Skip to main content
SpringerLink
Log in

Next-Generation Sequencing

  • Chapter
  • First Online:
Book cover Molecular Genetics of Endometrial Carcinoma

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 943))

Abstract

Endometrial cancers are the most frequently diagnosed gynecological malignancy and were expected to be the seventh leading cause of cancer death among American women in 2015. The majority of endometrial cancers are of serous or endometrioid histology. Most human tumors, including endometrial tumors, are driven by the acquisition of pathogenic mutations in cancer genes. Thus, the identification of somatic mutations within tumor genomes is an entry point toward cancer gene discovery. However, efforts to pinpoint somatic mutations in human cancers have, until recently, relied on high-throughput sequencing of single genes or gene families using Sanger sequencing. Although this approach has been fruitful, the cost and throughput of Sanger sequencing generally prohibits systematic sequencing of the ~22,000 genes that make up the exome. The recent development of next-generation sequencing technologies changed this paradigm by providing the capability to rapidly sequence exomes, transcriptomes, and genomes at relatively low cost. Remarkably, the application of this technology to catalog the mutational landscapes of endometrial tumor exomes, transcriptomes, and genomes has revealed, for the first time, that serous and endometrioid endometrial cancers can be classified into four distinct molecular subgroups. In this chapter, we overview the characteristic genomic features of each subgroup and discuss the known and putative cancer genes that have emerged from next-generation sequencing of endometrial carcinomas.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Parada LF, Tabin CJ, Shih C, Weinberg RA. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature. 1982;297(5866):474–8.

    CAS  PubMed  Google Scholar 

  2. Reddy EP, Reynolds RK, Santos E, Barbacid M. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature. 1982;300(5888):149–52.

    CAS  PubMed  Google Scholar 

  3. Tabin CJ, Bradley SM, Bargmann CI, Weinberg RA, Papageorge AG, Scolnick EM, Dhar R, Lowy DR, Chang EH. Mechanism of activation of a human oncogene. Nature. 1982;300(5888):143–9.

    CAS  PubMed  Google Scholar 

  4. Taparowsky E, Suard Y, Fasano O, Shimizu K, Goldfarb M, Wigler M. Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature. 1982;300(5894):762–5.

    CAS  PubMed  Google Scholar 

  5. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004;431(7011):931–45.

    Google Scholar 

  6. McPherson JD, Marra M, Hillier L, Waterston RH, Chinwalla A, Wallis J, Sekhon M, Wylie K, Mardis ER, Wilson RK, et al. A physical map of the human genome. Nature. 2001;409(6822):934–41.

    CAS  PubMed  Google Scholar 

  7. Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, et al. The sequence of the human genome. Science. 2001;291(5507):1304–51.

    CAS  PubMed  Google Scholar 

  8. Mardis ER. Next-generation sequencing platforms. Annu Rev Anal Chem. 2013;6:287–303.

    CAS  Google Scholar 

  9. Downing JR, Wilson RK, Zhang J, Mardis ER, Pui CH, Ding L, Ley TJ, Evans WE. The Pediatric Cancer Genome Project. Nat Genet. 2012;44(6):619–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Hudson TJ, Anderson W, Artez A, Barker AD, Bell C, Bernabe RR, Bhan MK, Calvo F, Eerola I, Gerhard DS, et al. International Network of Cancer Genome Projects. Nature. 2010;464(7291):993–8.

    CAS  PubMed  Google Scholar 

  11. Kuhn E, Wu RC, Guan B, Wu G, Zhang J, Wang Y, Song L, Yuan X, Wei L, Roden RB, et al. Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses. J Natl Cancer Inst. 2012;104(19):1503–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Le Gallo M, O’Hara AJ, Rudd ML, Urick ME, Hansen NF, O’Neil NJ, Price JC, Zhang S, England BM, Godwin AK, et al. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet. 2012;44(12):1310–5.

    PubMed  PubMed Central  Google Scholar 

  13. Zhao S, Choi M, Overton JD, Bellone S, Roque DM, Cocco E, Guzzo F, English DP, Varughese J, Gasparrini S, et al. Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proc Natl Acad Sci U S A. 2013;110(8):2916–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kinde I, Bettegowda C, Wang Y, Wu J, Agrawal N, Shih Ie M, Kurman R, Dao F, Levine DA, Giuntoli R, et al. Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers. Sci Transl Med. 2013;5(167):167ra164.

    Google Scholar 

  15. Liang H, Cheung LW, Li J, Ju Z, Yu S, Stemke-Hale K, Dogruluk T, Lu Y, Liu X, Gu C, et al. Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer. Genome Res. 2012;22(11):2120–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, Benz CC, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.

    PubMed  Google Scholar 

  17. American Cancer Society. Cancer facts & figures 2015. Atlanta: American Cancer Society; 2015. p. 1–56.

    Google Scholar 

  18. Walker C, Goodfellow PJ. Traditional approaches to molecular genetic analysis. In: Ellenson L, editor. Molecular genetics of endometrial carcinoma. New York: Springer, 2017.

    Google Scholar 

  19. O'Hara AJ, Bell DW. The genomics and genetics of endometrial cancer. Adv Genomics Genet. 2012;2012(2):33–47.

    PubMed  PubMed Central  Google Scholar 

  20. Matias-Guiu X. Specific targeted pathways. In: Ellenson L, editor. Molecular genetics of endometrial carcinoma. New York: Springer, 2017.

    Google Scholar 

  21. McConechy MK, Ding J, Cheang MC, Wiegand K, Senz J, Tone A, Yang W, Prentice L, Tse K, Zeng T, et al. Use of mutation profiles to refine the classification of endometrial carcinomas. J Pathol. 2012;228(1):20–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lax SF, Kendall B, Tashiro H, Slebos RJ, 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(4):814–24.

    CAS  PubMed  Google Scholar 

  23. Ambros RA, Sheehan CE, Kallakury BV, Ross JS, Malfetano J, Paunovich E, Figge J. MDM2 and p53 protein expression in the histologic subtypes of endometrial carcinoma. Mod Pathol. 1996;9(12):1165–9.

    CAS  PubMed  Google Scholar 

  24. Kovalev S, Marchenko ND, Gugliotta BG, Chalas E, Chumas J, Moll UM. Loss of p53 function in uterine papillary serous carcinoma. Hum Pathol. 1998;29(6):613–9.

    CAS  PubMed  Google Scholar 

  25. Moll UM, Chalas E, Auguste M, Meaney D, Chumas J. Uterine papillary serous carcinoma evolves via a p53-driven pathway. Hum Pathol. 1996;27(12):1295–300.

    CAS  PubMed  Google Scholar 

  26. Sherman ME, Bur ME, Kurman RJ. p53 in endometrial cancer and its putative precursors: evidence for diverse pathways of tumorigenesis. Hum Pathol. 1995;26(11):1268–74.

    CAS  PubMed  Google Scholar 

  27. Tashiro H, Isacson C, Levine R, Kurman RJ, Cho KR, Hedrick L. p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Am J Pathol. 1997;150(1):177–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Cheung LW, Hennessy BT, Li J, Yu S, Myers AP, Djordjevic B, Lu Y, Stemke-Hale K, Dyer MD, Zhang F, et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011;1(2):170–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Shoji K, Oda K, Nakagawa S, Hosokawa S, Nagae G, Uehara Y, Sone K, Miyamoto Y, Hiraike H, Hiraike-Wada O, et al. The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas. Br J Cancer. 2009;101(1):145–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Oda K, Stokoe D, Taketani Y, McCormick F. High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res. 2005;65(23):10669–73.

