH 8.0), 0.02% xylene cyanol FF, and 0.02% bromphenol blue], heated at 94°C for 5 min, and placed on ice, and 4 µl were loaded for electrophoresis. Gels for SSCP analysis consisted of 0.5x MDE solution (FMC BioProducts) and 0.6x TBE buffer, and were run in 0.6x TBE buffer at 6–8 W for 16 h at room temperature. Gels were dried and exposed to Hyperfilm MP autoradiography film (Amersham) for 4–16 h.

For sequence analysis, variant and wild-type bands were excised from SSCP gels following autoradiography and suspended in 50 µl of TE buffer for 1 h at room temperature. One µl of the eluted DNA sample was used as a template for PCR amplification under conditions identical to those described above for SSCP analysis, except that all dNTPs were at 200 µM and radiolabeled dCTP was omitted. Each PCR product was electrophoresed in its entirety in NuSieve 3:1 agarose (FMC BioProducts), visualized with ethidium bromide, excised from the gel, and purified using the Qiaex II gel extraction kit (Qiagen). Two ng of each DNA template were sequenced using the Thermo Sequenase radiolabeled terminator cycle sequencing kit (Amersham). All products were sequenced in both directions, using one or the other PCR primer. Following the sequencing reactions, 6 µl of each termination reaction were added to 4 µl of stop solution and heated to 70°C for 10 min, and 4 µl were loaded into each gel lane. Sequencing gels consisted of 6% polyacrylamide and 7 M urea in TBE buffer. After electrophoresis at 70 W for 2–3 h, gels were fixed in 10% methanol-10% acetic acid, dried, and subjected to autoradiography as above for 16 h.

MLH1 Promoter Methylation Assay.
Methylation of the MLH1 promoter region was examined using the procedure described previously (19) , with the following modifications. Following restriction endonuclease digestion, 12.5 ng of DNA were used as template for PCR amplification in a volume of 20 µl. One PCR primer (25266) was radiolabeled with [{gamma}-33P]ATP as described above, and half of each PCR product (10 µl) was electrophoresed in a 10% polyacrylamide/TBE gel (Bio-Rad). Gels were dried and subjected to autoradiography as above.

Mutation Analysis of MI Target Genes.
Mutations were detected in genes containing coding region microsatellites by PCR amplification of the appropriate segment of each gene followed by gel electrophoresis as described for the MI analysis above. Primers for PCRs were as described previously for TGFßRII (30) , IGFIIR (25) , BAX (26) , E2F4 (28) , MSH3 and MSH6 (27) , and BRCA1 and BRCA2 (29) . Mutation analysis of the PTEN gene was performed by screening the entire coding region and exon-intron junctions by SSCP and sequencing analyses as described above for the mismatch repair gene mutation analysis. Eleven sets of intron-based PCR primers were used to amplify the nine exons of PTEN as described (34) .


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A consecutive series of 57 endometrial carcinomas were examined for the presence of MI using the diagnostic criteria described in "Materials and Methods." Fourteen (25%) tumors displayed unambiguous evidence of MI, as shown in Fig. 1Citation . These tumors were examined further for the molecular etiology and downstream molecular effects of this phenomenon. A complete mutation screen of MSH2 and MLH1 failed to reveal a clearly deleterious mutation in any tumor. Two sequence alterations of unknown significance were identified in MLH1: a somatic missense mutation at codon 718, CAC(His) -> TAC(Tyr) (Fig. 2)Citation and a 2-bp insertion at position -13 (relative to exon 11) of intron 10 that did not obviously affect the splice junction.



View larger version (66K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Representative examples of MI in sporadic endometrial carcinomas. A, analysis of the nonpolymorphic BAT26 marker using tumor DNA samples only revealed MI in two tumors (arrows). B, analysis of the polymorphic Mfd15 marker in matched pairs of normal (N) and tumor (T) DNA samples revealed MI in two tumors (arrows).

 


View larger version (42K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Detection and characterization of a somatic missense mutation in MLH1. A, mutation screening by SSCP analysis indicated a sequence variant in DNA from tumor in Lane 2. B, sequence analysis of the variant PCR product confirmed a C -> T transition mutation in codon 718 of MLH1.

 
To determine whether methylation of the MLH1 promoter region was associated with MI in these tumors, paired DNA samples from each of the 14 MI+ endometrial cancers and their corresponding normal reproductive tract tissues were examined. Methylation of the MLH1 promoter was not observed in any of the normal tissues but was seen in 10 of 14 (71%) of the MI+ cancers (Fig. 3)Citation . Adequate clinical material was not available to perform an expression analysis of MLH1 in these tissues; thus, 28 MI- cancers were examined to determine the extent of correlation of MLH1 promoter methylation with the MI phenotype. Only two (7%) of these tumors displayed bands of weak autoradiographic intensity corresponding to a partially methylated MLH1 promoter. Thus, there was a highly significant correlation of MLH1 promoter methylation with the presence of MI in the corresponding tumor (P = 0.01, Fisher’s exact test, two-sided).



