1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Pathology: Mechanisms of Disease
  4. Volume 14, 2019
  5. Article

Annual Review of Pathology: Mechanisms of Disease

Volume 14, 2019

Molecular Genetics of Endometrial Carcinoma

Abstract

Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States. Endometrioid endometrial carcinomas constitute approximately 85% of newly diagnosed cases; serous carcinomas represent approximately 3–10% of diagnoses; clear cell carcinoma accounts for <5% of diagnoses; and uterine carcinosarcomas are rare, biphasic tumors. Longstanding molecular observations implicate inactivation as a major driver of endometrioid carcinomas; inactivation as a major driver of most serous carcinomas, some high-grade endometrioid carcinomas, and many uterine carcinosarcomas; and inactivation of either gene as drivers of some clear cell carcinomas. In the past decade, targeted gene and exome sequencing have uncovered additional pathogenic aberrations in each histotype. Moreover, an integrated genomic analysis by The Cancer Genome Atlas (TCGA) resulted in the molecular classification of endometrioid and serous carcinomas into four distinct subgroups, (ultramutated), microsatellite instability (hypermutated), copy number low (endometrioid), and copy number high (serous-like). In this review, we provide an overview of the major molecular features of the aforementioned histopathological subtypes and TCGA subgroups and discuss potential prognostic and therapeutic implications for endometrial carcinoma.

Keyword(s): carcinoma, carcinosarcoma, endometrioid, genomic, histopathology, molecular classification, serous
Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathol-020117-043609
2019-01-24
2024-04-18
Loading full text...

Full text loading...

/deliver/fulltext/pathmechdis/14/1/annurev-pathol-020117-043609.html?itemId=/content/journals/10.1146/annurev-pathol-020117-043609&mimeType=html&fmt=ahah

Literature Cited

  1. 1. Am. Cancer Soc. 2018. Cancer facts and figures 2018 Rep., Am. Cancer Soc Atlanta, GA: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2018.html
  2. 2.  Gaber C, Meza R, Ruterbusch JJ, Cote ML 2017. Endometrial cancer trends by race and histology in the USA: projecting the number of new cases from 2015 to 2040. J. Racial Ethn. Health Disparities 4:895–903
     [Google Scholar]
  3. 3.  Bokhman JV 1983. Two pathogenetic types of endometrial carcinoma. Gynecol. Oncol. 15:10–17
     [Google Scholar]
  4. 4.  Dedes KJ, Wetterskog D, Ashworth A, Kaye SB, Reis-Filho JS 2011. Emerging therapeutic targets in endometrial cancer. Nat. Rev. Clin. Oncol. 8:261–71
     [Google Scholar]
  5. 5.  Suarez AA, Felix AS, Cohn DE 2017. Bokhman redux: endometrial cancer “types” in the 21st century. Gynecol. Oncol. 144:243–49
     [Google Scholar]
  6. 6.  Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y et al. 2013. Integrated genomic characterization of endometrial carcinoma. Nature 497:67–73
     [Google Scholar]
  7. 7.  Kurman RJ, Carcangiu ML, Herrington CS, Young RH 2014. WHO Classification of Tumours of Female Reproductive Organs. Geneva: World Health Organ.
     [Google Scholar]
  8. 8.  Lax SF, Kendall B, Tashiro H, Slebos RJ, Hedrick L 2000. The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways. Cancer 88:814–24
     [Google Scholar]
  9. 9.  Lax SF, Kurman RJ, Pizer ES, Wu L, Ronnett BM 2000. A binary architectural grading system for uterine endometrial endometrioid carcinoma has superior reproducibility compared with FIGO grading and identifies subsets of advance-stage tumors with favorable and unfavorable prognosis. Am. J. Surg. Pathol. 24:1201–8
     [Google Scholar]
  10. 10.  Kurman RJ, Kaminski PF, Norris HJ 1985. The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients. Cancer 56:403–12
     [Google Scholar]
  11. 11.  Lacey JV, Ioffe OB, Ronnett BM, Rush BB, Richesson DA et al. 2008. Endometrial carcinoma risk among women diagnosed with endometrial hyperplasia: the 34-year experience in a large health plan. Br. J. Cancer 98:45–53
     [Google Scholar]
  12. 12.  Kendall BS, Ronnett BM, Isacson C, Cho KR, Hedrick L et al. 1998. Reproducibility of the diagnosis of endometrial hyperplasia, atypical hyperplasia, and well-differentiated carcinoma. Am. J. Surg. Pathol. 22:1012–19
