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01.03.2023 | Endometriumkarzinom | Leitthema

Molekulare Klassifikation beim Endometriumkarzinom

verfasst von: Dr. Peter Bronsert, Konrad Kurowski, Prof. Dr. Martin Werner, Dr. Clara Unger, Dr. Sylvia Timme

Erschienen in: Die Gynäkologie | Ausgabe 3/2023

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Zusammenfassung

Die von Bokhman et al. propagierte dualistische Subtypisierung stellte über mehrere Jahrzehnte das Fundament zur Prädiktion von Endometriumkarzinomen dar, das jedoch über die Jahre eine gewisse Unschärfe in Bezug auf Graduierung und Gesamtüberleben der Patientinnen aufwies. Molekulare Analysen identifizierten die Subgruppen POLE-ultramutiert, MMRd („mismatch repair deficient“), p53-mutiert und Endometriumkarzinome mit einem unspezifischen molekularen Profil. Die prädiktive Evidenz der molekularen Subgruppen und ihre Überlegenheit gegenüber dem von Bokhman et al. publizierten Modell, konnte durch mehrere Studien bestätigt werden. Im vorliegenden Übersichtsartikel werden anhand von 5 Fallbeispielen aus der Routinediagnostik die Typisierung von endometrioiden Adenokarzinomen und der zugehörige molekularpathologische Hintergrund beschrieben. Weiterhin wird im letzten Fallbeispiel eine sich aktuell noch nicht in der WHO(World Health Organization)-Klassifikation weiblicher Genitaltumoren genannte Subgruppe beschrieben.

Herrington CS (2020) Female genital tumours. https://www.research.ed.ac.uk/en/publications/who-classification-of-tumours-female-genital-tumours. Zugegriffen: 27. Okt. 2022

Bokhman JV (1983) Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 15(1):10–17. https://doi.org/10.1016/0090-8258(83)90111-7CrossRefPubMed

Lajer H, Jensen MB, Kilsmark J et al (2010) The value of gynecologic cancer follow-up: evidence-based ignorance? Int J Gynecol Cancer 20(8):1. https://doi.org/10.1111/IGC.0B013E3181F3BEE0CrossRef

Stelloo E, Nout RA, Osse EM et al (2016) Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts. Clin Cancer Res 22(16):4215–4224. https://doi.org/10.1158/1078-0432.CCR-15-2878CrossRefPubMed

Getz G, Gabriel SB, Cibulskis K et al (2013) Integrated genomic characterization of endometrial carcinoma. Nature 497(7447):67–73. https://doi.org/10.1038/NATURE12113CrossRef

Kunkel TA, Sabatino RD, Bambara RA (1987) Exonucleolytic proofreading by calf thymus DNA polymerase delta. Proc Natl Acad Sci U S A 84(14):4865–4869. https://doi.org/10.1073/PNAS.84.14.4865CrossRefPubMedPubMedCentral

Tsurimoto T, Stillman B (1991) Replication factors required for SV40 DNA replication in vitro. II. Switching of DNA polymerase α and 6 during initiation of leading and lagging strand synthesis. J Biol Chem 266(3):1961–1968. https://doi.org/10.1016/s0021-9258(18)52386-3CrossRefPubMed

Tsurimoto T, Melendy T, Stillman B (1990) Sequential initiation of lagging and leading strand synthesis by two different polymerase complexes at the SV40 DNA replication origin. Nature 346(6284):534–539. https://doi.org/10.1038/346534A0CrossRefPubMed

Tsurimoto T, Stillman B (1991) Replication factors required for SV40 DNA replication in vitro. I. DNA structure-specific recognition of a primer-template junction by eukaryotic DNA polymerases and their accessory proteins. J Biol Chem 266(3):1950–1960. https://doi.org/10.1016/s0021-9258(18)52385-1CrossRefPubMed

10.

Johnson RE, Klassen R, Prakash L, Prakash S (2015) A major role of DNA polymerase 6 in replication of both the leading and lagging DNA strands. Mol Cell 59(2):163–175. https://doi.org/10.1016/J.MOLCEL.2015.05.038CrossRefPubMedPubMedCentral

11.

Church DN, Briggs SEW, Palles C et al (2013) DNA polymerase ε and 6 exonuclease domain mutations in endometrial cancer. Hum Mol Genet 22(14):2820–2828. https://doi.org/10.1093/HMG/DDT131CrossRefPubMedPubMedCentral

12.