    CAS  PubMed  Google Scholar 

  31. Risinger JI, Hayes AK, Berchuck A, Barrett JC. PTEN/MMAC1 mutations in endometrial cancers. Cancer Res. 1997;57(21):4736–8.

    CAS  PubMed  Google Scholar 

  32. Rudd ML, Price JC, Fogoros S, Godwin AK, Sgroi DC, Merino MJ, Bell DW. A unique spectrum of somatic PIK3CA (p110alpha) mutations within primary endometrial carcinomas. Clin Cancer Res. 2011;17(6):1331–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Tashiro H, Blazes MS, Wu R, Cho KR, Bose S, Wang SI, Li J, Parsons R, Ellenson LH. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res. 1997;57(18):3935–40.

    CAS  PubMed  Google Scholar 

  34. Urick ME, Rudd ML, Godwin AK, Sgroi D, Merino M, Bell DW. PIK3R1 (p85alpha) is somatically mutated at high frequency in primary endometrial cancer. Cancer Res. 2011;71(12):4061–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Salvesen HB, Stefansson I, Kalvenes MB, Das S, Akslen LA. Loss of PTEN expression is associated with metastatic disease in patients with endometrial carcinoma. Cancer. 2002;94(8):2185–91.

    CAS  PubMed  Google Scholar 

  36. Dutt A, Salvesen HB, Greulich H, Sellers WR, Beroukhim R, Meyerson M. Somatic mutations are present in all members of the AKT family in endometrial carcinoma. Br J Cancer. 2009;101(7):1218–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Peiffer SL, Herzog TJ, Tribune DJ, Mutch DG, Gersell DJ, Goodfellow PJ. Allelic loss of sequences from the long arm of chromosome 10 and replication errors in endometrial cancers. Cancer Res. 1995;55(9):1922–6.

    CAS  PubMed  Google Scholar 

  38. Konopka B, Janiec-Jankowska A, Kwiatkowska E, Najmola U, Bidzinski M, Olszewski W, Goluda C. PIK3CA mutations and amplification in endometrioid endometrial carcinomas: relation to other genetic defects and clinicopathologic status of the tumors. Hum Pathol. 2011;42(11):1710–9.

    CAS  PubMed  Google Scholar 

  39. Kang S, Seo SS, Chang HJ, Yoo CW, Park SY, Dong SM. Mutual exclusiveness between PIK3CA and KRAS mutations in endometrial carcinoma. Int J Gynecol Cancer. 2008;18(6):1339–43.

    CAS  PubMed  Google Scholar 

  40. Miyake T, Yoshino K, Enomoto T, Takata T, Ugaki H, Kim A, Fujiwara K, Miyatake T, Fujita M, Kimura T. PIK3CA gene mutations and amplifications in uterine cancers, identified by methods that avoid confounding by PIK3CA pseudogene sequences. Cancer Lett. 2008;261(1):120–6.

    CAS  PubMed  Google Scholar 

  41. Lu KH, Wu W, Dave B, Slomovitz BM, Burke TW, Munsell MF, Broaddus RR, Walker CL. Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma. Clin Cancer Res. 2008;14(9):2543–50.

    CAS  PubMed  Google Scholar 

  42. Maxwell GL, Risinger JI, Gumbs C, Shaw H, Bentley RC, Barrett JC, Berchuck A, Futreal PA. Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias. Cancer Res. 1998;58(12):2500–3.

    CAS  PubMed  Google Scholar 

  43. Levine RL, Cargile CB, Blazes MS, van Rees B, Kurman RJ, Ellenson LH. PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma. Cancer Res. 1998;58(15):3254–8.

    CAS  PubMed  Google Scholar 

  44. Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JP, Lees JA, Weng LP, Eng C. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst. 2000;92(11):924–30.

    CAS  PubMed  Google Scholar 

  45. Hayes MP, Wang H, Espinal-Witter R, Douglas W, Solomon GJ, Baker SJ, Ellenson LH. PIK3CA and PTEN mutations in uterine endometrioid carcinoma and complex atypical hyperplasia. Clin Cancer Res. 2006;12(20 Pt 1):5932–5.

    CAS  PubMed  Google Scholar 

  46. McConechy MK, Anglesio MS, Kalloger SE, Yang W, Senz J, Chow C, Heravi-Moussavi A, Morin GB, Mes-Masson AM, Carey MS, et al. Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas. J Pathol. 2011;223(5):567–73.

    CAS  PubMed  Google Scholar 

  47. Nagendra DC, Burke III J, Maxwell GL, Risinger JI. PPP2R1A mutations are common in the serous type of endometrial cancer. Mol Carcinog. 2012;51(10):826–31.

    CAS  PubMed  Google Scholar 

  48. Shih Ie M, Panuganti PK, Kuo KT, Mao TL, Kuhn E, Jones S, Velculescu VE, Kurman RJ, Wang TL. Somatic mutations of PPP2R1A in ovarian and uterine carcinomas. Am J Pathol. 2011;178(4):1442–7.

    PubMed  Google Scholar 

  49. Morrison C, Zanagnolo V, Ramirez N, Cohn DE, Kelbick N, Copeland L, Maxwell GL, Fowler JM. HER-2 is an independent prognostic factor in endometrial cancer: association with outcome in a large cohort of surgically staged patients. J Clin Oncol. 2006;24(15):2376–85.

    CAS  PubMed  Google Scholar 

  50. Engelsen IB, Stefansson IM, Beroukhim R, Sellers WR, Meyerson M, Akslen LA, Salvesen HB. HER-2/neu expression is associated with high tumor cell proliferation and aggressive phenotype in a population based patient series of endometrial carcinomas. Int J Oncol. 2008;32(2):307–16.

    CAS  PubMed  Google Scholar 

  51. Grushko TA, Filiaci VL, Mundt AJ, Ridderstrale K, Olopade OI, Fleming GF. An exploratory analysis of HER-2 amplification and overexpression in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2008;108(1):3–9.

    CAS  PubMed  Google Scholar 

  52. Halperin R, Zehavi S, Habler L, Hadas E, Bukovsky I, Schneider D. Comparative immunohistochemical study of endometrioid and serous papillary carcinoma of endometrium. Eur J Gynaecol Oncol. 2001;22(2):122–6.

    CAS  PubMed  Google Scholar 

  53. Konecny GE, Santos L, Winterhoff B, Hatmal M, Keeney GL, Mariani A, Jones M, Neuper C, Thomas B, Muderspach L, et al. HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer. Br J Cancer. 2009;100(1):89–95.

    CAS  PubMed  Google Scholar 

  54. Odicino FE, Bignotti E, Rossi E, Pasinetti B, Tassi RA, Donzelli C, Falchetti M, Fontana P, Grigolato PG, Pecorelli S. HER-2/neu overexpression and amplification in uterine serous papillary carcinoma: comparative analysis of immunohistochemistry, real-time reverse transcription-polymerase chain reaction, and fluorescence in situ hybridization. Int J Gynecol Cancer. 2008;18(1):14–21.