View larger version (33K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 3. Detection of MLH1 promoter hypermethylation in tumors 28 and 30. Shown is the 604-bp PCR product, corresponding to the MLH1 promoter region, obtained following restriction enzyme digestion under the conditions indicated. Lanes U, undigested; Lanes M, MspI; Lanes H, HpaII; Lanes N, DNA from normal uterus; Lanes T, DNA from corresponding tumor tissue; Lane S, standards. A PCR product is obtained following HpaII digestion only when all four restriction sites within this region are methylated. No PCR product is obtained following digestion with the isoschizomer MspI, which is not sensitive to restriction site methylation.

 
The MI+ tumors were next examined for the presence of frameshift inactivating mutations in microsatellite-containing genes believed to be the result of MI (Fig. 4)Citation . Generally, mutations in these genes were uncommon in MI+ endometrial cancers, with a range of 0–29% of tumors containing such alterations (Table 1)Citation . Microsatellite repeats within the TGFßRII, MSH3, MSH6, BRCA1, and BRCA2 genes appeared rarely, if ever, mutated, whereas mutations in the BAX gene were most common. A mutation analysis of the complete PTEN coding region was also performed (Fig. 5)Citation . Four of 14 (29%) MI+ endometrial cancers were affected by inactivating mutations of PTEN: two of these four mutations were frameshift alterations, one of which occurred in a coding region microsatellite; one was a nonsense mutation; and one was a nucleotide substitution at the splice acceptor site of intron 6 (Table 2)Citation .



View larger version (52K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 4. Frameshift mutations in coding region microsatellites. Arrows, PCR products containing frameshift mutations in the microsatellite sequences indicated.

 

View this table:
[in this window]
[in a new window]

  		Table 1 Coding region microsatellite mutations in MI+ endometrial carcinomas

 


View larger version (47K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 5. Characterization of a somatic inactivating mutation in the PTEN gene. A, mutation screening by SSCP analysis indicated a sequence variant in DNA from tumor in Lane 2. B, sequence analysis of the variant PCR product confirmed an insertion A frameshift mutation in codons 182–183 of PTEN.

 

View this table:
[in this window]
[in a new window]

  		Table 2 Mutations of PTEN in MI+ endometrial carcinomas

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The finding that 25% of sporadic endometrial carcinomas display MI is consistent with previous estimates of this phenomenon, which have ranged from 17 to 23% (11, 12, 13, 14) . A comprehensive analysis of these MI+ tumors for the underlying molecular defect responsible for MI revealed that somatic mutations in the mismatch repair genes known to sustain somatic alterations in MI+ gastrointestinal tumors, MSH2 and MLH1, are likely to be very rare. These findings are also consistent with previous studies in which MSH2 and MLH1 were screened for mutations in MI+ endometrial cancers; only four somatic mutations, two in MSH2 and two in MLH1, have been identified in a total of 51 MI+ endometrial cancers (20, 21, 22) . Collectively, these data imply strongly that the molecular etiology of MI in sporadic endometrial cancers involves an alternative mechanism(s) to that operative in HNPCC and sporadic gastrointestinal cancers.

Inactivation of the MLH1 gene through promoter hypermethylation has been proposed as a mechanism for the induction of MI in sporadic colorectal cancers exhibiting attenuated expression of MLH1 (19) . A recent detailed analysis of this phenomenon demonstrates that MLH1 promoter methylation is common in colorectal cancer cell lines and primary tumors with mismatch repair deficiencies, that the promoter methylation is correlated with decreased expression of MLH1 at both the mRNA and protein levels, and that demethylation of the MLH1 promoter results in the reexpression of MLH1 in cell lines (40) . This phenomenon has also been observed in the endometrial carcinoma cell line AN3CA (19 , 41) . Our data indicate that the MLH1 promoter is extensively methylated in the majority (71%) of sporadic MI+ endometrial cancers. Although we were unable to examine MLH1 expression in these tumors because of inadequate clinical material, the MLH1 promoter methylation was highly correlated with the presence of MI because only 7% of MI- tumors displayed MLH1 methylation. Furthermore, only a fraction of cells in these two MI- cases appeared to be affected by this phenomenon. Results from the colorectal carcinoma analysis are very similar, in that 2 of 21 (10%) sporadic MI- tumors exhibit methylation of MLH1 (40) .

Finally, we examined the molecular consequences of MI in this series of endometrial cancers by quantitating the extent of frameshift mutations in microsatellite-containing genes known to be altered in gastrointestinal cancers. None of the genes examined were found to be commonly mutated. The TGFßRII gene is altered in the majority of MI+ colorectal and gastric carcinomas, 90% and 71%, respectively (24 , 30) , but we failed to identify any MI+ endometrial cancer with this alteration. A previous study reported a low incidence of TGFßRII mutations in MI+ endometrial compared to MI+ colorectal cancers (30) . Together, these data indicate that mutational inactivation of TGFßRII does not provide a significant contribution to the tumorigenic process in the endometrium.