Van Gool IC, Ubachs JEH, Stelloo E et al (2018) Blinded histopathological characterisation of POLE exonuclease domain-mutant endometrial cancers: sheep in wolf’s clothing. Histopathology 72(2):248–258. https://doi.org/10.1111/HIS.13338CrossRefPubMed

13.

Meng B, Hoang LN, McIntyre JB et al (2014) POLE exonuclease domain mutation predicts long progression-free survival in grade 3 endometrioid carcinoma of the endometrium. Gynecol Oncol 134(1):15–19. https://doi.org/10.1016/J.YGYNO.2014.05.006CrossRefPubMed

14.

Church DN, Stelloo E, Nout RA et al (2014) Prognostic significance of POLE proofreading mutations in endometrial cancer. J Natl Cancer Inst. https://doi.org/10.1093/JNCI/DJU402CrossRefPubMedPubMedCentral

15.

Linzer DIH, Levine AJ (1979) Characterization tumor antigen and uninfected of a54K Dalton cellular SV40 present in SV40-transformed cells. Cell 17(1):43–52CrossRefPubMed

16.

Lane DP (1992) Cancer. p53, guardian of the genome. Nature 358(6381):15–16. https://doi.org/10.1038/358015A0CrossRefPubMed

17.

Royds JA, Iacopetta B (2006) p53 and disease: when the guardian angel fails. Cell Death Differ 13(6):1017–1026. https://doi.org/10.1038/SJ.CDD.4401913CrossRefPubMed

18.

Thomas AF, Kelly GL, Strasser A (2022) Of the many cellular responses activated by TP53, which ones are critical for tumour suppression? Cell Death Differ 29(5):961–971. https://doi.org/10.1038/S41418-022-00996-ZCrossRefPubMed

19.

Aubrey BJ, Kelly GL, Janic A, Herold MJ, Strasser A (2018) How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ 25(1):104–113. https://doi.org/10.1038/CDD.2017.169CrossRefPubMed

20.

Yonish-Rouach E, Resnftzky D, Lotem J, Sachs L, Kimchi A, Oren M (1991) Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin‑6. Nature 352(6333):345–347. https://doi.org/10.1038/352345A0CrossRefPubMed

21.

Shaw P, Bovey R, Tardy S, Sahli R, Sordat B, Costa J (1992) Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc Natl Acad Sci USA 89(10):4495–4499. https://doi.org/10.1073/PNAS.89.10.4495CrossRefPubMedPubMedCentral

22.

Jiang P, Du W, Wang X et al (2011) p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol 13(3):310–316. https://doi.org/10.1038/NCB2172CrossRefPubMedPubMedCentral

23.

El-Deiry WS, Tokino T, Velculescu VE et al (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75(4):817–825. https://doi.org/10.1016/0092-8674(93)90500-PCrossRefPubMed

24.

Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8(4):275–283. https://doi.org/10.1038/NRM2147CrossRefPubMed

25.

Freed-Pastor WA, Prives C (2012) Mutant p53: one name, many proteins. Genes Dev 26(12):1268–1286. https://doi.org/10.1101/GAD.190678.112CrossRefPubMedPubMedCentral

26.

Oren M (1999) Regulation of the p53 tumor suppressor protein. J Biol Chem 274(51):36031–36034. https://doi.org/10.1074/JBC.274.51.36031CrossRefPubMed

27.

Honda R, Tanaka H, Yasuda H (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 420(1):25–27. https://doi.org/10.1016/S0014-5793(97)01480-4CrossRefPubMed

28.

Haupt Y, Maya R, Kazaz A, Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387(6630):296–299. https://doi.org/10.1038/387296A0CrossRefPubMed

29.

Kawai H, Wiederschain D, Yuan ZM (2003) Critical contribution of the MDM2 acidic domain to p53 ubiquitination. Mol Cell Biol 23(14):4939–4947. https://doi.org/10.1128/MCB.23.14.4939-4947.2003/FORMAT/EPUBCrossRefPubMedPubMedCentral

30.

Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM (2000) Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem 275(12):8945–8951. https://doi.org/10.1074/JBC.275.12.8945CrossRefPubMed

31.

Stenger JE, Mayr GA, Mann K, Tegtmeyer P (1992) Formation of stable p53 homotetramers and multiples of tetramers. Mol Carcinog 5(2):102–106. https://doi.org/10.1002/MC.2940050204CrossRefPubMed

32.