    CAS  PubMed  Google Scholar 

  55. Santin AD, Bellone S, Gokden M, Palmieri M, Dunn D, Agha J, Roman JJ, Hutchins L, Pecorelli S, O’Brien T, et al. Overexpression of HER-2/neu in uterine serous papillary cancer. Clin Cancer Res. 2002;8(5):1271–9.

    CAS  PubMed  Google Scholar 

  56. Santin AD, Bellone S, Van Stedum S, Bushen W, De Las Casas LE, Korourian S, Tian E, Roman JJ, Burnett A, Pecorelli S. Determination of HER2/neu status in uterine serous papillary carcinoma: comparative analysis of immunohistochemistry and fluorescence in situ hybridization. Gynecol Oncol. 2005;98(1):24–30.

    CAS  PubMed  Google Scholar 

  57. Santin AD, Bellone S, Van Stedum S, Bushen W, Palmieri M, Siegel ER, De Las Casas LE, Roman JJ, Burnett A, Pecorelli S. Amplification of c-erbB2 oncogene: a major prognostic indicator in uterine serous papillary carcinoma. Cancer. 2005;104(7):1391–7.

    CAS  PubMed  Google Scholar 

  58. Singh P, Smith CL, Cheetham G, Dodd TJ, Davy ML. Serous carcinoma of the uterus-determination of HER-2/neu status using immunohistochemistry, chromogenic in situ hybridization, and quantitative polymerase chain reaction techniques: its significance and clinical correlation. Int J Gynecol Cancer. 2008;18(6):1344–51.

    CAS  PubMed  Google Scholar 

  59. Slomovitz BM, Broaddus RR, Burke TW, Sneige N, Soliman PT, Wu W, Sun CC, Munsell MF, Gershenson DM, Lu KH. Her-2/neu overexpression and amplification in uterine papillary serous carcinoma. J Clin Oncol. 2004;22(15):3126–32.

    CAS  PubMed  Google Scholar 

  60. Alkushi A, Kobel M, Kalloger SE, Gilks CB. High-grade endometrial carcinoma: serous and grade 3 endometrioid carcinomas have different immunophenotypes and outcomes. Int J Gynecol Pathol. 2010;29(4):343–50.

    PubMed  Google Scholar 

  61. Netzer IM, Kerner H, Litwin L, Lowenstein L, Amit A. Diagnostic implications of p16 expression in serous papillary endometrial cancer. Int J Gynecol Cancer. 2011;21(8):1441–5.

    PubMed  Google Scholar 

  62. Reid-Nicholson M, Iyengar P, Hummer AJ, Linkov I, Asher M, Soslow RA. Immunophenotypic diversity of endometrial adenocarcinomas: implications for differential diagnosis. Mod Pathol. 2006;19(8):1091–100.

    CAS  PubMed  Google Scholar 

  63. Yemelyanova A, Ji H, Shih Ie M, Wang TL, Wu LS, Ronnett BM. Utility of p16 expression for distinction of uterine serous carcinomas from endometrial endometrioid and endocervical adenocarcinomas: immunohistochemical analysis of 201 cases. Am J Surg Pathol. 2009;33(10):1504–14.

    PubMed  Google Scholar 

  64. Holcomb K, Delatorre R, Pedemonte B, McLeod C, Anderson L, Chambers J. E-cadherin expression in endometrioid, papillary serous, and clear cell carcinoma of the endometrium. Obstet Gynecol. 2002;100(6):1290–5.

    CAS  PubMed  Google Scholar 

  65. Moreno-Bueno G, Hardisson D, Sarrio D, Sanchez C, Cassia R, Prat J, Herman JG, Esteller M, Matias-Guiu X, Palacios J. Abnormalities of E- and P-cadherin and catenin (beta-, gamma-catenin, and p120ctn) expression in endometrial cancer and endometrial atypical hyperplasia. J Pathol. 2003;199(4):471–8.

    CAS  PubMed  Google Scholar 

  66. Scholten AN, Aliredjo R, Creutzberg CL, Smit VT. Combined E-cadherin, alpha-catenin, and beta-catenin expression is a favorable prognostic factor in endometrial carcinoma. Int J Gynecol Cancer. 2006;16(3):1379–85.

    CAS  PubMed  Google Scholar 

  67. Stefansson IM, Salvesen HB, Akslen LA. Prognostic impact of alterations in P-cadherin expression and related cell adhesion markers in endometrial cancer. J Clin Oncol. 2004;22(7):1242–52.

    CAS  PubMed  Google Scholar 

  68. Konecny GE, Agarwal R, Keeney GA, Winterhoff B, Jones MB, Mariani A, Riehle D, Neuper C, Dowdy SC, Wang HJ, et al. Claudin-3 and claudin-4 expression in serous papillary, clear-cell, and endometrioid endometrial cancer. Gynecol Oncol. 2008;109(2):263–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Santin AD, Zhan F, Cane S, Bellone S, Palmieri M, Thomas M, Burnett A, Roman JJ, Cannon MJ, Shaughnessy Jr J, et al. Gene expression fingerprint of uterine serous papillary carcinoma: identification of novel molecular markers for uterine serous cancer diagnosis and therapy. Br J Cancer. 2005;92(8):1561–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. El-Sahwi K, Bellone S, Cocco E, Casagrande F, Bellone M, Abu-Khalaf M, Buza N, Tavassoli FA, Hui P, Ruttinger D, et al. Overexpression of EpCAM in uterine serous papillary carcinoma: implications for EpCAM-specific immunotherapy with human monoclonal antibody adecatumumab (MT201). Mol Cancer Ther. 2010;9(1):57–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Goodfellow PJ, Buttin BM, Herzog TJ, Rader JS, Gibb RK, Swisher E, Look K, Walls KC, Fan MY, Mutch DG. Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci U S A. 2003;100(10):5908–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Pollock PM, Gartside MG, Dejeza LC, Powell MA, Mallon MA, Davies H, Mohammadi M, Futreal PA, Stratton MR, Trent JM, et al. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene. 2007;26(50):7158–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Liao X, Siu MK, Chan KY, Wong ES, Ngan HY, Chan QK, Li AS, Khoo US, Cheung AN. Hypermethylation of RAS effector related genes and DNA methyltransferase 1 expression in endometrial carcinogenesis. Int J Cancer. 2008;123(2):296–302.

    CAS  PubMed  Google Scholar 

  74. Pallares J, Velasco A, Eritja N, Santacana M, Dolcet X, Cuatrecasas M, Palomar-Asenjo V, Catasus L, Prat J, Matias-Guiu X. Promoter hypermethylation and reduced expression of RASSF1A are frequent molecular alterations of endometrial carcinoma. Mod Pathol. 2008;21(6):691–9.

    CAS  PubMed  Google Scholar 

  75. Schlosshauer PW, Ellenson LH, Soslow RA. Beta-catenin and E-cadherin expression patterns in high-grade endometrial carcinoma are associated with histological subtype. Mod Pathol. 2002;15(10):1032–7.

