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

Causes and Consequences of Microsatellite Instability in Endometrial Carcinoma¹

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

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.

This article has been cited by other articles:

				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]

				D. E. Cohn, W. L. Frankel, K. E. Resnick, V. L. Zanagnolo, L. J. Copeland, H. Hampel, N. Kelbick, C. D. Morrison, and J. M. Fowler Improved Survival With an Intact DNA Mismatch Repair System in Endometrial Cancer. Obstet. Gynecol., November 1, 2006; 108(5): 1208 - 1215. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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 Experimental Biology and Medicine, September 1, 2002; 227(8): 579 - 586. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				G. L. MAXWELL, J. I. RISINGER, A. A. ALVAREZ, J. C. BARRETT, and A. BERCHUCK Favorable Survival Associated With Microsatellite Instability in Endometrioid Endometrial Cancers Obstet. Gynecol., March 1, 2001; 97(3): 417 - 422. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]