The mismatch repair genes MSH3 and MSH6, which both containing coding region microsatellites, are inactivated in 30–40% of MI+ colorectal (27) and 50–60% of MI+ gastric (29) carcinomas. These observations suggest a progressive model in which "primary" mutations in mismatch repair genes such as MSH2 or MLH1 lead to MI, a result of which is then "secondary" mutation of additional mismatch repair genes, such as MSH3 and MSH6, with the acceleration of genomic instability and the accumulation of additional mutations in cancer-related genes (27) . Interestingly, however, we observed only one MSH6 mutation and no MSH3 mutations in MI+ endometrial cancers, again suggesting that discrete pathways exist for tumorigenesis in association with MI in the gastrointestinal tract and endometrium.

Somewhat more common were frameshift mutations of the regulator of apoptosis BAX, detected in 29% of MI+ endometrial cancers compared to 50% of MI+ colorectal (26) and 67% of MI+ gastric (29) carcinomas. The growth factor receptor IGFIIR appears to be mutated at a similarly low frequency in MI+ endometrial (15%) and gastrointestinal (6–25%) cancers (25 , 31) . Mutations of the transcription factor E2F4 are less common in MI+ endometrial (20%) than gastrointestinal (31–65%) cancers (28 , 42) , and frameshift mutations of microsatellites within the tumor suppressors BRCA1 and BRCA2 are equally rare in endometrial (0–7%) and gastrointestinal (0–12%) cancers (29) . These data imply that a significant proportion of the molecular targets of MI in endometrial cancer remains to be identified.

The PTEN tumor suppressor gene is a plausible candidate for such a target of MI in endometrial carcinoma. The gene is frequently inactivated in endometrial cancers (32, 33, 34) , and most tumors with mutations display the MI phenotype (32 , 33) . Furthermore, the coding region of PTEN contains two [A]6 tracts (43 , 44) , which, although of shorter length than the typical microsatellite, represent potential mutational targets in tumors with defective mismatch repair. Only one of the MI+ endometrial cancers in our series displayed a frameshift mutation in one of these poly(A) tracts, however. An additional two MI+ tumors contained nucleotide substitution mutations, and one MI+ tumor contained an insertion mutation that are not obviously related to the MI phenotype. Overall, our data suggest that the majority of MI+ endometrial carcinomas do not sustain PTEN mutations during tumor development. Furthermore, the mutations that occur are not obviously attributable to MI; this view is supported by a previous observation that frameshift mutations in a poly(A) tract of PTEN are found in MI- endometrial cancers as well (33) .

In summary, these and previous published data support a model in which ~25% of all sporadic endometrial carcinomas are characterized by MI, and in which the great majority of these tumors are not causally associated with somatic mutations in the mismatch repair genes responsible for HNPCC and some sporadic gastrointestinal cancers. Instead, our data suggest that MI in most of these cancers develops as a result of MLH1 inactivation through promoter hypermethylation. Further studies will be required to establish a cause-and-effect relationship between MLH1 hypermethylation and MI in endometrial carcinoma, but the strong statistical correlation between these two phenomena and the demonstration of a direct mechanistic relationship in colorectal cancer cells (40) suggest that such a direct relationship in endometrial cancer is likely. Finally, our data imply that the majority of molecular genetic targets for MI in endometrial tumorigenesis remain to be identified.


   ACKNOWLEDGMENTS
 
We are grateful to Dr. William L. Gerald for assistance in obtaining the clinical material used in this study and to Dr. William J. Hoskins for his support of this research program.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by NIH Grant R01-CA67164. Back

2 To whom requests for reprints should be addressed, at Department of Surgery, Box 201, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Back

3 The abbreviations used are: HNPCC, hereditary nonpolyposis colorectal cancer; MI, microsatellite instability; SSCP, single-strand conformational polymorphism; TBE, Tris-borate EDTA. Back