    PubMed  Google Scholar 

  76. Wiegand KC, Lee AF, Al-Agha OM, Chow C, Kalloger SE, Scott DW, Steidl C, Wiseman SM, Gascoyne RD, Gilks B, et al. Loss of BAF250a (ARID1A) is frequent in high-grade endometrial carcinomas. J Pathol. 2011;224(3):328–33.

    CAS  PubMed  Google Scholar 

  77. Zighelboim I, Mutch DG, Knapp A, Ding L, Xie M, Cohn DE, Goodfellow PJ. High frequency strand slippage mutations in CTCF in MSI-positive endometrial cancers. Hum Mutat. 2014;35(1):63–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Jones S, Stransky N, McCord CL, Cerami E, Lagowski J, Kelly D, Angiuoli SV, Sausen M, Kann L, Shukla M, et al. Genomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes. Nat Commun. 2014;5:5006.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Konski AA, Domenico D, Irving D, Tyrkus M, Neisler J, Phibbs G, Mah J, Eggleston W. Clinicopathologic correlation of DNA flow cytometric content analysis (DFCA), surgical staging, and estrogen/progesterone receptor status in endometrial adenocarcinoma. Am J Clin Oncol. 1996;19(2):164–8.

    CAS  PubMed  Google Scholar 

  80. Micci F, Teixeira MR, Haugom L, Kristensen G, Abeler VM, Heim S. Genomic aberrations in carcinomas of the uterine corpus. Genes Chromosomes Cancer. 2004;40(3):229–46.

    CAS  PubMed  Google Scholar 

  81. Newbury R, Schuerch C, Goodspeed N, Fanning J, Glidewell O, Evans M. DNA content as a prognostic factor in endometrial carcinoma. Obstet Gynecol. 1990;76(2):251–7.

    CAS  PubMed  Google Scholar 

  82. Pere H, Tapper J, Wahlstrom T, Knuutila S, Butzow R. Distinct chromosomal imbalances in uterine serous and endometrioid carcinomas. Cancer Res. 1998;58(5):892–5.

    CAS  PubMed  Google Scholar 

  83. Pradhan M, Abeler VM, Danielsen HE, Trope CG, Risberg BA. Image cytometry DNA ploidy correlates with histological subtypes in endometrial carcinomas. Mod Pathol. 2006;19(9):1227–35.

    CAS  PubMed  Google Scholar 

  84. Prat J, Oliva E, Lerma E, Vaquero M, Matias-Guiu X. Uterine papillary serous adenocarcinoma. A 10-case study of p53 and c-erbB-2 expression and DNA content. Cancer. 1994;74(6):1778–83.

    CAS  PubMed  Google Scholar 

  85. Rosenberg P, Wingren S, Simonsen E, Stal O, Risberg B, Nordenskjold B. Flow cytometric measurements of DNA index and S-phase on paraffin-embedded early stage endometrial cancer: an important prognostic indicator. Gynecol Oncol. 1989;35(1):50–4.

    CAS  PubMed  Google Scholar 

  86. Gilks CB, Oliva E, Soslow RA. Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma. Am J Surg Pathol. 2013;37(6):874–81.

    PubMed  Google Scholar 

  87. Davis RJ, Welcker M, Clurman BE. Tumor suppression by the Fbw7 ubiquitin ligase: mechanisms and opportunities. Cancer Cell. 2014;26(4):455–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Akhoondi S, Sun D, von der Lehr N, Apostolidou S, Klotz K, Maljukova A, Cepeda D, Fiegl H, Dofou D, Marth C, et al. FBXW7/hCDC4 is a general tumor suppressor in human cancer. Cancer Res. 2007;67(19):9006–12.

    CAS  PubMed  Google Scholar 

  89. Teng CL, Hsieh YC, Phan L, Shin J, Gully C, Velazquez-Torres G, Skerl S, Yeung SC, Hsu SL, Lee MH. FBXW7 is involved in Aurora B degradation. Cell Cycle. 2012;11(21):4059–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, Maser RS, Zhai B, Wan L, Gutierrez A, Lau AW, et al. SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature. 2011;471(7336):104–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ, Helgason E, Ernst JA, Eby M, Liu J, et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature. 2011;471(7336):110–4.

    CAS  PubMed  Google Scholar 

  92. Thompson BJ, Buonamici S, Sulis ML, Palomero T, Vilimas T, Basso G, Ferrando A, Aifantis I. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J Exp Med. 2007;204(8):1825–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502(7471):333–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Hoang LN, McConechy MK, Meng B, McIntyre JB, Ewanowich C, Gilks CB, Huntsman DG, Kobel M, Lee CH. Targeted mutation analysis of endometrial clear cell carcinoma. Histopathology. 2015;66(5):664–74.

    PubMed  Google Scholar 

  95. Theurillat JP, Udeshi ND, Errington WJ, Svinkina T, Baca SC, Pop M, Wild PJ, Blattner M, Groner AC, Rubin MA, et al. Prostate cancer. Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer. Science. 2014;346(6205):85–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. An J, Wang C, Deng Y, Yu L, Huang H. Destruction of full-length androgen receptor by wild-type SPOP, but not prostate-cancer-associated mutants. Cell Rep. 2014;6(4):657–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Byun B, Jung Y. Repression of transcriptional activity of estrogen receptor alpha by a Cullin3/SPOP ubiquitin E3 ligase complex. Mol Cells. 2008;25(2):289–93.

    CAS  PubMed  Google Scholar 

  98. Kim B, Nam HJ, Pyo KE, Jang MJ, Kim IS, Kim D, Boo K, Lee SH, Yoon JB, Baek SH, et al. Breast cancer metastasis suppressor 1 (BRMS1) is destabilized by the Cul3-SPOP E3 ubiquitin ligase complex. Biochem Biophys Res Commun. 2011;415(4):720–6.

    CAS  PubMed  Google Scholar 

  99. Li C, Ao J, Fu J, Lee DF, Xu J, Lonard D, O’Malley BW. Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1. Oncogene. 2011;30(42):4350–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhang P, Gao K, Tang Y, Jin X, An J, Yu H, Wang H, Zhang Y, Wang D, Huang H, et al. Destruction of DDIT3/CHOP protein by wild-type SPOP but not prostate cancer-associated mutants. Hum Mutat. 2014;35(9):1142–51.

    CAS  PubMed  Google Scholar 

  101. Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat JP, White TA, Stojanov P, Van Allen E, Stransky N, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012;44:685–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Geng C, He B, Xu L, Barbieri CE, Eedunuri VK, Chew SA, Zimmermann M, Bond R, Shou J, Li C, et al. Prostate cancer-associated mutations in speckle-type POZ protein (SPOP) regulate steroid receptor coactivator 3 protein turnover. Proc Natl Acad Sci U S A. 2013;110(17):6997–7002.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Zhang P, Gao K, Jin X, Ma J, Peng J, Wumaier R, Tang Y, Zhang Y, An J, Yan Q, et al. Endometrial cancer-associated mutants of SPOP are defective in regulating estrogen receptor-alpha protein turnover. Cell Death Dis. 2015;6:e1687.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Lai AY, Wade PA. Cancer biology and NuRD, a multifaceted chromatin remodelling complex. Nat Rev Cancer. 2011;11(8):588–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Malkowska M, Kokoszynska K, Rychlewski L, Wyrwicz L. Structural bioinformatics of the general transcription factor TFIID. Biochimie. 2013;95(4):680–91.