     [Google Scholar]
  13. 13.  Hayes MP, Wang H, Espinal-Witter R, Douglas W, Solomon GJ et al. 2006. PIK3CA and PTEN mutations in uterine endometrioid carcinoma and complex atypical hyperplasia. Clin. Cancer Res. 12:5932–35
     [Google Scholar]
  14. 14.  Tashiro H, Isacson C, Levine R, Kurman RJ, Cho KR, Hedrick L 1997. p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Am. J. Pathol. 150:177–85
     [Google Scholar]
  15. 15.  Sherman ME, Bur ME, Kurman RJ 1995. p53 in endometrial cancer and its putative precursors: evidence for diverse pathways of tumorigenesis. Hum. Pathol. 26:1268–74
     [Google Scholar]
  16. 16.  Lax SF, Pizer ES, Ronnett BM, Kurman RJ 1998. Clear cell carcinoma of the endometrium is characterized by a distinctive profile of p53, Ki-67, estrogen, and progesterone receptor expression. Hum. Pathol. 29:551–58
     [Google Scholar]
  17. 17.  Fadare O, Zhao C, Khabele D, Parkash V, Quick CM et al. 2015. Comparative analysis of Napsin A, alpha-methylacyl-coenzyme A racemase (AMACR, P504S), and hepatocyte nuclear factor 1 beta as diagnostic markers of ovarian clear cell carcinoma: an immunohistochemical study of 279 ovarian tumours. Pathology 47:105–11
     [Google Scholar]
  18. 18.  DeLair DF, Burke KA, Selenica P, Lim RS, Scott SN et al. 2017. The genetic landscape of endometrial clear cell carcinomas. J. Pathol. 243:230–41
     [Google Scholar]
  19. 19.  Altrabulsi B, Malpica A, Deavers MT, Bodurka DC, Broaddus R, Silva EG 2005. Undifferentiated carcinoma of the endometrium. Am. J. Surg. Pathol. 29:1316–21
     [Google Scholar]
  20. 20.  Matsuo K, Takazawa Y, Ross MS, Elishaev E, Podzielinski I et al. 2016. Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma. Ann. Oncol. 27:1257–66
     [Google Scholar]
  21. 21.  El-Nashar SA, Mariani A 2011. Uterine carcinosarcoma. Clin. Obstet. Gynecol. 54:292–304
     [Google Scholar]
  22. 22.  McCluggage WG 2002. Malignant biphasic uterine tumours: carcinosarcomas or metaplastic carcinomas?. J. Clin. Pathol. 55:321–25
     [Google Scholar]
  23. 23.  Taylor NP, Zighelboim I, Huettner PC, Powell MA, Gibb RK et al. 2006. DNA mismatch repair and TP53 defects are early events in uterine carcinosarcoma tumorigenesis. Mod. Pathol. 19:1333–38
     [Google Scholar]
  24. 24.  McConechy MK, Hoang LN, Chui MH, Senz J, Yang W et al. 2015. In-depth molecular profiling of the biphasic components of uterine carcinosarcomas. J. Pathol. Clin. Res. 1:173–85
     [Google Scholar]
  25. 25.  Zhao S, Santin AD 2016. Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition. PNAS 113:12238–43
     [Google Scholar]
  26. 26.  Wiegand KC, Lee AF, Al-Agha OM, Chow C, Kalloger SE et al. 2011. Loss of BAF250a (ARID1A) is frequent in high-grade endometrial carcinomas. J. Pathol. 224:328–33
     [Google Scholar]
  27. 27.  Urick ME, Rudd ML, Godwin AK, Sgroi D, Merino M, Bell DW 2011. PIK3R1 (p85alpha) is somatically mutated at high frequency in primary endometrial cancer. Cancer Res 71:4061–67
     [Google Scholar]
  28. 28.  Cheung LW, Hennessy BT, Li J, Yu S, Myers AP et al. 2011. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov 1:170–85
     [Google Scholar]
  29. 29.  McConechy MK, Ding J, Cheang MC, Wiegand K, Senz J et al. 2012. Use of mutation profiles to refine the classification of endometrial carcinomas. J. Pathol. 228:20–30
     [Google Scholar]
  30. 30.  Levine RL, Cargile CB, Blazes MS, van Rees B, Kurman RJ, Ellenson LH 1998. PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma. Cancer Res 58:3254–58
     [Google Scholar]
  31. 31.  Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JP et al. 2000. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J. Natl. Cancer Inst. 92:924–30
     [Google Scholar]
  32. 32.  Rudd ML, Price JC, Fogoros S, Godwin AK, Sgroi DC et al. 2011. A unique spectrum of somatic PIK3CA (p110alpha) mutations within primary endometrial carcinomas. Clin. Cancer Res. 17:1331–40
     [Google Scholar]
  33. 33.  Oda K, Okada J, Timmerman L, Rodriguez-Viciana P, Stokoe D et al. 2008. PIK3CA cooperates with other phosphatidylinositol 3′-kinase pathway mutations to effect oncogenic transformation. Cancer Res 68:8127–36
     [Google Scholar]
  34. 34.  Oda K, Stokoe D, Taketani Y, McCormick F 2005. High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res 65:10669–73