PubMed New insights into p53 function from structural studies. https://pubmed.ncbi.nlm.nih.gov/8622853/. Zugegriffen: 21. Okt. 2022

33.

Enoch T, Norbury C (1995) Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM. Trends Biochem Sci 20(10):426–430. https://doi.org/10.1016/S0968-0004(00)89093-3CrossRefPubMed

34.

Horeweg N, de Bruyn M, Nout RA et al (2020) Prognostic integrated image-based immune and molecular profiling in early-stage endometrial cancer. Cancer Immunol Res 8(12):1508–1519. https://doi.org/10.1158/2326-6066.CIR-20-0149CrossRefPubMed

35.

Ross DS, Devereaux KA, Jin C et al (2022) Histopathologic features and molecular genetic landscape of HER2-amplified endometrial carcinomas. Mod Pathol 35(7):962–971. https://doi.org/10.1038/S41379-021-00997-2CrossRefPubMed

36.

AWMF (2022) S3-Leitlinie Endometriumkarzinom Leitlinie (Langversion ) Wesentliche Neuerungen

37.

Kunkel TA (2009) Evolving views of DNA replication (in)fidelity. Cold Spring Harb Symp Quant Biol 74:91–101. https://doi.org/10.1101/SQB.2009.74.027CrossRefPubMedPubMedCentral

38.

Bębenek A, Ziuzia-Graczyk I (2018) Fidelity of DNA replication—a matter of proofreading. Curr Genet 64(5):985–996. https://doi.org/10.1007/S00294-018-0820-1CrossRefPubMedPubMedCentral

39.

Tiraby JG, Fox MS (1973) Marker discrimination in transformation and mutation of pneumococcus. Proc Natl Acad Sci U S A 70(12):3541–3545. https://doi.org/10.1073/PNAS.70.12.3541CrossRefPubMedPubMedCentral

40.

Sancar A, Lindsey-Boltz LA, Ünsal-Kaçmaz K, Linn S (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 73:39–85. https://doi.org/10.1146/ANNUREV.BIOCHEM.73.011303.073723CrossRefPubMed

41.

PubMed The role of mismatch repair in DNA damage-induced apoptosis. https://pubmed.ncbi.nlm.nih.gov/10821533/. Zugegriffen: 24. Okt. 2022

42.

Hoeijmakers JHJ (2001) Genome maintenance mechanisms for preventing cancer. Nature 411(6835):366–374. https://doi.org/10.1038/35077232CrossRefPubMed

43.

Kolodner RD, Marsischky GT (1999) Eukaryotic DNA mismatch repair. Curr Opin Genet Dev 9(1):89–96. https://doi.org/10.1016/S0959-437X(99)80013-6CrossRefPubMed

44.

Modrich P, Lahue R (1996) Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu Rev Biochem 65:101–133. https://doi.org/10.1146/ANNUREV.BI.65.070196.000533CrossRefPubMed

45.

Lyer RR, Pluciennik A, Burdett V, Modrich PL (2006) DNA mismatch repair: functions and mechanisms. Chem Rev 106(2):302–323. https://doi.org/10.1021/CR0404794CrossRef

46.

Vaksman Z, Garner HR (2015) Somatic microsatellite variability as a predictive marker for colorectal cancer and liver cancer progression. Oncotarget 6(8):5760–5771. https://doi.org/10.18632/ONCOTARGET.3306CrossRefPubMedPubMedCentral

47.

Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363(6429):558–561. https://doi.org/10.1038/363558A0CrossRefPubMed

48.

Jiricny J (2006) The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol 7(5):335–346. https://doi.org/10.1038/NRM1907CrossRefPubMed

49.

Umar A, Boyer JC, Thomas DC et al (1994) Defective mismatch repair in extracts of colorectal and endometrial cancer cell lines exhibiting microsatellite instability. J Biol Chem 269(20):14367–14370. https://doi.org/10.1016/S0021-9258(17)36630-9CrossRefPubMed

50.

Helland Å, Børresen-Dale AL, Peltomäki P et al (1997) Microsatellite instability in cervical and endometrial carcinomas. Int J Cancer 70(5):499–501. https://doi.org/10.1002/(SICI)1097-0215(19970304)70:5<499::AID-IJC1>3.0.CO;2-TCrossRefPubMed

51.

McMeekin DS, Tritchler DL, Cohn DE et al (2016) Clinicopathologic significance of mismatch repair defects in endometrial cancer: an NRG oncology/gynecologic oncology group study. J Clin Oncol 34(25):3062–3068. https://doi.org/10.1200/JCO.2016.67.8722CrossRefPubMedPubMedCentral

52.