    CAS  PubMed  Google Scholar 

  106. Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C. Emerging landscape of oncogenic signatures across human cancers. Nat Genet. 2013;45(10):1127–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Shinbrot E, Henninger EE, Weinhold N, Covington KR, Goksenin AY, Schultz N, Chao H, Doddapaneni H, Muzny DM, Gibbs RA, et al. Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication. Genome Res. 2014;24(11):1740–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Church DN, Briggs SE, Palles C, Domingo E, Kearsey SJ, Grimes JM, Gorman M, Martin L, Howarth KM, Hodgson SV, et al. DNA polymerase {varepsilon} and delta exonuclease domain mutations in endometrial cancer. Hum Mol Genet. 2013;22(14):2820–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Church DN, Stelloo E, Nout RA, Valtcheva N, Depreeuw J, ter Haar N, Noske A, Amant F, Tomlinson IP, Wild PJ, et al. Prognostic significance of POLE proofreading mutations in endometrial cancer. J Natl Cancer Inst. 2015;107(1):402.

    PubMed  Google Scholar 

  111. Stelloo E, Bosse T, Nout RA, MacKay HJ, Church DN, Nijman HW, Leary A, Edmondson RJ, Powell ME, Crosbie EJ, et al. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative. Mod Pathol. 2015;28(6):836–44.

    CAS  PubMed  Google Scholar 

  112. Meng B, Hoang LN, McIntyre JB, Duggan MA, Nelson GS, Lee CH, Kobel M. POLE exonuclease domain mutation predicts long progression-free survival in grade 3 endometrioid carcinoma of the endometrium. Gynecol Oncol. 2014;134(1):15–9.

    CAS  PubMed  Google Scholar 

  113. Billingsley CC, Cohn DE, Mutch DG, Stephens JA, Suarez AA, Goodfellow PJ. Polymerase varepsilon (POLE) mutations in endometrial cancer: clinical outcomes and implications for Lynch syndrome testing. Cancer. 2015;121(3):386–94.

    CAS  PubMed  Google Scholar 

  114. Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Warlam-Rodenhuis CC, De Winter KA, Lutgens LC, van den Bergh AC, van de Steen-Banasik E, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet. 2000;355(9213):1404–11.

    CAS  PubMed  Google Scholar 

  115. Nout RA, Smit VT, Putter H, Jurgenliemk-Schulz IM, Jobsen JJ, Lutgens LC, van der Steen-Banasik EM, Mens JW, Slot A, Kroese MC, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet. 2010;375(9717):816–23.

    CAS  PubMed  Google Scholar 

  116. Kim TM, Laird PW, Park PJ. The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell. 2013;155(4):858–68.

    CAS  PubMed  Google Scholar 

  117. Esteller M, Levine R, Baylin SB, Ellenson LH, Herman JG. MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene. 1998;17(18):2413–7.

    CAS  PubMed  Google Scholar 

  118. Simpkins SB, Bocker T, Swisher EM, Mutch DG, Gersell DJ, Kovatich AJ, Palazzo JP, Fishel R, Goodfellow PJ. MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers. Hum Mol Genet. 1999;8(4):661–6.

    CAS  PubMed  Google Scholar 

  119. Felton KE, Gilchrist DM, Andrew SE. Constitutive deficiency in DNA mismatch repair. Clin Genet. 2007;71(6):483–98.

    CAS  PubMed  Google Scholar 

  120. Ricciardone MD, Ozcelik T, Cevher B, Ozdag H, Tuncer M, Gurgey A, Uzunalimoglu O, Cetinkaya H, Tanyeli A, Erken E, et al. Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res. 1999;59(2):290–3.

    CAS  PubMed  Google Scholar 

  121. Wang Q, Lasset C, Desseigne F, Frappaz D, Bergeron C, Navarro C, Ruano E, Puisieux A. Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res. 1999;59(2):294–7.

    CAS  PubMed  Google Scholar 

  122. Shlien A, Campbell BB, de Borja R, Alexandrov LB, Merico D, Wedge D, Van Loo P, Tarpey PS, Coupland P, Behjati S, et al. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nat Genet. 2015;47(3):257–62.

    CAS  PubMed  Google Scholar 

  123. Gurin CC, Federici MG, Kang L, Boyd J. Causes and consequences of microsatellite instability in endometrial carcinoma. Cancer Res. 1999;59(2):462–6.

    CAS  PubMed  Google Scholar 

  124. Salvesen HB, MacDonald N, Ryan A, Iversen OE, Jacobs IJ, Akslen LA, Das S. Methylation of hMLH1 in a population-based series of endometrial carcinomas. Clin Cancer Res. 2000;6(9):3607–13.

    CAS  PubMed  Google Scholar 

  125. Swisher EM, Mutch DG, Herzog TJ, Rader JS, Kowalski LD, Elbendary A, Goodfellow PJ. Analysis of MSH3 in endometrial cancers with defective DNA mismatch repair. J Soc Gynecol Investig. 1998;5(4):210–6.

    CAS  PubMed  Google Scholar 

  126. Kawaguchi M, Banno K, Yanokura M, Kobayashi Y, Kishimi A, Ogawa S, Kisu I, Nomura H, Hirasawa A, Susumu N, et al. Analysis of candidate target genes for mononucleotide repeat mutation in microsatellite instability-high (MSI-H) endometrial cancer. Int J Oncol. 2009;35(5):977–82.

    CAS  PubMed  Google Scholar 

  127. Fujii H, Jiang W, Matsumoto T, Miyai K, Sashara K, Ohtsuji N, Hino O. Birt-Hogg-Dube gene mutations in human endometrial carcinomas with microsatellite instability. J Pathol. 2006;209(3):328–35.

    CAS  PubMed  Google Scholar 

  128. Furlan D, Casati B, Cerutti R, Facco C, Terracciano L, Capella C, Chiaravalli AM. Genetic progression in sporadic endometrial and gastrointestinal cancers with high microsatellite instability. J Pathol. 2002;197(5):603–9.

    CAS  PubMed  Google Scholar 

  129. Vassileva V, Millar A, Briollais L, Chapman W, Bapat B. Genes involved in DNA repair are mutational targets in endometrial cancers with microsatellite instability. Cancer Res. 2002;62(14):4095–9.

    CAS  PubMed  Google Scholar 

  130. Catasus L, Matias-Guiu X, Machin P, Munoz J, Prat J. BAX somatic frameshift mutations in endometrioid adenocarcinomas of the endometrium: evidence for a tumor progression role in endometrial carcinomas with microsatellite instability. Lab Investig. 1998;78(11):1439–44.

    CAS  PubMed  Google Scholar 

  131. Sakaguchi J, Kyo S, Kanaya T, Maida Y, Hashimoto M, Nakamura M, Yamada K, Inoue M. Aberrant expression and mutations of TGF-beta receptor type II gene in endometrial cancer. Gynecol Oncol. 2005;98(3):427–33.

    CAS  PubMed  Google Scholar 

  132. Myeroff LL, Parsons R, Kim SJ, Hedrick L, Cho KR, Orth K, Mathis M, Kinzler KW, Lutterbaugh J, Park K, et al. A transforming growth factor beta receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res. 1995;55(23):5545–7.