     [Google Scholar]
  35. 35.  Gymnopoulos M, Elsliger MA, Vogt PK 2007. Rare cancer-specific mutations in PIK3CA show gain of function. PNAS 104:5569–74
     [Google Scholar]
  36. 36.  Cheung LW, Yu S, Zhang D, Li J, Ng PK et al. 2014. Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors. Cancer Cell 26:479–94
     [Google Scholar]
  37. 37.  Joshi A, Miller C Jr, Baker SJ, Ellenson LH 2015. Activated mutant p110α causes endometrial carcinoma in the setting of biallelic Pten deletion. Am. J. Pathol 185:1104–13
     [Google Scholar]
  38. 38.  Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M et al. 1999. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. PNAS 96:1563–68
     [Google Scholar]
  39. 39.  Lu KH, Wu W, Dave B, Slomovitz BM, Burke TW et al. 2008. Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma. Clin. Cancer Res. 14:2543–50
     [Google Scholar]
  40. 40.  Contreras CM, Akbay EA, Gallardo TD, Haynie JM, Sharma S et al. 2010. Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy. Dis. Model. Mech. 3:181–93
     [Google Scholar]
  41. 41.  Contreras CM, Gurumurthy S, Haynie JM, Shirley LJ, Akbay EA et al. 2008. Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas. Cancer Res 68:759–66
     [Google Scholar]
  42. 42.  Cheng H, Liu P, Zhang F, Xu E, Symonds L et al. 2014. A genetic mouse model of invasive endometrial cancer driven by concurrent loss of Pten and Lkb1 is highly responsive to mTOR inhibition. Cancer Res 74:15–23
     [Google Scholar]
  43. 43.  Philip CA, Laskov I, Beauchamp MC, Marques M, Amin O et al. 2017. Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors. BMC Cancer 17:638
     [Google Scholar]
  44. 44.  Lheureux S, Oza AM 2016. Endometrial cancer-targeted therapies myth or reality? Review of current targeted treatments. Eur. J. Cancer 59:99–108
     [Google Scholar]
  45. 45.  Bregar AJ, Growdon WB 2016. Emerging strategies for targeting PI3K in gynecologic cancer. Gynecol. Oncol. 140:333–44
     [Google Scholar]
  46. 46.  Matulonis U, Vergote I, Backes F, Martin LP, McMeekin S et al. 2015. Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma. Gynecol. Oncol. 136:246–53
     [Google Scholar]
  47. 47.  Heudel PE, Fabbro M, Roemer-Becuwe C, Kaminsky MC, Arnaud A et al. 2017. Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group. Br. J. Cancer 116:303–9
     [Google Scholar]
  48. 48.  Makker V, Recio FO, Ma L, Matulonis UA, Lauchle JO et al. 2016. A multicenter, single-arm, open-label, phase 2 study of apitolisib (GDC-0980) for the treatment of recurrent or persistent endometrial carcinoma (MAGGIE study). Cancer 122:3519–28
     [Google Scholar]
  49. 49.  Del Campo JM, Birrer M, Davis C, Fujiwara K, Gollerkeri A et al. 2016. A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer. Gynecol. Oncol. 142:62–69
     [Google Scholar]
  50. 50.  Byron SA, Gartside M, Powell MA, Wellens CL, Gao F et al. 2012. FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features. PLOS ONE 7:e30801
     [Google Scholar]
  51. 51.  Jones NL, Xiu J, Chatterjee-Paer S, Buckley de Meritens A, Burke WM et al. 2017. Distinct molecular landscapes between endometrioid and nonendometrioid uterine carcinomas. Int. J. Cancer 140:1396–404
     [Google Scholar]
  52. 52.  Weigelt B, Warne PH, Lambros MB, Reis-Filho JS, Downward J 2013. PI3K pathway dependencies in endometrioid endometrial cancer cell lines. Clin. Cancer Res. 19:3533–44
     [Google Scholar]
  53. 53.  Coleman RL, Sill MW, Thaker PH, Bender DP, Street D et al. 2015. A phase II evaluation of selumetinib (AZD6244, ARRY-142886), a selective MEK-1/2 inhibitor in the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group study. Gynecol. Oncol. 138:30–35
     [Google Scholar]
  54. 54.  Aslan O, Cremona M, Morgan C, Cheung LW, Mills GB, Hennessy BT 2018. Preclinical evaluation and reverse phase protein array-based profiling of PI3K and MEK inhibitors in endometrial carcinoma in vitro. BMC Cancer 18:168
     [Google Scholar]
  55. 55.  Schrauwen S, Depreeuw J, Coenegrachts L, Hermans E, Lambrechts D, Amant F 2015. Dual blockade of PI3K/AKT/mTOR (NVP-BEZ235) and Ras/Raf/MEK (AZD6244) pathways synergistically inhibit growth of primary endometrioid endometrial carcinoma cultures, whereas NVP-BEZ235 reduces tumor growth in the corresponding xenograft models. Gynecol. Oncol. 138:165–73