Received 8/14/98. Accepted 11/10/98.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Peltomaki P., Vasen H. F. A., the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. Gastroenterology, 113: 1146-1158, 1997.[Medline]
  2. Marra G., Boland C. R. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J. Natl. Cancer Inst. (Bethesda), 87: 1114-1125, 1995.[Abstract/Free Full Text]
  3. Fishel R., Kolodner R. Identification of mismatch repair genes and their role in the development of cancer. Curr. Opin. Genet. Dev, 5: 382-395, 1995.[Medline]
  4. Aaltonen L. A., Peltomäki P., Leach F. S., Sistonen P., Pylkkänen L., Mecklin J-P, Järvinen H., Powell S. M., Jen J., Hamilton S. R., Petersen G. M., Kinzler K. W., Vogelstein B., de la Chapelle A. Clues to the pathogenesis of familial colorectal cancer. Science (Washington DC), 260: 812-816, 1993.[Abstract/Free Full Text]
  5. Thibodeau S. N., Bren G., Schaid D. Microsatellite instability in cancer of the proximal colon. Science (Washington DC), 260: 816-819, 1993.[Abstract/Free Full Text]
  6. Ionov Y., Peinado M. A., Malkhosyan S., Shibata D., Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature (Lond.), 363: 558-561, 1993.[Medline]
  7. Han H-J., Yanagisawa A., Kato Y., Park J-G., Nakamura Y. Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer. Cancer Res, 53: 5087-5089, 1993.[Abstract/Free Full Text]
  8. Mironov N. M., Aguelon M. A-M., Potapova G. I., Omori Y., Gorbunov O. V., Klimenkov A. A., Yamasaki H. Alterations of (CA)n DNA repeats and tumor suppressor genes in human gastric cancer. Cancer Res., 54: 41-44, 1994.[Abstract/Free Full Text]
  9. Chong J-M., Fukayama M., Hayashi Y., Takizawa T., Koike M., Konishi M., Kikuchi-Yanoshita R., Miyaki M. Microsatellite instability in the progression of gastric cancer. Cancer Res, 54: 4595-4597, 1994.[Abstract/Free Full Text]
  10. Strickler J. G., Zheng J., Shu Q., Burgart L. J., Alberts S. R., Shibata D. p53 mutations and microsatellite instability in sporadic gastric cancer: when guardians fail. Cancer Res., 54: 4750-4755, 1994.[Abstract/Free Full Text]
  11. Risinger J. I., Berchuck A., Kohler M. F., Watson P., Lynch H. T., Boyd J. Genetic instability of microsatellites in endometrial carcinoma. Cancer Res, 53: 5100-5103, 1993.[Abstract/Free Full Text]
  12. Burks R. T., Kessis T. D., Cho K. R., Hedrick L. Microsatellite instability in endometrial carcinoma. Oncogene, 9: 1163-1166, 1994.[Medline]
  13. Duggan B. D., Felix J. C., Muderspach L. I., Tourgeman D., Zheng J., Shibata D. Microsatellite instability in sporadic endometrial carcinoma. J. Natl. Cancer Inst. (Bethesda), 86: 1216-1221, 1994.[Abstract/Free Full Text]
  14. Peiffer S. L., Herzog T. J., Tribune D. J., Mutch D. G., Gersell D. J., Goodfellow P. J. Allelic loss of sequences from the long arm of chromosome 10 and replication errors in endometrial cancers. Cancer Res, 55: 1922-1926, 1995.[Abstract/Free Full Text]
  15. Liu B., Nicolaides N. C., Markowitz S., Willson J. K. V., Parsons R. E., Jen J., Papadopolous N., Peltomaki P., de la Chapelle A, Hamilton S. R., Kinzler K. W., Vogelstein B. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat. Genet, 9: 48-55, 1995.[Medline]
  16. Borresen A. L., Lothe R. A., Meling G. I., Lystad S., Morrison P., Lipford J., Kane M. F., Rognum T. O., Kolodner R. D. Somatic mutations in the hMSH2 gene in microsatellite unstable colorectal carcinomas. Hum. Mol. Genet., 4: 2065-2072, 1995.[Abstract/Free Full Text]
  17. Moslein G., Tester D. J., Lindor N. M., Honchel R., Cunningham J. M., French A. J., Halling K. C., Schwab M., Goretzki P., Thibodeau S. N. Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer. Hum. Mol. Genet, 5: 1245-1252, 1996.[Abstract/Free Full Text]
  18. Kinzler K. W., Vogelstein B. Lessons from hereditary colorectal cancer. Cell, 87: 159-170, 1996.[Medline]
  19. Kane M. F., Loda M., Gaida G. M., Lipman J., Mishra R., Goldman H., Jessup J. M., Kolodner R. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res., 57: 808-811, 1997.[Abstract/Free Full Text]
  20. Katabuchi H., van Rees B., Lambers A. R., Ronnett B. M., Blazes M. S., Leach F. S., Cho K. R., Hedrick L. Mutations in DNA mismatch repair genes are not responsible for microsatellite instability in most sporadic endometrial carcinomas. Cancer Res, 55: 5556-5560, 1995.[Abstract/Free Full Text]
  21. Kobayashi K., Matsushima M., Koi S., Saito H., Sagae S., Kudo R., Nakamura Y. Mutational analysis of mismatch repair genes, hMLH1 and hMSH2, in sporadic endometrial carcinomas with microsatellite instability. Jpn. J. Cancer Res, 87: 141-145, 1996.[Medline]
  22. Kowalski L. D., Mutch D. G., Herzog T. J., Rader J. S., Goodfellow P. J. Mutational analysis of MLH1 and MSH2 in 25 prospectively acquired RER endometrial cancers. Genes Chromosomes Cancer, 18: 219-227, 1997.[Medline]
  23. Markowitz S., Wang J., Myeroff L., Parsons R., Sun L., Lutterbaugh J., Fan R. S., Zborowska E., Kinzler K. W., Vogelstein B., Brattain M., Willson J. K. V. Inactivation of the type II TGF-ß receptor in colon cancer cells with microsatellite instability. Science (Washington DC), 268: 1336-1338, 1995.[Abstract/Free Full Text]
  24. Parsons R., Myeroff L., Liu B., Willson J. K. V., Markowitz S., Kinzler K. W., Vogelstein B. Microsatellite instability and mutations of the transforming growth factor ß type II receptor gene in colorectal cancer. Cancer Res, 55: 5548-5550, 1995.[Abstract/Free Full Text]
