Zentralbl Gynakol 2002; 124(1): 10 -16
DOI: 10.1055/s-2002-20303
Molekulare Pathogenese und Diagnostik

© Georg Thieme Verlag Stuttgart · New York

Molekulare Pathogenese des Endometriumkarzinoms auf Basis eines dualistischen Modells

Dualistic Model of Molecular Pathogenesis in Endometrial CarcinomaS. F. Lax
  • Institut für Pathologie, Universität Graz, Österreich
Further Information

Publication History

Publication Date:
25 February 2002 (online)

Zusammenfassung

In biologischer und klinischer Hinsicht unterscheidet man 2 unterschiedliche Typen des Endometriumkarzinoms, von denen einer östrogenabhängig (Typ I), der andere östrogenunabhängig (Typ II) ist. Typ-I-Karzinome haben eine günstige Prognose, kommen in jüngerem Alter vor, exprimieren meist Östrogen- (ÖR) und Progesteronrezeptoren (PR), sind häufig mit einer Endometriumhyperplasie assoziiert und entsprechen histopathologisch endometrioiden Karzinomen. Der Prototyp der Typ-II-Karzinome, die prognostisch ungünstig sind, in höherem Alter vorkommen, meist ÖR und PR negativ und mit atrophem Endometrium assoziiert sind, sind seröse Karzinome. Endometrioide und seröse Endometriumkarzinome unterscheiden sich signifikant bezüglich ihrer molekularen Veränderungen. Endometrioide Karzinome sind in bis zu 45 % mikrosatelliteninstabil (MIN-positiv), zeigen häufige K-ras- und PTEN-Mutationen, aber nur in ca. 10 % p53-Mutationen, einen Verlust der p16-Expression bzw. eine Her2/neu-Amplifikation. Andererseits zeigen seröse Karzinome in bis zu 90 % der Fälle p53-Mutationen, in 40-50 % eine fehlende p16-Expression bzw. in ca. 60 % eine Her2/neu-Amplifikation, wohingegen MIN- und K-ras-Mutationen fehlen. Familiäre Endometriumkarzinome im Rahmen des HNPCC treten 2 Jahrzehnte früher auf als sporadische Karzinome, sind vom endometrioiden Typ und meist infolge einer Keimbahnmutation der DNA-Reparaturgene MLH1 bzw. MSH2 MIN-positiv. Im Rahmen der Entstehung endometrioider Karzinome treten MIN- und PTEN-Mutationen früh auf, zum Teil bereits in der atypischen Hyperplasie, während p53-Mutationen, p16-Verlust und Her2/neu-Amplifikation späte Veränderungen im Rahmen der Progression darstellen. In der Enstehung seröser Karzinome sind p53-Mutationen wahrscheinlich frühe Veränderungen, da sie bereits im endometrialen intraepithelialen Karzinom (EIC), der möglichen Vorstufe, auftreten. Die zukünftige Forschung mit neuen technologischen Möglichkeiten wird neben der Entdeckung neuer bedeutender Gene die Interaktion der bisher bekannten Schlüsselgene und die Erfassung deren klinischer Bedeutung zum Ziel haben.

Summary

Sporadic endometrial carcinoma can be divided into two biologically and clinically distinctive subtypes of which one is estrogen-related (type I), the other estrogen-unrelated (type II). Type I carcinomas occur at younger age, express estrogen (ER) and progesterone receptors (PR), are frequently associated with endometrial hyperplasia and show a good prognosis. Type II carcinomas occur at older age, are negative for ER and PR, arise in the background of atrophic endometrium and show poor prognosis. Histologically, endometrioid carcinomas correspond to type I carcinomas whereas serous carcinoma is the prototype of type II carcinomas. Endometrioid and serous carcinomas are significantly different with respect to their molecular changes. Endometrioid carcinomas frequently show microsatellite instability (MIN), PTEN and K-ras mutation but infrequently p53 mutations, loss of p16 expression and her2/neu amplification, respectively. In contrast, serous carcinomas show a high frequency of p53 mutations and often loss of p16 expression whereas MIN and PTEN and K-ras mutations are uncommon. Familial endometrial carcinoma associated with HNPCC occur about two decades earlier than sporadic carcinomas, show endometrioid histology and are frequently MIN positiv due to germline mutations of mismatch repair genes (mostly MLH1 and MSH2). During the progression of endometrioid carcinoma PTEN mutations and MIN are considered early changes since they are present in a high frequency in atypical endometrial hyperplasia whereas p53 mutations, loss of p16 expression and her2/neu amplification are considered late events since they are predominantly found in poorly differentiated tumors. In contrast, p53 mutations are considered an early event in the pathogenesis of serous carcinoma occurring already in its putative precursor endometrial intraepithelial carcinoma (EIC). The future research will focus, besides the discovery of new relevant genes, on the interaction of known genes as well as their clinical relevance.