     [Google Scholar]
  56. 56.  Jeske YW, Ali S, Byron SA, Gao F, Mannel RS et al. 2017. FGFR2 mutations are associated with poor outcomes in endometrioid endometrial cancer: an NRG Oncology/Gynecologic Oncology Group study. Gynecol. Oncol. 145:366–73
     [Google Scholar]
  57. 57.  Dutt A, Salvesen HB, Chen TH, Ramos AH, Onofrio RC et al. 2008. Drug-sensitive FGFR2 mutations in endometrial carcinoma. PNAS 105:8713–17
     [Google Scholar]
  58. 58.  Powell MA, Sill MW, Goodfellow PJ, Benbrook DM, Lankes HA et al. 2014. A phase II trial of brivanib in recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group study. Gynecol. Oncol. 135:38–43
     [Google Scholar]
  59. 59.  Konecny GE, Finkler N, Garcia AA, Lorusso D, Lee PS et al. 2015. Second-line dovitinib (TKI258) in patients with FGFR2-mutated or FGFR2-non-mutated advanced or metastatic endometrial cancer: a non-randomised, open-label, two-group, two-stage, phase 2 study. Lancet Oncol 16:686–94
     [Google Scholar]
  60. 60.  Dizon DS, Sill MW, Schilder JM, McGonigle KF, Rahman Z et al. 2014. A phase II evaluation of nintedanib (BIBF-1120) in the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group study. Gynecol. Oncol. 135:441–45
     [Google Scholar]
  61. 61.  Machin P, Catasus L, Pons C, Munoz J, Matias-Guiu X, Prat J 2002. CTNNB1 mutations and beta-catenin expression in endometrial carcinomas. Hum. Pathol. 33:206–12
     [Google Scholar]
  62. 62.  Kinde I, Bettegowda C, Wang Y, Wu J, Agrawal N et al. 2013. Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers. Sci. Transl. Med. 5:167ra4
     [Google Scholar]
  63. 63.  Byron SA, Loch DC, Pollock PM 2012. Fibroblast growth factor receptor inhibition synergizes with Paclitaxel and Doxorubicin in endometrial cancer cells. Int. J. Gynecol. Cancer 22:1517–26
     [Google Scholar]
  64. 64.  Liu Y, Patel L, Mills GB, Lu KH, Sood AK et al. 2014. Clinical significance of CTNNB1 mutation and Wnt pathway activation in endometrioid endometrial carcinoma. J. Natl. Cancer Inst. 106:dju245
     [Google Scholar]
  65. 65.  Myers A, Barry WT, Hirsch MS, Matulonis U, Lee L 2014. Beta-catenin mutations in recurrent FIGO IA grade I endometrioid endometrial cancers. Gynecol. Oncol. 134:426–27
     [Google Scholar]
  66. 66.  Kurnit KC, Kim GN, Fellman BM, Urbauer DL, Mills GB et al. 2017. CTNNB1 (beta-catenin) mutation identifies low grade, early stage endometrial cancer patients at increased risk of recurrence. Mod. Pathol. 30:1032–41
     [Google Scholar]
  67. 67.  Stelloo E, Nout RA, Osse EM, Jurgenliemk-Schulz IJ, Jobsen JJ 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. 22:4215–24
     [Google Scholar]
  68. 68.  Giannakis M, Hodis E, Jasmine Mu X, Yamauchi M, Rosenbluh J et al. 2014. RNF43 is frequently mutated in colorectal and endometrial cancers. Nat. Genet. 46:1264–66
     [Google Scholar]
  69. 69.  Koo BK, Spit M, Jordens I, Low TY, Stange DE et al. 2012. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488:665–69
     [Google Scholar]
  70. 70.  Walker CJ, O'Hern MJ, Serna VA, Kurita T, Miranda MA et al. 2017. Novel SOX17 frameshift mutations in endometrial cancer are functionally distinct from recurrent missense mutations. Oncotarget 8:68758–68
     [Google Scholar]
  71. 71.  Zhang Y, Bao W, Wang K, Lu W, Wang H et al. 2016. SOX17 is a tumor suppressor in endometrial cancer. Oncotarget 7:76036–46
     [Google Scholar]
  72. 72.  Kandoth C, McLellan MD, Vandin F, Ye K, Niu B et al. 2013. Mutational landscape and significance across 12 major cancer types. Nature 502:333–39
     [Google Scholar]
  73. 73.  Zighelboim I, Mutch DG, Knapp A, Ding L, Xie M et al. 2014. High frequency strand slippage mutations in CTCF in MSI-positive endometrial cancers. Hum. Mutat. 35:63–65
     [Google Scholar]
  74. 74.  Novetsky AP, Zighelboim I, Thompson DM Jr, Powell MA, Mutch DG, Goodfellow PJ 2013. Frequent mutations in the RPL22 gene and its clinical and functional implications. Gynecol. Oncol 128:470–74
     [Google Scholar]
  75. 75.  Zighelboim I, Schmidt AP, Gao F, Thaker PH, Powell MA et al. 2009. ATR mutation in endometrioid endometrial cancer is associated with poor clinical outcomes. J. Clin. Oncol. 27:3091–96