  25. Souza R. F., Appel R., Yin J., Wang S., Smolinski K. N., Abraham J. M., Zou T. T., Shi Y-Q., Lei J., Cottrell J., Cymes K., Biden K., Simms L., Leggett B., Lynch P. M., Frazier M., Powell S. M., Harpaz N., Sugimura H., Young J., Meltzer S. J. Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumours. Nat. Genet, 14: 255-257, 1996.[Medline]
  26. Rampino N., Yamamoto H., Ionov Y., Li Y., Sawai H., Reed J. C., Perucho M. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science (Washington DC), 275: 967-969, 1997.[Abstract/Free Full Text]
  27. Malkhosyan S., Rampino N., Yamamoto H., Perucho M. Frameshift mutator mutations. Nature (Lond.), 382: 499-500, 1996.[Medline]
  28. Souza R. F., Yin J., Smolinski N. K., Zou T-T., Wang S., Shi Y-Q., Rhyu M-G., Cottrell J., Abraham J. M., Biden K., Simms L., Leggett B., Bova G. S., Frank T., Powell S. M., Sugimura H., Young J., Harpaz N., Shimizu K., Matsubara N., Meltzer S. J. Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors. Cancer Res., 57: 2350-2353, 1997.[Abstract/Free Full Text]
  29. Yamamoto H., Sawai H., Perucho M. Frameshift somatic mutations in gastrointestinal cancer of the microsatellite mutator phenotype. Cancer Res, 57: 4420-4426, 1997.[Abstract/Free Full Text]
  30. Myeroff L. L., Parsons R., Kim S-J, Hedrick L., Cho K. R., Orth K., Mathis M., Kinzler K. W., Lutterbaugh J., Park K., Bang Y-J., Lee H. Y., Park J-G., Lynch H. T., Roberts A. B., Vogelstein B., Markowitz S. D. A transforming growth factor ß receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res, 55: 5545-5547, 1995.[Abstract/Free Full Text]
  31. Ouyang H., Shiwaku H. O., Hagiwara H., Miura K., Abe T., Kato Y., Ohtani H., Shiiba K., Souza R. F., Meltzer S. J., Horii A. The insulin-like growth factor II receptor gene is mutated in genetically unstable cancers of the endometrium, stomach, and colorectum. Cancer Res., 57: 1851-1854, 1997.[Abstract/Free Full Text]
  32. Tashiro H., Blazes M. S., Wu R., Cho K. R., Bose S., Wang S. I., Li J., Parsons R., Hedrick Ellenson L. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res., 57: 3935-3940, 1997.[Abstract/Free Full Text]
  33. Kong D., Suzuki A., Zou T-T., Sakurada A., Kemp L. W., Wakatsuki S., Yokoyama T., Yamakawa H., Furukawa T., Sato M., Ohuchi N., Sato S., Yin J., Wang S., Abraham J. M., Souza R. F., Smolinski K. N., Meltzer S. J., Horii A. PTEN is frequently mutated in primary endometrial carcinomas. Nat. Genet., 17: 143-144, 1997.[Medline]
  34. Risinger J. I., Hayes A. K., Berchuck A., Barrett J. C. PTEN/MMAC1 mutations in endometrial cancers. Cancer Res., 57: 4736-4738, 1997.[Abstract/Free Full Text]
  35. Bocker T., Diermann J., Friedl W., Gebert J., Holinski-Feder E., Karner-Hanusch J., von Knebel-Doeberitz M., Koelble K., Moeslein G., Schackert H-K., Wirtz H-C., Fishel R., Ruschoff J. Microsatellite instability analysis: a multicenter study for reliability and quality control. Cancer Res, 57: 4739-4743, 1997.[Abstract/Free Full Text]
  36. Dietmaier W., Wallinger S., Bocker T., Kullmann F., Fishel R., Ruschoff J. Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res, 57: 4749-4756, 1997.[Abstract/Free Full Text]
  37. Sambrook J., Fritsch E. F., Maniatis T. Molecular Cloning: A Laboratory Manual Ed. 2 Cold Spring Harbor Laboratory Cold Spring Harbor, NY 1989.
  38. Kolodner R. D., Hall N. R., Lipford J., Kane M. F., Rao M. R. S., Morrison P., Wirth L., Finan P. J., Burn J., Chapman P., Earabino C., Merchant E., Bishop D. T. Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations. Genomics, 24: 516-526, 1994.[Medline]
  39. Kolodner R. D., Hall N. R., Lipford J., Kane M. F., Morrison P. T., Finan P. J., Burn J., Chapman P., Earabino C., Merchant E., Bishop D. T. Structure of the human MLH1 locus and analysis of a large hereditary nonpolyposis colorectal cancer kindred for mlh1 mutations. Cancer Res., 55: 242-248, 1995.[Abstract/Free Full Text]
  40. Herman J. G., Umar A., Polyak K., Graff J. R., Ahuja N., Issa J-P. J., Markowitz S., Willson J. K. V., Hamilton S. R., Kinzler K. W., Kane M. F., Kolodner R. D., Vogelstein B., Kunkel T. A., Baylin S. B. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc. Natl. Acad. Sci. USA, 95: 6870-6875, 1998.[Abstract/Free Full Text]
  41. Veigl M. L., Kasturi L., Olechnowicz J., Ma A. H., Lutterbaugh J. D., Periyasamy S., Li G. M., Drummond J., Modrich P. L., Sedwick W. D., Markowitz S. D. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc. Natl. Acad. Sci. USA, 95: 8698-8702, 1998.[Abstract/Free Full Text]
  42. Ikeda M., Orimo H., Moriyama H., Nakajima E., Matsubara N., Mibu R., Tanaka N., Shimada T., Kimura A., Shimizu K. Close correlation between mutations of E2F4 and hMSH3 genes in colorectal cancers with microsatellite instability. Cancer Res., 58: 594-598, 1998.[Abstract/Free Full Text]
  43. Li J., Yen C., Liaw D., Podsypanina K., Bose S., Wang S. I., Puc J., Miliaresis C., Rodgers L., McCombie R., Bigner S. H., Giovanella B. C., Ittmann M., Tycko B., Hibshoosh H., Wigler M. H., Parsons R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science (Washington DC), 275: 1943-1947, 1997.[Abstract/Free Full Text]
  44. Steck P. A., Pershouse M. A., Jasser S. A., Yung W. K. A., Lin H., Ligon A. H., Langford L. A., Baumgard M. L., Hattier T., Davis T., Frye C., Hu R., Swedlund B., Teng D. H. F., Tavtigian S. V. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat. Genet., 15: 356-362, 1997.[Medline]