Literatur

  • 1 Ambros R A, Sherman M E, Zahn C M, Bitterman P, Kurman R J. Endometrial intraepithelial carcinoma: a distinctive lesion specifically associated with tumors displaying serous differentiation.  Hum Pathol. 1995;  26 1260-1267
  • 2 Berends M J, Hollema H, Wu Y, van Der Sluis T, Mensink R G, ten Hoor K A, Sijmons R H, de Vries E G, Pras E, Mourits M J, Hofstra R M, Buys C  H, Kleibeuker J H, van Der Zee A G. MLH1 and MSH2 protein expression as a pre-screening marker in hereditary and non-hereditary endometrial hyperplasia and cancer.  Int J Cancer . 2001;  92 398-403
  • 3 Bokhman J V. Two pathogenetic types of endometrial carcinoma.  Gynecol Oncol. 1983;  15 0-17
  • 4 Brown G J, St John D J, Macrae F A, Aittomaki K. Cancer risk in young women at risk of hereditary nonpolyposis colorectal cancer: implications for gynecologic surveillance.  Gynecol Oncol. 2001;  80 346-349
  • 5 Burks R T, Kessis T D, Cho K R, Hedrick L. Microsatellite instability in endometrial carcinoma.  Oncogene. 1994;  9 1163-1166
  • 6 Caduff R F, Johnston C M, Frank T S. Mutations of the Ki-ras oncogene in carcinoma of the endometrium.  Am J Pathol. 1995;  146 182-188
  • 7 Caduff R F, Johnston C M, Svoboda Newman S M, Poy E L , Merajver S D, Frank T S. Clinical and pathological significance of microsatellite instability in sporadic endometrial carcinoma.  Am J Pathol. 1996;  148 1671-1678
  • 8 Catasus L, Machin P, Matias Guiu X, Prat J. Microsatellite instability in endometrial carcinomas: clinicopathologic correlations in a series of 42 cases.  Hum Pathol. 1998;  29 1160-1164
  • 9 Duggan B D, Felix J C, Muderspach L I, Tsao J L, Shibata D K. Early mutational activation of the c-Ki-ras oncogene in endometrial carcinoma.  Cancer Res. 1994;  54 1604-1607
  • 10 Esteller M, Levine R, Baylin S B , Ellenson L H, Herman J G. MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas.  Oncogene . 1998;  17 2413-2417
  • 11 Fearon E R, Vogelstein B. A genetic model for colorectal tumorigenesis.   Cell. 1990;  61 759-767
  • 12 Graeber T G, Osmanian C, Jacks T, Housman D E, Koch C J, Lowe S W, Giaccia  A J. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours.  Nature. 1996;  379 88-91
  • 13 Gurin C C, Federici M G, Kang L, Boyd J. Causes and consequences of microsatellite instability in endometrial carcinoma.  Cancer Res. 1999;  59 462-466
  • 14 Hanstein B, Beckmann M, Bender H. Charakterisierung und Bedeutung verschiedener Östrogenrezeptortypen unter besonderer Berücksichtigung des Endometriumkarzinoms.  Zentrabl Gynakol. 2002;  124 17-19
  • 15 Ikeda T, Yoshinaga K, Suzuki A, Sakurada A , Ohmori H, Horii A. Anticorresponding mutations of the KRAS and PTEN genes in human endometrial cancer.  Oncol Rep. 2000;  7 567-570
  • 16 Khalifa M A, Mannel R S, Haraway S D, Walker J, Min K W. Expression of EGFR, HER-2/neu, P53, and PCNA in endometrioid, serous papillary, and clear cell endometrial adenocarcinomas.  Gynecol Oncol. 1994;  53 84-92
  • 17 Kiechle M, Hinrichs M, Jacobsen A, Luttges  J, Pfisterer J, Kommoss F, Arnold N. Genetic imbalances in precursor lesions of endometrial cancer detected by comparative genomic hybridization.  Am J Pathol. 2000;  156 1827-1833
  • 18 Kihana T, Hamada K, Inoue Y, Yano N, Iketani H, Murao S, Ukita M, Matsuura S. Mutation and allelic loss of the p53 gene in endometrial carcinoma. Incidence and outcome in 92 surgical patients.  Cancer. 1995;  76 72-78