     [Google Scholar]
  76. 76.  Kim TM, Laird PW, Park PJ 2013. The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell 155:858–68
     [Google Scholar]
  77. 77.  McMeekin DS, Tritchler DL, Cohn DE, Mutch DG, Lankes HA et al. 2016. Clinicopathologic significance of mismatch repair defects in endometrial cancer: an NRG Oncology/Gynecologic Oncology Group study. J. Clin. Oncol. 34:3062–68
     [Google Scholar]
  78. 78.  McConechy MK, Talhouk A, Leung S, Chiu D, Yang W et al. 2016. Endometrial carcinomas with POLE exonuclease domain mutations have a favorable prognosis. Clin. Cancer Res. 22:2865–73
     [Google Scholar]
  79. 79.  Cosgrove CM, Tritchler DL, Cohn DE, Mutch DG, Rush CM et al. 2017. An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer. Gynecol. Oncol. 148:174–80
     [Google Scholar]
  80. 80.  Church DN, Stelloo E, Nout RA, Valtcheva N, Depreeuw J et al. 2015. Prognostic significance of POLE proofreading mutations in endometrial cancer. J. Natl. Cancer Inst. 107:402
     [Google Scholar]
  81. 81.  Meng X, Laidler LL, Kosmacek EA, Yang S, Xiong Z et al. 2013. Induction of mitotic cell death by overriding G2/M checkpoint in endometrial cancer cells with non-functional p53. Gynecol. Oncol. 128:461–69
     [Google Scholar]
  82. 82.  Billingsley CC, Cohn DE, Mutch DG, Stephens JA, Suarez AA, Goodfellow PJ 2015. Polymerase ε (POLE) mutations in endometrial cancer: clinical outcomes and implications for Lynch syndrome testing. Cancer 121:386–94
     [Google Scholar]
  83. 83.  Meng B, Hoang LN, McIntyre JB, Duggan MA, Nelson GS et al. 2014. POLE exonuclease domain mutation predicts long progression-free survival in grade 3 endometrioid carcinoma of the endometrium. Gynecol. Oncol. 134:15–19
     [Google Scholar]
  84. 84.  Hussein YR, Weigelt B, Levine DA, Schoolmeester JK, Dao LN et al. 2015. Clinicopathological analysis of endometrial carcinomas harboring somatic POLE exonuclease domain mutations. Mod. Pathol. 28:505–14
     [Google Scholar]
  85. 85.  Billingsley CC, Cohn DE, Mutch DG, Hade EM, Goodfellow PJ 2016. Prognostic significance of POLE exonuclease domain mutations in high-grade endometrioid endometrial cancer on survival and recurrence: a subanalysis. Int. J. Gynecol. Cancer 26:933–38
     [Google Scholar]
  86. 86.  van Gool IC, Eggink FA, Freeman-Mills L, Stelloo E, Marchi E et al. 2015. POLE proofreading mutations elicit an antitumor immune response in endometrial cancer. Clin. Cancer Res. 21:3347–55
     [Google Scholar]
  87. 87.  Shukla SA, Howitt BE, Wu CJ, Konstantinopoulos PA 2017. Predicted neoantigen load in non-hypermutated endometrial cancers: correlation with outcome and tumor-specific genomic alterations. Gynecol. Oncol. Rep. 19:42–45
     [Google Scholar]
  88. 88.  Bellone S, Centritto F, Black J, Schwab C, English D et al. 2015. Polymerase epsilon (POLE) ultra-mutated tumors induce robust tumor-specific CD4+ T cell responses in endometrial cancer patients. Gynecol. Oncol. 138:11–17
     [Google Scholar]
  89. 89.  Howitt BE, Shukla SA, Sholl LM, Ritterhouse LL, Watkins JC et al. 2015. Association of polymerase E-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol 1:1319–23
     [Google Scholar]
  90. 90.  Eggink FA, Van Gool IC, Leary A, Pollock PM, Crosbie EJ et al. 2017. Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition. Oncoimmunology 6:e1264565
     [Google Scholar]
  91. 91.  Bellone S, Bignotti E, Lonardi S, Ferrari F, Centritto F et al. 2017. Polymerase epsilon (POLE) ultra-mutation in uterine tumors correlates with T lymphocyte infiltration and increased resistance to platinum-based chemotherapy in vitro. Gynecol. Oncol. 144:146–52
     [Google Scholar]
  92. 92.  Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H et al. 2015. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372:2509–20
     [Google Scholar]
  93. 93.  Le DT, Durham JN, Smith KN, Wang H, Bartlett BR et al. 2017. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357:409–13
     [Google Scholar]
  94. 94.  Ott PA, Bang YJ, Berton-Rigaud D, Elez E, Pishvaian MJ et al. 2017. Safety and antitumor activity of pembrolizumab in advanced Programmed Death Ligand 1-positive endometrial cancer: results from the KEYNOTE-028 study. J. Clin. Oncol. 35:2535–41