    CAS  PubMed  Google Scholar 

  133. Bilbao C, Ramirez R, Rodriguez G, Falcon O, Leon L, Diaz-Chico N, Perucho M, Diaz-Chico JC. Double strand break repair components are frequent targets of microsatellite instability in endometrial cancer. Eur J Cancer. 2010;46(15):2821–7.

    CAS  PubMed  Google Scholar 

  134. Giannini G, Rinaldi C, Ristori E, Ambrosini MI, Cerignoli F, Viel A, Bidoli E, Berni S, D’Amati G, Scambia G, et al. Mutations of an intronic repeat induce impaired MRE11 expression in primary human cancer with microsatellite instability. Oncogene. 2004;23(15):2640–7.

    CAS  PubMed  Google Scholar 

  135. Zighelboim I, Schmidt AP, Gao F, Thaker PH, Powell MA, Rader JS, Gibb RK, Mutch DG, Goodfellow PJ. ATR mutation in endometrioid endometrial cancer is associated with poor clinical outcomes. J Clin Oncol. 2009;27(19):3091–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Novetsky AP, Zighelboim I, Thompson Jr DM, Powell MA, Mutch DG, Goodfellow PJ. Frequent mutations in the RPL22 gene and its clinical and functional implications. Gynecol Oncol. 2013;128(3):470–4.

    CAS  PubMed  Google Scholar 

  137. Giannakis M, Hodis E, Jasmine Mu X, Yamauchi M, Rosenbluh J, Cibulskis K, Saksena G, Lawrence MS, Qian ZR, Nishihara R, et al. RNF43 is frequently mutated in colorectal and endometrial cancers. Nat Genet. 2014;46(12):1264–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Rao S, Lee SY, Gutierrez A, Perrigoue J, Thapa RJ, Tu Z, Jeffers JR, Rhodes M, Anderson S, Oravecz T, et al. Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B. Blood. 2012;120(18):3764–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Ferreira AM, Tuominen I, Sousa S, Gerbens F, van Dijk-Bos K, Osinga J, Kooi KA, Sanjabi B, Esendam C, Oliveira C, et al. New target genes in endometrial tumors show a role for the estrogen-receptor pathway in microsatellite-unstable cancers. Hum Mutat. 2014;35(12):1514–23.

    CAS  PubMed  Google Scholar 

  140. Ong CT, Corces VG. CTCF: an architectural protein bridging genome topology and function. Nat Rev Genet. 2014;15(4):234–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Holwerda SJ, de Laat W. CTCF: the protein, the binding partners, the binding sites and their chromatin loops. Philos Trans R Soc Lond Ser B Biol Sci. 2013;368(1620):369.

    Google Scholar 

  142. Wu J, Jiao Y, Dal Molin M, Maitra A, de Wilde RF, Wood LD, Eshleman JR, Goggins MG, Wolfgang CL, Canto MI, et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci U S A. 2011;108(52):21188–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Koo BK, Spit M, Jordens I, Low TY, Stange DE, van de Wetering M, van Es JH, Mohammed S, Heck AJ, Maurice MM, et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature. 2012;488(7413):665–9.

    CAS  PubMed  Google Scholar 

  144. Wang K, Yuen ST, Xu J, Lee SP, Yan HH, Shi ST, Siu HC, Deng S, Chu KM, Law S, et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet. 2014;46(6):573–82.

    CAS  PubMed  Google Scholar 

  145. Quintas-Cardama A, Verstovsek S. Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance. Clin Cancer Res. 2013;19(8):1933–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Ren Y, Zhang Y, Liu RZ, Fenstermacher DA, Wright KL, Teer JK, Wu J. JAK1 truncating mutations in gynecologic cancer define new role of cancer-associated protein tyrosine kinase aberrations. Sci Rep. 2013;3:3042.

    PubMed  PubMed Central  Google Scholar 

  147. Byron SA, Gartside M, Powell MA, Wellens CL, Gao F, Mutch DG, Goodfellow PJ, Pollock PM. FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features. PLoS One. 2012;7(2):e30801.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Dutt A, Salvesen HB, Chen TH, Ramos AH, Onofrio RC, Hatton C, Nicoletti R, Winckler W, Grewal R, Hanna M, et al. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc Natl Acad Sci U S A. 2008;105(25):8713–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Lester DR, Cauchi MN. Point mutations at codon 12 of C-K-ras in human endometrial carcinomas. Cancer Lett. 1990;51(1):7–10.

    CAS  PubMed  Google Scholar 

  150. Enomoto T, Inoue M, Perantoni AO, Terakawa N, Tanizawa O, Rice JM. K-ras activation in neoplasms of the human female reproductive tract. Cancer Res. 1990;50(19):6139–45.

    CAS  PubMed  Google Scholar 

  151. Moreno-Bueno G, Rodriguez-Perales S, Sanchez-Estevez C, Hardisson D, Sarrio D, Prat J, Cigudosa JC, Matias-Guiu X, Palacios J. Cyclin D1 gene (CCND1) mutations in endometrial cancer. Oncogene. 2003;22(38):6115–8.

    CAS  PubMed  Google Scholar 

  152. Moreno-Bueno G, Rodriguez-Perales S, Sanchez-Estevez C, Marcos R, Hardisson D, Cigudosa JC, Palacios J. Molecular alterations associated with cyclin D1 overexpression in endometrial cancer. Int J Cancer. 2004;110(2):194–200.

    CAS  PubMed  Google Scholar 

  153. Gatius S, Velasco A, Azueta A, Santacana M, Pallares J, Valls J, Dolcet X, Prat J, Matias-Guiu X. FGFR2 alterations in endometrial carcinoma. Mod Pathol. 2011;24(11):1500–10.

    CAS  PubMed  Google Scholar 

  154. Machin P, Catasus L, Pons C, Munoz J, Matias-Guiu X, Prat J. CTNNB1 mutations and beta-catenin expression in endometrial carcinomas. Hum Pathol. 2002;33(2):206–12.

    CAS  PubMed  Google Scholar 

  155. Mirabelli-Primdahl L, Gryfe R, Kim H, Millar A, Luceri C, Dale D, Holowaty E, Bapat B, Gallinger S, Redston M. Beta-catenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway. Cancer Res. 1999;59(14):3346–51.

    CAS  PubMed  Google Scholar 

  156. Fukuchi T, Sakamoto M, Tsuda H, Maruyama K, Nozawa S, Hirohashi S. Beta-catenin mutation in carcinoma of the uterine endometrium. Cancer Res. 1998;58(16):3526–8.

    CAS  PubMed  Google Scholar 

  157. Saegusa M, Hashimura M, Yoshida T, Okayasu I. Beta-Catenin mutations and aberrant nuclear expression during endometrial tumorigenesis. Br J Cancer. 2001;84(2):209–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 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(5):464–9.

    CAS  PubMed  Google Scholar 

  159. Guan B, Mao TL, Panuganti PK, Kuhn E, Kurman RJ, Maeda D, Chen E, Jeng YM, Wang TL, Shih Ie M. Mutation and loss of expression of ARID1A in uterine low-grade endometrioid carcinoma. Am J Surg Pathol. 2011;35(5):625–32.