  • 19 Kinzler K W, Vogelstein B. Lessons from hereditary colorectal cancer.   Cell. 1996;  87 59-170
  • 20 Lax S F, Kendall B, Tashiro H, Slebos  R J, Hedrick L. The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways.  Cancer . 2000;  88 814-824
  • 21 Lax S F, Kurman R J. A dualistic model for endometrial carcinogenesis based on immunohistochemical and molecular genetic analyses.  Verh Dtsch Ges Pathol. 1997;  81 228-232
  • 22 Lax S  F, Pizer E S, Ronnett B M, Kurman R J . Clear cell carcinoma of the endometrium is characterized by a distinctive profile of p53, Ki-67, estrogen, and progesterone receptor expression.  Hum Pathol. 1998;  29 551-558
  • 23 Lax S F, Pizer E S, Ronnett B M, Kurman R J. Comparison of estrogen and progesterone receptor, Ki-67, and p53 immunoreactivity in uterine endometrioid carcinoma and endometrioid carcinoma with squamous, mucinous, secretory, and ciliated cell differentiation.  Hum Pathol. 1998;  29 924 -931
  • 24 Lengauer C, Kinzler K  W, Vogelstein B. Genetic instability in colorectal cancers.  Nature. 1997;  386 623-627
  • 25 Levine R L, Cargile C B, Blazes M S, van Rees B, Kurman R J, Ellenson L H. PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma.  Cancer Res. 1998;  58 3254-3258
  • 26 MacDonald N D, Salvesen H B, Ryan A , Iversen O E, Akslen L A, Jacobs I J . Frequency and prognostic impact of microsatellite instability in a large population-based study of endometrial carcinomas.  Cancer Res. 2000;  60 1750-1752
  • 27 Maxwell G L, Risinger J I, Alvarez  A A, Barrett J C, Berchuck A. Favorable survival associated with microsatellite instability in endometrioid endometrial cancers.  Obstet Gynecol. 2001 ;  97 417-422
  • 28 Mutter G  L, Boynton K A, Faquin W C, Ruiz R E, Jovanovic A S. Allelotype mapping of unstable microsatellites establishes direct lineage continuity between endometrial precancers and cancer.  Cancer Res. 1996;  56 4483-4486
  • 29 Mutter G L, Lin M C, Fitzgerald J T, Kum J B, Baak  J P, Lees J A, Weng L P, Eng C . Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers.  J Natl Cancer Inst . 2000;  92 924-930
  • 30 Nakashima R, Fujita M, Enomoto T, Haba T, Yoshino K, Wada H, Kurachi H, Sasaki M, Wakasa K, Inoue M, Buzard G, Murata Y. Alteration of p16 and p15 genes in human uterine tumours.  Br J Cancer. 1999;  80 458-467
  • 31 Palacios J, Catasus L, Moreno Bueno G, Matias Guiu X, Prat J, Gamallo C. Beta- and gamma-catenin expression in endometrial carcinoma. Relationship with clinicopathological features and microsatellite instability.  Virchows Arch. 2001;  438 464-469
  • 32 Parc Y R, Halling K C, Burgart L J, McDonnell S K, Schaid D J, Thibodeau S N, Halling A C. Microsatellite instability and hMLH1/hMSH2 expression in young endometrial carcinoma patients: associations with family history and histopathology.  Int J Cancer. 2000;  86 60-66
  • 33 Pisani A L, Barbuto D A, Chen  D, Ramos L, Lagasse L D, Karlan B Y. HER-2/neu, p53, and DNA analyses as prognosticators for survival in endometrial carcinoma.  Obstet Gynecol. 1995;  85 729-734
  • 34 Riethdorf L, Begemann C, Riethdorf S, Milde-Langosch K , Loning T. Comparison of benign and malignant endometrial lesions for their p53 state, using immunohistochemistry and temperature-gradient gel electrophoresis.  Virchows Arch. 1996;  428 47-51
  • 35 Risinger J I, Berchuck A, Kohler M F, Watson P, Lynch H  T, Boyd J. Genetic instability of microsatellites in endometrial carcinoma.  Cancer Res. 1993;  53 5100-5103