     [Google Scholar]
  95. 95. FDA (US Food Drug Admin.). 2017. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm560040.htm
  96. 96.  Santin AD, Bellone S, Buza N, Choi J, Schwartz PE et al. 2016. Regression of chemotherapy-resistant polymerase epsilon (POLE) ultra-mutated and MSH6 hyper-mutated endometrial tumors with Nivolumab. Clin. Cancer Res. 22:5682–87
     [Google Scholar]
  97. 97.  Mehnert JM, Panda A, Zhong H, Hirshfield K, Damare S et al. 2016. Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer. J. Clin. Investig. 126:2334–40
     [Google Scholar]
  98. 98.  Winder AD, Maniar KP, Wei JJ, Liu D, Scholtens DM et al. 2017. Synuclein-gamma in uterine serous carcinoma impacts survival: an NRG Oncology/Gynecologic Oncology Group study. Cancer 123:1144–55
     [Google Scholar]
  99. 99.  Wild PJ, Ikenberg K, Fuchs TJ, Rechsteiner M, Georgiev S et al. 2012. p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans. EMBO Mol. Med. 4:808–24
     [Google Scholar]
  100. 100.  Reid-Nicholson M, Iyengar P, Hummer AJ, Linkov I, Asher M, Soslow RA 2006. Immunophenotypic diversity of endometrial adenocarcinomas: implications for differential diagnosis. Mod. Pathol. 19:1091–100
     [Google Scholar]
  101. 101.  Morgan J, Hoekstra AV, Chapman-Davis E, Hardt JL, Kim JJ, Buttin BM 2009. Synuclein-gamma (SNCG) may be a novel prognostic biomarker in uterine papillary serous carcinoma. Gynecol. Oncol. 114:293–98
     [Google Scholar]
  102. 102.  Bashir S, Jiang G, Joshi A, Miller C Jr, Matrai C et al. 2014. Molecular alterations of PIK3CA in uterine carcinosarcoma, clear cell, and serous tumors. Int. J. Gynecol. Cancer 24:1262–67
     [Google Scholar]
  103. 103.  Kuhn E, Wu RC, Guan B, Wu G, Zhang J et al. 2012. Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses. J. Natl. Cancer Inst. 104:1503–13
     [Google Scholar]
  104. 104.  Zhao S, Choi M, Overton JD, Bellone S, Roque DM et al. 2013. Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. PNAS 110:2916–21
     [Google Scholar]
  105. 105.  Eichhorn PJ, Creyghton MP, Bernards R 2009. Protein phosphatase 2A regulatory subunits and cancer. Biochim. Biophys. Acta 1795:1–15
     [Google Scholar]
  106. 106.  Westermarck J, Hahn WC 2008. Multiple pathways regulated by the tumor suppressor PP2A in transformation. Trends Mol. Med. 14:152–60
     [Google Scholar]
  107. 107.  McConechy MK, Anglesio MS, Kalloger SE, Yang W, Senz J et al. 2011. Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas. J. Pathol. 223:567–73
     [Google Scholar]
  108. 108.  Haesen D, Abbasi Asbagh L, Derua R, Hubert A, Schrauwen S et al. 2016. Recurrent PPP2R1A mutations in uterine cancer act through a dominant-negative mechanism to promote malignant cell growth. Cancer Res 76:5719–31
     [Google Scholar]
  109. 109.  Le Gallo M, O'Hara AJ, Rudd ML, Urick ME, Hansen NF et al. 2012. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat. Genet. 44:1310–15
     [Google Scholar]
  110. 110.  Janouskova H, El Tekle G, Bellini E, Udeshi ND, Rinaldi A et al. 2017. Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors. Nat. Med. 23:1046–54
     [Google Scholar]
  111. 111.  Polo SE, Kaidi A, Baskcomb L, Galanty Y, Jackson SP 2010. Regulation of DNA-damage responses and cell-cycle progression by the chromatin remodelling factor CHD4. EMBO J 29:3130–39
     [Google Scholar]
  112. 112.  Smeenk G, Wiegant WW, Vrolijk H, Solari AP, Pastink A, van Attikum H 2010. The NuRD chromatin-remodeling complex regulates signaling and repair of DNA damage. J. Cell Biol. 190:741–49
     [Google Scholar]
  113. 113.  Larsen DH, Poinsignon C, Gudjonsson T, Dinant C, Payne MR et al. 2010. The chromatin-remodeling factor CHD4 coordinates signaling and repair after DNA damage. J. Cell Biol. 190:731–40
     [Google Scholar]
  114. 114.  Pan MR, Hsieh HJ, Dai H, Hung WC, Li K et al. 2012. Chromodomain helicase DNA-binding protein 4 (CHD4) regulates homologous recombination DNA repair, and its deficiency sensitizes cells to poly(ADP-ribose) polymerase (PARP) inhibitor treatment. J. Biol. Chem. 287:6764–72
     [Google Scholar]
  115. 115.  Buza N, Roque DM, Santin AD 2014. HER2/neu in endometrial cancer: a promising therapeutic target with diagnostic challenges. Arch. Pathol. Lab. Med. 138:343–50
     [Google Scholar]