    PubMed  PubMed Central  Google Scholar 

  160. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol. 2010;28(6):1075–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Marchio C, De Filippo MR, Ng CK, Piscuoglio S, Soslow RA, Reis-Filho JS, Weigelt B. PIKing the type and pattern of PI3K pathway mutations in endometrioid endometrial carcinomas. Gynecol Oncol. 2015;137(2):321–8.

    CAS  PubMed  Google Scholar 

  162. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.

    PubMed  Google Scholar 

  163. Bosse T, Ter Haar NT, Seeber LM, Diest PJ, Hes FJ, Vasen HF, Nout RA, Creutzberg CL, Morreau H, Smit VT. Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer. Mod Pathol. 2013;26(11):1525–35.

    CAS  PubMed  Google Scholar 

  164. Allo G, Bernardini MQ, Wu RC, Shih Ie M, Kalloger S, Pollett A, Gilks CB, Clarke BA. ARID1A loss correlates with mismatch repair deficiency and intact p53 expression in high-grade endometrial carcinomas. Mod Pathol. 2014;27(2):255–61.

    CAS  PubMed  Google Scholar 

  165. Huang HN, Lin MC, Tseng LH, Chiang YC, Lin LI, Lin YF, Huang HY, Kuo KT. Ovarian and endometrial endometrioid adenocarcinomas have distinct profiles of microsatellite instability, PTEN expression, and ARID1A expression. Histopathology. 2015;66(4):517–28.

    PubMed  Google Scholar 

  166. Baba A, Ohtake F, Okuno Y, Yokota K, Okada M, Imai Y, Ni M, Meyer CA, Igarashi K, Kanno J, et al. PKA-dependent regulation of the histone lysine demethylase complex PHF2-ARID5B. Nat Cell Biol. 2011;13(6):668–75.

    PubMed  Google Scholar 

  167. Healy J, Richer C, Bourgey M, Kritikou EA, Sinnett D. Replication analysis confirms the association of ARID5B with childhood B-cell acute lymphoblastic leukemia. Haematologica. 2010;95(9):1608–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Papaemmanuil E, Hosking FJ, Vijayakrishnan J, Price A, Olver B, Sheridan E, Kinsey SE, Lightfoot T, Roman E, Irving JA, et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet. 2009;41(9):1006–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Chokkalingam AP, Hsu LI, Metayer C, Hansen HM, Month SR, Barcellos LF, Wiemels JL, Buffler PA. Genetic variants in ARID5B and CEBPE are childhood ALL susceptibility loci in Hispanics. Cancer Causes Control. 2013;24(10):1789–95.

    PubMed  PubMed Central  Google Scholar 

  170. Guo LM, Xi JS, Ma Y, Shao L, Nie CL, Wang GJ. ARID5B gene rs10821936 polymorphism is associated with childhood acute lymphoblastic leukemia: a meta-analysis based on 39,116 subjects. Tumour Biol. 2014;35(1):709–13.

    CAS  PubMed  Google Scholar 

  171. Linabery AM, Blommer CN, Spector LG, Davies SM, Robison LL, Ross JA. ARID5B and IKZF1 variants, selected demographic factors, and childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Leuk Res. 2013;37(8):936–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Paulsson K, Forestier E, Lilljebjorn H, Heldrup J, Behrendtz M, Young BD, Johansson B. Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2010;107(50):21719–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Morinaga T, Yasuda H, Hashimoto T, Higashio K, Tamaoki T. A human alpha-fetoprotein enhancer-binding protein, ATBF1, contains four homeodomains and seventeen zinc fingers. Mol Cell Biol. 1991;11(12):6041–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Yasuda H, Mizuno A, Tamaoki T, Morinaga T. ATBF1, a multiple-homeodomain zinc finger protein, selectively down-regulates AT-rich elements of the human alpha-fetoprotein gene. Mol Cell Biol. 1994;14(2):1395–401.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Sun X, Frierson HF, Chen C, Li C, Ran Q, Otto KB, Cantarel BL, Vessella RL, Gao AC, Petros J, et al. Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer. Nat Genet. 2005;37(4):407–12.

    CAS  PubMed  Google Scholar 

  176. Sun X, Fu X, Li J, Xing C, Frierson HF, Wu H, Ding X, Ju T, Cummings RD, Dong JT. Deletion of atbf1/zfhx3 in mouse prostate causes neoplastic lesions, likely by attenuation of membrane and secretory proteins and multiple signaling pathways. Neoplasia. 2014;16(5):377–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Giovannone B, Lee E, Laviola L, Giorgino F, Cleveland KA, Smith RJ. Two novel proteins that are linked to insulin-like growth factor (IGF-I) receptors by the Grb10 adapter and modulate IGF-I signaling. J Biol Chem. 2003;278(34):31564–73.

    CAS  PubMed  Google Scholar 

  178. Higashi S, Iseki E, Minegishi M, Togo T, Kabuta T, Wada K. GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation. J Neurochem. 2010;115(2):423–37.

    CAS  PubMed  Google Scholar 

  179. Morita M, Ler LW, Fabian MR, Siddiqui N, Mullin M, Henderson VC, Alain T, Fonseca BD, Karashchuk G, Bennett CF, et al. A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development. Mol Cell Biol. 2012;32(17):3585–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Tan EK, Schapira AH. Summary of GIGYF2 studies in Parkinson’s disease: the burden of proof. Eur J Neurol. 2010;17(2):175–6.

    CAS  PubMed  Google Scholar 

  181. Giovannone B, Tsiaras WG, de la Monte S, Klysik J, Lautier C, Karashchuk G, Goldwurm S, Smith RJ. GIGYF2 gene disruption in mice results in neurodegeneration and altered insulin-like growth factor signaling. Hum Mol Genet. 2009;18(23):4629–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Triqueneaux G, Velten M, Franzon P, Dautry F, Jacquemin-Sablon H. RNA binding specificity of Unr, a protein with five cold shock domains. Nucleic Acids Res. 1999;27(8):1926–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Adamson B, Smogorzewska A, Sigoillot FD, King RW, Elledge SJ. A genome-wide homologous recombination screen identifies the RNA-binding protein RBMX as a component of the DNA-damage response. Nat Cell Biol. 2012;14(3):318–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Lingenfelter PA, Delbridge ML, Thomas S, Hoekstra HE, Mitchell MJ, Graves JA, Disteche CM. Expression and conservation of processed copies of the RBMX gene. Mamm Genome. 2001;12(7):538–45.

    CAS  PubMed  Google Scholar 

  185. Matsunaga S, Takata H, Morimoto A, Hayashihara K, Higashi T, Akatsuchi K, Mizusawa E, Yamakawa M, Ashida M, Matsunaga TM, et al. RBMX: a regulator for maintenance and centromeric protection of sister chromatid cohesion. Cell Rep. 2012;1(4):299–308.

    CAS  PubMed  Google Scholar 

  186. Takemoto T, Nishio Y, Sekine O, Ikeuchi C, Nagai Y, Maeno Y, Maegawa H, Kimura H, Kashiwagi A. RBMX is a novel hepatic transcriptional regulator of SREBP-1c gene response to high-fructose diet. FEBS Lett. 2007;581(2):218–22.