  • 36 Risinger J I, Dent G A, Ignar-Trowbridge D , McLachlan J A, Tsao M S, Senterman M, Boyd J. p53 gene mutations in human endometrial carcinoma.  Mol Carcinog. 1992 ;  5 50-253
  • 37 Rolitsky C  D, Theil K S, McGaughy V R, Copeland L  J, Niemann T H. HER-2/neu amplification and overexpression in endometrial carcinoma.  Int J Gynecol Pathol. 1999;  18 138-143
  • 38 Saegusa M, Hashimura M, Yoshida T, Okayasu I. beta- Catenin mutations and aberrant nuclear expression during endometrial tumorigenesis.  Br J Cancer. 2001;  84 209-217
  • 39 Salvesen H B, Das S, Akslen L  A. Loss of nuclear p16 protein expression is not associated with promoter methylation but defines a subgroup of aggressive endometrial carcinomas with poor prognosis.  Clin Cancer Res. 2000;  6 153-159
  • 40 Schmidt D, Horn L-C. Präkanzeröse Läsionen des Endometriums und Veränderungen nach Tamoxifentherapie.  Zentrabl Gynakol. 2002;  124 3-9
  • 41 Semczuk A, Schneider Stock R, Berbec H, Marzec B, Jakowicki J A, Roessner A. K-ras exon 2 point mutations in human endometrial cancer.  Cancer Lett. 2001;  164 207-212
  • 42 Sherman M E, Bur M E, Kurman R J. p53 in endometrial cancer and its putative precursors: evidence for diverse pathways of tumorigenesis.  Hum Pathol. 1995;  26 1268-1274
  • 43 Sherman M E, Sturgeon S, Brinton L A, Potischman N, Kurman R  J, Berman M L, Mortel R, Twiggs L B, Barrett R J, Wilbanks G D. Risk factors and hormone levels in patients with serous and endometrioid uterine carcinomas.  Mod Pathol. 1997;  10 963-968
  • 44 Simpkins S B, Bocker T, Swisher E M, Mutch D G, Gersell  D J, Kovatich A J, Palazzo J P, Fishel  R, Goodfellow P J. MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers.  Hum Mol Genet. 1999;  8 661-666
  • 45 Sonoda G, du Manoir S, Godwin A K, Bell D W, Liu Z , Hogan M, Yakushiji M, Testa J R. Detection of DNA gains and losses in primary endometrial carcinomas by comparative genomic hybridization.  Genes Chromosomes Cancer. 1997;  18 115-125
  • 46 Staebler A, Lax S F, Ellenson L H. Altered expression of hMLH1 and hMSH2 protein in endometrial carcinomas with microsatellite instability.  Hum Pathol. 2000;  31 354-358
  • 47 Sumoi R, Hakala Ala Pietila T, Leminen A, Mecklin J P, Lehtovirta P. Hereditary aspects of endometrial adenocarcinoma.  Int J Cancer . 1995;  62 132-137
  • 48 Tashiro H, Blazes M S, Wu R, Cho K R , Bose S, Wang S I, Li J, Parsons R, Ellenson L H. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies.  Cancer Res. 1997;  57 3935-3940
  • 49 Tashiro H, Isacson C, Levine R, Kurman R J, Cho K R, Hedrick  L. p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis.  Am J Pathol. 1997;  150 177-185
  • 50 Tashiro H, Lax S F, Gaudin P B, Isacson C, Cho K R, Hedrick L. Microsatellite instability is uncommon in uterine serous carcinoma.  Am J Pathol. 1997;  150 75 -79
  • 51 Vasen H F, Watson P, Mecklin J P, Jass J R, Green J S, Nomizu T, Muller H, Lynch H T. The epidemiology of endometrial cancer in hereditary nonpolyposis colorectal cancer.  Anticancer Res. 1994;  14 1675-1678
  • 52 Watson P, Vasen H F, Mecklin J P, Jarvinen H, Lynch H T. The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer.  Am J Med. 1994;  96 516-520

Univ. Prof. Dr. Sigurd F. Lax

Institut für Pathologie, Universität Graz

Auenbruggerplatz 25

A-8036 Graz

Österreich

Phone: +43 316 380 44 45

Fax: +43 316 38 43 29

Email: sigurd.lax@kfunigraz.ac.at