  116. 116.  Villella JA, Cohen S, Smith DH, Hibshoosh H, Hershman D 2006. HER-2/neu overexpression in uterine papillary serous cancers and its possible therapeutic implications. Int. J. Gynecol. Cancer 16:1897–902
     [Google Scholar]
  117. 117.  Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S 2008. Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu. Int. J. Gynaecol. Obstet. 102:128–31
     [Google Scholar]
  118. 118.  Fleming GF, Sill MW, Darcy KM, McMeekin DS, Thigpen JT et al. 2010. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol. Oncol. 116:15–20
     [Google Scholar]
  119. 119.  Santin AD 2010. Letter to the Editor referring to the manuscript entitled: “Phase II trial of trastuzumab in women with advanced or recurrent HER-positive endometrial carcinoma: a Gynecologic Oncology Group study” recently reported by Fleming et al. (Gynecol. Oncol., 116; 15–20; 2010). Gynecol. Oncol. 118:95–96 author reply 97
    [Google Scholar]
  120. 120.  Leslie KK, Sill MW, Lankes HA, Fischer EG, Godwin AK et al. 2012. Lapatinib and potential prognostic value of EGFR mutations in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer. Gynecol. Oncol. 127:345–50
     [Google Scholar]
  121. 121.  Al-Maghrabi JA, Butt NS, Anfinan N, Sait K, Sait H et al. 2017. Infrequent immunohistochemical expression of Napsin A in endometrial carcinomas. Appl. Immunohistochem. Mol. Morphol. 25:632–38
     [Google Scholar]
  122. 122.  Lim D, Ip PP, Cheung AN, Kiyokawa T, Oliva E 2015. Immunohistochemical comparison of ovarian and uterine endometrioid carcinoma, endometrioid carcinoma with clear cell change, and clear cell carcinoma. Am. J. Surg. Pathol. 39:1061–69
     [Google Scholar]
  123. 123.  Nemejcova K, Ticha I, Kleiblova P, Bartu M, Cibula D et al. 2016. Expression, epigenetic and genetic changes of HNF1B in endometrial lesions. Pathol. Oncol. Res. 22:523–30
     [Google Scholar]
  124. 124.  Chen W, Husain A, Nelson GS, Rambau PF, Liu S et al. 2017. Immunohistochemical profiling of endometrial serous carcinoma. Int. J. Gynecol. Pathol. 36:128–39
     [Google Scholar]
  125. 125.  Le Gallo M, Rudd ML, Urick ME, Hansen NF, Zhang S et al. 2017. Somatic mutation profiles of clear cell endometrial tumors revealed by whole exome and targeted gene sequencing. Cancer 123:3261–68
     [Google Scholar]
  126. 126.  An HJ, Logani S, Isacson C, Ellenson LH 2004. Molecular characterization of uterine clear cell carcinoma. Mod. Pathol. 17:530–37
     [Google Scholar]
  127. 127.  Hoang LN, McConechy MK, Meng B, McIntyre JB, Ewanowich C et al. 2014. Targeted mutation analysis of endometrial clear cell carcinoma. Histopathology 66:664–74
     [Google Scholar]
  128. 128.  Stelloo E, Bosse T, Nout RA, MacKay HJ, Church DN et al. 2015. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative. Mod. Pathol. 28:836–44
     [Google Scholar]
  129. 129.  Han G, Soslow RA, Wethington S, Levine DA, Bogomolniy F et al. 2015. Endometrial carcinomas with clear cells: a study of a heterogeneous group of tumors including interobserver variability, mutation analysis, and immunohistochemistry with HNF-1beta. Int. J. Gynecol. Pathol. 34:323–33
     [Google Scholar]
  130. 130.  Fadare O, Parkash V, Dupont WD, Acs G, Atkins KA et al. 2012. The diagnosis of endometrial carcinomas with clear cells by gynecologic pathologists: an assessment of interobserver variability and associated morphologic features. Am. J. Surg. Pathol. 36:1107–18
     [Google Scholar]
  131. 131.  Cherniack AD, Shen H, Walter V, Stewart C, Murray BA et al. 2017. Integrated molecular characterization of uterine carcinosarcoma. Cancer Cell 31:411–23
     [Google Scholar]
  132. 132.  Jones S, Stransky N, McCord CL, Cerami E, Lagowski J et al. 2014. Genomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes. Nat. Commun. 5:5006
     [Google Scholar]
  133. 133.  Le Gallo M, Rudd ML, Urick ME, Hansen NF, Natl. Inst. Health Intramur. Seq. Cent. Comp. Seq. Progr., et al. 2018. The FOXA2 transcription factor is frequently somatically mutated in uterine carcinosarcomas and carcinomas. Cancer 124:65–73
     [Google Scholar]
  134. 134.  Biscuola M, Van de Vijver K, Castilla MA, Romero-Perez L, Lopez-Garcia MA et al. 2013. Oncogene alterations in endometrial carcinosarcomas. Hum. Pathol. 44:852–59