This article has been cited by other articles:


Home page
 J. Clin. Pathol.Home page
D Llobet, J Pallares, A Yeramian, M Santacana, N Eritja, A Velasco, X Dolcet, and X Matias-Guiu
Molecular pathology of endometrial carcinoma: practical aspects from the diagnostic and therapeutic viewpoints
J. Clin. Pathol., September 1, 2009; 62(9): 777 - 785.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
K Garg and R A Soslow
Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma
J. Clin. Pathol., August 1, 2009; 62(8): 679 - 684.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
A.H.S. Gylling, T.T. Nieminen, W.M. Abdel-Rahman, K. Nuorva, M. Juhola, E.I. Joensuu, H.J. Jarvinen, J.-P. Mecklin, M. Aarnio, and P.T. Peltomaki
Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors
Carcinogenesis, July 1, 2008; 29(7): 1351 - 1359.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
J. L. Hecht and G. L. Mutter
Molecular and Pathologic Aspects of Endometrial Carcinogenesis
J. Clin. Oncol., October 10, 2006; 24(29): 4783 - 4791.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
N. P. Taylor, M. A. Powell, R. K. Gibb, J. S. Rader, P. C. Huettner, S. N. Thibodeau, D. G. Mutch, and P. J. Goodfellow
MLH3 Mutation in Endometrial Cancer.
Cancer Res., August 1, 2006; 66(15): 7502 - 7508.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
S. Demokan, Y. Suoglu, D. Demir, M. Gozeler, and N. Dalay
Microsatellite instability and methylation of the DNA mismatch repair genes in head and neck cancer
Ann. Onc., June 1, 2006; 17(6): 995 - 999.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
L. Deng, R. R. Broaddus, A. McCampbell, G. L. Shipley, D. S. Loose, G. M. Stancel, J. H. Pickar, and P. J.A. Davies
Identification of a Novel Estrogen-Regulated Gene, EIG121, Induced by Hormone Replacement Therapy and Differentially Expressed in Type I and Type II Endometrial Cancer
Clin. Cancer Res., December 1, 2005; 11(23): 8258 - 8264.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. I. Risinger, G. L. Maxwell, G. V.R. Chandramouli, O. Aprelikova, T. Litzi, A. Umar, A. Berchuck, and J. C. Barrett
Gene Expression Profiling of Microsatellite Unstable and Microsatellite Stable Endometrial Cancers Indicates Distinct Pathways of Aberrant Signaling
Cancer Res., June 15, 2005; 65(12): 5031 - 5037.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
P. J. Goodfellow, B. M. Buttin, T. J. Herzog, J. S. Rader, R. K. Gibb, E. Swisher, K. Look, K. C. Walls, M.-Y. Fan, and D. G. Mutch
Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers
PNAS, May 13, 2003; 100(10): 5908 - 5913.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
C. Shannon, J. Kirk, R. Barnetson, J. Evans, M. Schnitzler, M. Quinn, N. Hacker, A. Crandon, and P. Harnett
Incidence of Microsatellite Instability in Synchronous Tumors of the Ovary and Endometrium
Clin. Cancer Res., April 1, 2003; 9(4): 1387 - 1392.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
S. M. Mallya, J. J. Gallagher, and A. Arnold
Analysis of Microsatellite Instability in Sporadic Parathyroid Adenomas
J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1248 - 1251.
[Abstract] [Full Text] [PDF]