Loukovaara M, Pasanen A, Bützow R (2021) Mismatch repair protein and MLH1 methylation status as predictors of response to adjuvant therapy in endometrial cancer. Cancer Med 10(3):1034–1042. https://doi.org/10.1002/CAM4.3691CrossRefPubMedPubMedCentral

53.

Marabelle A, Fakih M, Lopez J et al (2020) Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 21(10):1353–1365. https://doi.org/10.1016/S1470-2045(20)30445-9CrossRefPubMed

54.

Pasanen A, Ahvenainen T, Pellinen T, Vahteristo P, Loukovaara M, Bützow R (2020) PD-L1 expression in endometrial carcinoma cells and Intratumoral immune cells: differences across histologic and TCGA-based molecular subgroups. Am J Surg Pathol 44(2):174–181. https://doi.org/10.1097/PAS.0000000000001395CrossRefPubMed

55.

Kommoss S, McConechy MK, Kommoss F et al (2018) Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Ann Oncol 29(5):1180–1188. https://doi.org/10.1093/ANNONC/MDY058CrossRefPubMed

56.

Raffone A, Travaglino A, Mascolo M et al (2020) Histopathological characterization of ProMisE molecular groups of endometrial cancer. Gynecol Oncol 157(1):252–259. https://doi.org/10.1016/J.YGYNO.2020.01.008CrossRefPubMed

57.

Horn LC, Höhn AK, Krücken I, Stiller M, Obeck U, Brambs CE (2020) Mesonephric-like adenocarcinomas of the uterine corpus: report of a case series and review of the literature indicating poor prognosis for this subtype of endometrial adenocarcinoma. J Cancer Res Clin Oncol 146(4):971–983. https://doi.org/10.1007/S00432-019-03123-7CrossRefPubMed

58.

Travaglino A, Raffone A, Mascolo M et al (2020) TCGA molecular subgroups in endometrial undifferentiated/dedifferentiated carcinoma. Pathol Oncol Res 26(3):1411–1416. https://doi.org/10.1007/S12253-019-00784-0CrossRefPubMed

59.

de Freitas D, Aguiar FN, Anton C, Bacchi CE, Carvalho JP, Carvalho FM (2018) L1 cell adhesion molecule (L1CAM) expression in endometrioid endometrial carcinomas: a possible pre-operative surrogate of lymph vascular space invasion. PLoS One. https://doi.org/10.1371/JOURNAL.PONE.0209294CrossRefPubMedPubMedCentral

60.

Kommoss FKF, Karnezis AN, Kommoss F et al (2018) L1CAM further stratifies endometrial carcinoma patients with no specific molecular risk profile. Br J Cancer 119(4):480–486. https://doi.org/10.1038/S41416-018-0187-6CrossRefPubMedPubMedCentral

61.

Djabali M, Mattei MG, Nguyen C et al (1990) The gene encoding L1, a neural adhesion molecule of the immunoglobulin family, is located on the X chromosome in mouse and man. Genomics 7(4):587–593. https://doi.org/10.1016/0888-7543(90)90203-7CrossRefPubMed

62.

Stelloo E, Bosse T, Nout RA et al (2015) Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative. Mod Pathol 28(6):836–844. https://doi.org/10.1038/MODPATHOL.2015.43CrossRefPubMed

63.

León-Castillo A, Britton H, McConechy MK et al (2020) Interpretation of somatic POLE mutations in endometrial carcinoma. J Pathol 250(3):323–335. https://doi.org/10.1002/PATH.5372CrossRefPubMedPubMedCentral

Titel: Molekulare Klassifikation beim Endometriumkarzinom
verfasst von: Dr. Peter Bronsert
Konrad Kurowski
Prof. Dr. Martin Werner
Dr. Clara Unger
Dr. Sylvia Timme
Publikationsdatum: 01.03.2023
Verlag: Springer Medizin
Schlagwörter: Endometriumkarzinom
Pathologie
Endometriumkarzinom
Erschienen in: Die Gynäkologie / Ausgabe 3/2023
Print ISSN: 2731-7102
Elektronische ISSN: 2731-7110
DOI: https://doi.org/10.1007/s00129-023-05056-2

Springer Medizin

Molekulare Klassifikation beim Endometriumkarzinom

Zusammenfassung

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Springer Medizin

Zusammenfassung

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