     [Google Scholar]
  135. 135.  Hoang LN, Ali RH, Lau S, Gilks CB, Lee CH 2014. Immunohistochemical survey of mismatch repair protein expression in uterine sarcomas and carcinosarcomas. Int. J. Gynecol. Pathol. 33:483–91
     [Google Scholar]
  136. 136.  Bhangoo MS, Boasberg P, Mehta P, Elvin JA, Ali SM et al. 2018. Tumor mutational burden guides therapy in a treatment refractory POLE-mutant uterine carcinosarcoma. Oncologist 23:518–23
     [Google Scholar]
  137. 137.  Talhouk A, McConechy MK, Leung S, Li-Chang HH, Kwon JS et al. 2015. A clinically applicable molecular-based classification for endometrial cancers. Br. J. Cancer 113:299–310
     [Google Scholar]
  138. 138.  Hoang LN, Kinloch MA, Leo JM, Grondin K, Lee CH et al. 2017. Interobserver agreement in endometrial carcinoma histotype diagnosis varies depending on The Cancer Genome Atlas (TCGA)-based molecular subgroup. Am. J. Surg. Pathol. 41:245–52
     [Google Scholar]
  139. 139.  Talhouk A, McConechy MK, Leung S, Yang W, Lum A et al. 2017. Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer. Cancer 123:802–13
     [Google Scholar]
  140. 140.  Kommoss S, McConechty MK, Kommoss F, Leung S, Bunz A et al. 2018. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Ann. Oncol. 29:1180–88
     [Google Scholar]
  141. 141.  Depreeuw J, Stelloo E, Osse EM, Creutzberg CL, Nout RA et al. 2017. Amplification of 1q32.1 refines the molecular classification of endometrial carcinoma. Clin. Cancer Res. 23:7232–41
     [Google Scholar]
  142. 142.  Kohlmann W, Gruber SB 1993. Lynch syndrome. GeneReviews MP Adam, HH Ardinger, RA Pagon, SE Wallace, LJH Bean, K Stephens, A Amemiya Seattle: Univ. Wash.
     [Google Scholar]
  143. 143.  Rossi L, Le Frere-Belda MA, Laurent-Puig P, Buecher B, De Pauw A et al. 2017. Clinicopathologic characteristics of endometrial cancer in Lynch syndrome: a French multicenter study. Int. J. Gynecol. Cancer 27:953–60
     [Google Scholar]
  144. 144.  Huang M, Djordjevic B, Yates MS, Urbauer D, Sun C et al. 2013. Molecular pathogenesis of endometrial cancers in patients with Lynch syndrome. Cancer 119:3027–33
     [Google Scholar]
  145. 145.  Carcangiu ML, Radice P, Casalini P, Bertario L, Merola M, Sala P 2010. Lynch syndrome–related endometrial carcinomas show a high frequency of nonendometrioid types and of high FIGO grade endometrioid types. Int. J. Surg. Pathol. 18:21–26
     [Google Scholar]
  146. 146.  Broaddus RR, Lynch HT, Chen LM, Daniels MS, Conrad P et al. 2006. Pathologic features of endometrial carcinoma associated with HNPCC: a comparison with sporadic endometrial carcinoma. Cancer 106:87–94
     [Google Scholar]
  147. 147.  Bartosch C, Pires-Luis AS, Meireles C, Baptista M, Gouveia A et al. 2016. Pathologic findings in prophylactic and nonprophylactic hysterectomy specimens of patients with Lynch syndrome. Am. J. Surg. Pathol. 40:1177–91
     [Google Scholar]
  148. 148.  Pakish JB, Zhang Q, Chen Z, Liang H, Chisholm GB et al. 2017. Immune microenvironment in microsatellite-instable endometrial cancers: Hereditary or sporadic origin matters. Clin. Cancer Res. 23:4473–81
     [Google Scholar]
  149. 149.  Lu KH, Ring KL 2015. One size may not fit all: the debate of universal tumor testing for Lynch syndrome. Gynecol. Oncol. 137:2–3
     [Google Scholar]
  150. 150.  Batte BA, Bruegl AS, Daniels MS, Ring KL, Dempsey KM et al. 2014. Consequences of universal MSI/IHC in screening ENDOMETRIAL cancer patients for Lynch syndrome. Gynecol. Oncol. 134:319–25
     [Google Scholar]
  151. 151.  Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM et al. 2013. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat. Genet. 45:136–44
     [Google Scholar]
  152. 152.  Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E 2013. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J. Natl. Cancer Inst. 105:1607–16
     [Google Scholar]
/content/journals/10.1146/annurev-pathol-020117-043609
Loading
Molecular Genetics of Endometrial Carcinoma
Annual Review of Pathology: Mechanisms of Disease 14, 339 (2019); https://doi.org/10.1146/annurev-pathol-020117-043609
/content/journals/10.1146/annurev-pathol-020117-043609
/content/journals/10.1146/annurev-pathol-020117-043609
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error