Home page
 Exp Biol MedHome page
R. Miturski, M. Bogusiewicz, C. Ciotta, M. Bignami, M. Gogacz, and D. Burnouf
Mismatch Repair Genes and Microsatellite Instability as Molecular Markers for Gynecological Cancer Detection
Exp Biol Med, September 1, 2002; 227(8): 579 - 586.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
A. Duval and R. Hamelin
Mutations at Coding Repeat Sequences in Mismatch Repair-deficient Human Cancers: Toward a New Concept of Target Genes for Instability
Cancer Res., May 1, 2002; 62(9): 2447 - 2454.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
T. V. Parekh, P. Gama, X. Wen, R. Demopoulos, J. S. Munger, M.-L. Carcangiu, M. Reiss, and L. I. Gold
Transforming Growth Factor {beta} Signaling Is Disabled Early in Human Endometrial Carcinogenesis Concomitant with Loss of Growth Inhibition
Cancer Res., May 1, 2002; 62(10): 2778 - 2790.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
H. Wang, W. Douglas, M. Lia, W. Edelmann, R. Kucherlapati, K. Podsypanina, R. Parsons, and L. H. Ellenson
DNA Mismatch Repair Deficiency Accelerates Endometrial Tumorigenesis in Pten Heterozygous Mice
Am. J. Pathol., April 1, 2002; 160(4): 1481 - 1486.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
X.-P. Zhou, S. Kuismanen, M. Nystrom-Lahti, P. Peltomaki, and C. Eng
Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors
Hum. Mol. Genet., February 1, 2002; 11(4): 445 - 450.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
J M D Wheeler, B F Warren, N J McC Mortensen, H C Kim, S C Biddolph, G Elia, N E Beck, G T Williams, N A Shepherd, A C Bateman, et al.
An insight into the genetic pathway of adenocarcinoma of the small intestine
Gut, February 1, 2002; 50(2): 218 - 223.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
I. Stefansson, L. A. Akslen, N. MacDonald, A. Ryan, S. Das, I. J. Jacobs, and H. B. Salvesen
Loss of hMSH2 and hMSH6 Expression Is Frequent in Sporadic Endometrial Carcinomas with Microsatellite Instability: A Population-based Study
Clin. Cancer Res., January 1, 2002; 8(1): 138 - 143.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pathol.Home page
A J Alvi, J S Rader, M Broggini, F Latif, and E R Maher
Microsatellite instability and mutational analysis of transforming growth factor {beta} receptor type II gene (TGFBR2) in sporadic ovarian cancer
Mol. Pathol., August 1, 2001; 54(4): 240 - 243.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
H. Utsunomiya, T. Suzuki, C. Kaneko, J. Takeyama, J. Nakamura, K. Kimura, M. Yoshihama, N. Harada, K. Ito, R. Konno, et al.
The Analyses of 17{beta}-Hydroxysteroid Dehydrogenase Isozymes in Human Endometrial Hyperplasia and Carcinoma
J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3436 - 3443.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
R. B Chadwick, R. E Pyatt, T. H Niemann, S. K Richards, C. K Johnson, M. W Stevens, J. E Meek, H. Hampel, T. W Prior, and A. de la Chapelle
Hereditary and somatic DNA mismatch repair gene mutations in sporadic endometrial carcinoma
J. Med. Genet., July 1, 2001; 38(7): 461 - 466.
[Full Text]