    CAS  PubMed  Google Scholar 

  187. Kormish JD, Sinner D, Zorn AM. Interactions between SOX factors and Wnt/beta-catenin signaling in development and disease. Dev Dyn. 2010;239(1):56–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Liu X, Luo M, Xie W, Wells JM, Goodheart MJ, Engelhardt JF. Sox17 modulates Wnt3A/beta-catenin-mediated transcriptional activation of the Lef-1 promoter. Am J Physiol Lung Cell Mol Physiol. 2010;299(5):L694–710.

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Sinner D, Kordich JJ, Spence JR, Opoka R, Rankin S, Lin SC, Jonatan D, Zorn AM, Wells JM. Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells. Mol Cell Biol. 2007;27(22):7802–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Sinner D, Rankin S, Lee M, Zorn AM. Sox17 and beta-catenin cooperate to regulate the transcription of endodermal genes. Development. 2004;131(13):3069–80.

    CAS  PubMed  Google Scholar 

  191. Liu Y, Patel L, Mills GB, Lu KH, Sood AK, Ding L, Kucherlapati R, Mardis ER, Levine DA, Shmulevich I, et al. Clinical significance of CTNNB1 mutation and Wnt pathway activation in endometrioid endometrial carcinoma. J Natl Cancer Inst. 2014;106(9).

    Google Scholar 

  192. Byron SA, Gartside MG, Wellens CL, Mallon MA, Keenan JB, Powell MA, Goodfellow PJ, Pollock PM. Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation. Cancer Res. 2008;68(17):6902–7.

    CAS  PubMed  Google Scholar 

  193. Lang F, Voelkl J. Therapeutic potential of serum and glucocorticoid inducible kinase inhibition. Expert Opin Investig Drugs. 2013;22(6):701–14.

    CAS  PubMed  Google Scholar 

  194. Amato R, D'Antona L, Porciatti G, Agosti V, Menniti M, Rinaldo C, Costa N, Bellacchio E, Mattarocci S, Fuiano G, et al. Sgk1 activates MDM2-dependent p53 degradation and affects cell proliferation, survival, and differentiation. J Mol Med. 2009;87(12):1221–39.

    CAS  PubMed  Google Scholar 

  195. Fagerli UM, Ullrich K, Stuhmer T, Holien T, Kochert K, Holt RU, Bruland O, Chatterjee M, Nogai H, Lenz G, et al. Serum/glucocorticoid-regulated kinase 1 (SGK1) is a prominent target gene of the transcriptional response to cytokines in multiple myeloma and supports the growth of myeloma cells. Oncogene. 2011;30(28):3198–206.

    CAS  PubMed  Google Scholar 

  196. Gao D, Wan L, Inuzuka H, Berg AH, Tseng A, Zhai B, Shaik S, Bennett E, Tron AE, Gasser JA, et al. Rictor forms a complex with Cullin-1 to promote SGK1 ubiquitination and destruction. Mol Cell. 2010;39(5):797–808.

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Hall BA, Kim TY, Skor MN, Conzen SD. Serum and glucocorticoid-regulated kinase 1 (SGK1) activation in breast cancer: requirement for mTORC1 activity associates with ER-alpha expression. Breast Cancer Res Treat. 2012;135(2):469–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Heikamp EB, Patel CH, Collins S, Waickman A, Oh MH, Sun IH, Illei P, Sharma A, Naray-Fejes-Toth A, Fejes-Toth G, et al. The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex. Nat Immunol. 2014;15(5):457–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Hong F, Larrea MD, Doughty C, Kwiatkowski DJ, Squillace R, Slingerland JM. mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. Mol Cell. 2008;30(6): 701–11.

    CAS  PubMed  Google Scholar 

  200. Jo A, Yun HJ, Kim JY, Lim SC, Choi HJ, Kang BS, Choi BY, Choi HS. Prolyl isomerase PIN1 negatively regulates SGK1 stability to mediate tamoxifen resistance in breast cancer cells. Anticancer Res. 2015;35(2):785–94.

    CAS  PubMed  Google Scholar 

  201. Liu G, Honisch S, Liu G, Schmidt S, Pantelakos S, Alkahtani S, Toulany M, Lang F, Stournaras C. Inhibition of SGK1 enhances mAR-induced apoptosis in MCF-7 breast cancer cells. Cancer Biol Ther. 2015;16(1):52–9.

    CAS  PubMed  Google Scholar 

  202. Lyo D, Xu L, Foster DA. Phospholipase D stabilizes HDM2 through an mTORC2/SGK1 pathway. Biochem Biophys Res Commun. 2010;396(2):562–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Moniz LS, Vanhaesebroeck B. AKT-ing out: SGK kinases come to the fore. Biochem J. 2013;452(3):e11–3.

    CAS  PubMed  Google Scholar 

  204. Ronchi CL, Sbiera S, Leich E, Tissier F, Steinhauer S, Deutschbein T, Fassnacht M, Allolio B. Low SGK1 expression in human adrenocortical tumors is associated with ACTH-independent glucocorticoid secretion and poor prognosis. J Clin Endocrinol Metab. 2012;97(12):E2251–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Sommer EM, Dry H, Cross D, Guichard S, Davies BR, Alessi DR. Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors. Biochem J. 2013;452(3):499–508.

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Tangir J, Bonafe N, Gilmore-Hebert M, Henegariu O, Chambers SK. SGK1, a potential regulator of c-fms related breast cancer aggressiveness. Clin Exp Metastasis. 2004;21(6):477–83.

    CAS  PubMed  Google Scholar 

  207. Wang K, Gu S, Nasir O, Foller M, Ackermann TF, Klingel K, Kandolf R, Kuhl D, Stournaras C, Lang F. SGK1-dependent intestinal tumor growth in APC-deficient mice. Cell Physiol Biochem. 2010;25(2-3):271–8.

    CAS  PubMed  Google Scholar 

  208. Won M, Park KA, Byun HS, Kim YR, Choi BL, Hong JH, Park J, Seok JH, Lee YH, Cho CH, et al. Protein kinase SGK1 enhances MEK/ERK complex formation through the phosphorylation of ERK2: implication for the positive regulatory role of SGK1 on the ERK function during liver regeneration. J Hepatol. 2009;51(1):67–76.

    CAS  PubMed  Google Scholar 

  209. Huynh KD, Fischle W, Verdin E, Bardwell VJ. BCoR, a novel corepressor involved in BCL-6 repression. Genes Dev. 2000;14(14):1810–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014;10(2):93–5.

    CAS  PubMed  Google Scholar 

  211. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214–8.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Bethesda, MD, 20892, USA

    Matthieu Le Gallo Ph.D., Fred Lozy Ph.D. & Daphne W. Bell Ph.D.

Authors
  1. Matthieu Le Gallo Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fred Lozy Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daphne W. Bell Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daphne W. Bell Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA

    Lora Hedrick Ellenson

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Le Gallo, M., Lozy, F., Bell, D.W. (2017). Next-Generation Sequencing. In: Hedrick Ellenson, L. (eds) Molecular Genetics of Endometrial Carcinoma. Advances in Experimental Medicine and Biology, vol 943. Springer, Cham. https://doi.org/10.1007/978-3-319-43139-0_5

Download citation

Publish with us

Policies and ethics

Search

Navigation