Home page
 Cancer Res.Home page
A. K. Sood, R. Holmes, M. J. C. Hendrix, and R. E. Buller
Application of the National Cancer Institute International Criteria for Determination of Microsatellite Instability in Ovarian Cancer
Cancer Res., June 1, 2001; 61(11): 4371 - 4374.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
B. Elliott and M. Jasin
Repair of Double-Strand Breaks by Homologous Recombination in Mismatch Repair-Defective Mammalian Cells
Mol. Cell. Biol., April 15, 2001; 21(8): 2671 - 2682.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
S. Fiumicino, A. Ercoli, G. Ferrandina, P. Hess, G. Raspaglio, M. Genuardi, V. Rovella, A. Bellacosa, L. Cicchillitti, S. Mancuso, et al.
Microsatellite Instability Is an Independent Indicator of Recurrence in Sporadic Stage I-II Endometrial Adenocarcinoma
J. Clin. Oncol., February 15, 2001; 19(4): 1008 - 1014.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. A. Plumb, G. Strathdee, J. Sludden, S. B. Kaye, and R. Brown
Reversal of Drug Resistance in Human Tumor Xenografts by 2'-Deoxy-5-azacytidine-induced Demethylation of the hMLH1 Gene Promoter
Cancer Res., November 1, 2000; 60(21): 6039 - 6044.
[Abstract] [Full Text]

Home page
 Clin. Cancer Res.Home page
J. R. Navari, P. Y. Roland, P. Keh, H. B. Salvesen, L. A. Akslen, O. E. Iversen, S. Das, R. Kothari, S. Howey, and B. Phillips
Loss of Estrogen Receptor (ER) Expression in Endometrial Tumors Is Not Associated with de Novo Methylation of the 5' End of the ER Gene
Clin. Cancer Res., October 1, 2000; 6(10): 4026 - 4032.
[Abstract] [Full Text]

Home page
 Clin. Cancer Res.Home page
H. B. Salvesen, N. MacDonald, A. Ryan, O. E. Iversen, I. J. Jacobs, L. A. Akslen, and S. Das
Methylation of hMLH1 in a Population-based Series of Endometrial Carcinomas
Clin. Cancer Res., September 1, 2000; 6(9): 3607 - 3613.
[Abstract] [Full Text]

Home page
 Clin. Cancer Res.Home page
G. L. Maxwell, J. I. Risinger, K. A. Hayes, A. A. Alvarez, R. K. Dodge, J. C. Barrett, and A. Berchuck
Racial Disparity in the Frequency of PTEN Mutations, but not Microsatellite Instability, in Advanced Endometrial Cancers
Clin. Cancer Res., August 1, 2000; 6(8): 2999 - 3005.
[Abstract] [Full Text]

Home page
 Am. J. Pathol.Home page
M. Kiechle, M. Hinrichs, A. Jacobsen, J. Luttges, J. Pfisterer, F. Kommoss, and N. Arnold
Genetic Imbalances in Precursor Lesions of Endometrial Cancer Detected by Comparative Genomic Hybridization
Am. J. Pathol., June 1, 2000; 156(6): 1827 - 1833.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
N. D. MacDonald, H. B. Salvesen, A. Ryan, O.-E. Iversen, L. A. Akslen, and I. J. Jacobs
Frequency and Prognostic Impact of Microsatellite Instability in a Large Population-based Study of Endometrial Carcinomas
Cancer Res., March 1, 2000; 60(6): 1750 - 1752.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. Sarquis, E. Friedman, W. L. Boson, R. S. Gomez, A. F. Dias, and L. De Marco
Microsatellite Instability in Sporadic Parathyroid Adenoma
J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 250 - 252.
[Abstract] [Full Text]

Home page
 CarcinogenesisHome page
N. Mironov, L.A.M. Jansen, W.-B. Zhu, A.-M. Aguelon, G. Reguer, and H. Yamasaki
A novel sensitive method to detect frameshift mutations in exonic repeat sequences of cancer-related genes
Carcinogenesis, November 1, 1999; 20(11): 2189 - 2192.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
L. H. Ellenson
hMLH1 Promoter Hypermethylation in Microsatellite Instability-Positive Endometrial Carcinoma : Cause or Consequence?
Am. J. Pathol., November 1, 1999; 155(5): 1399 - 1402.
[Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
M. Esteller, L. Catasus, X. Matias-Guiu, G. L. Mutter, J. Prat, S. B. Baylin, and J. G. Herman
hMLH1 Promoter Hypermethylation Is an Early Event in Human Endometrial Tumorigenesis
Am. J. Pathol., November 1, 1999; 155(5): 1767 - 1772.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Mirabelli-Primdahl, R. Gryfe, H. Kim, A. Millar, C. Luceri, D. Dale, E. Holowaty, B. Bapat, S. Gallinger, and M. Redston
{beta}-Catenin Mutations Are Specific for Colorectal Carcinomas with Microsatellite Instability but Occur in Endometrial Carcinomas Irrespective of Mutator Pathway
Cancer Res., July 1, 1999; 59(14): 3346 - 3351.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gurin, C. C.
Right arrow Articles by Boyd, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gurin, C. C.
Right arrow Articles by Boyd, J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online