Skip to main content

Genomic Applications in Epithelial Ovarian Malignancies

  • Chapter
  • First Online:
Genomic Applications in Pathology
  • 2135 Accesses

Abstract

Recent advances in high-throughput genomic technologies have deepened our understanding of the molecular underpinnings and cell of origin of gynecologic malignancies. Genomic studies of uterine and ovarian cancers have the potential to refine the current classification of these most common gynecologic malignancies and promise the identification of novel prognostic parameters and novel therapeutic targets. Molecular genomic advances could finally alter the so far dismal outcome of patients with advanced epithelial ovarian carcinomas. This chapter reviews key approaches to diagnosis and stratification of epithelial ovarian carcinomas that are now needed to advance the field.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 239.00
Price excludes VAT (USA)
  • Compact, lightweight 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. Coleman MP, Forman D, Bryant H, Butler J, Rachet B, Maringe C, et al. Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995-2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data. Lancet. 2011;377(9760):127–38. Epub 2010/12/25.

    PubMed  CAS  PubMed Central  Google Scholar 

  2. Bookman MA, Brady MF, McGuire WP, Harper PG, Alberts DS, Friedlander M, et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the gynecologic cancer Intergroup. J Clin Oncol. 2009;27(9):1419–25.

    PubMed  CAS  PubMed Central  Google Scholar 

  3. du Bois A, Weber B, Rochon J, Meier W, Goupil A, Olbricht S, et al. Addition of epirubicin as a third drug to carboplatin-paclitaxel in first-line treatment of advanced ovarian cancer: a prospectively randomized gynecologic cancer intergroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens. J Clin Oncol. 2006;24(7):1127–35. Epub 2006/03/01.

    PubMed  Google Scholar 

  4. du Bois A, Herrstedt J, Hardy-Bessard AC, Muller HH, Harter P, Kristensen G, et al. Phase III trial of carboplatin plus paclitaxel with or without gemcitabine in first-line treatment of epithelial ovarian cancer. J Clin Oncol. 2010;28(27):4162–9. Epub 2010/08/25.

    PubMed  Google Scholar 

  5. Dubeau L. The cell of origin of ovarian epithelial tumors and the ovarian surface epithelium dogma: does the emperor have no clothes? Gynecol Oncol. 1999;72(3):437–42.

    PubMed  CAS  Google Scholar 

  6. Piek JM, van Diest PJ, Zweemer RP, Kenemans P, Verheijen RH. Tubal ligation and risk of ovarian cancer. Lancet. 2001;358(9284):844.

    PubMed  CAS  Google Scholar 

  7. Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol. 2001;195(4):451–6.

    PubMed  CAS  Google Scholar 

  8. Leeper K, Garcia R, Swisher E, Goff B, Greer B, Paley P. Pathologic findings in prophylactic oophorectomy specimens in high-risk women. Gynecol Oncol. 2002;87(1):52–6.

    PubMed  Google Scholar 

  9. Piek JMJ, Verheijen Re HM, Kenemans P, Massuger LF, Bulten H, van Diest PJ. BRCA1/2-related ovarian cancers are of tubal origin: a hypothesis. Gynecol Oncol. 2003;90(2):491.

    PubMed  Google Scholar 

  10. Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, et al. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol. 2007;211(1):26–35.

    PubMed  CAS  Google Scholar 

  11. Crum CP, Drapkin R, Kindelberger D, Medeiros F, Miron A, Lee Y. Lessons from BRCA: the tubal fimbria emerges as an origin for pelvic serous cancer. Clin Med Res. 2007;5(1):35–44.

    PubMed  PubMed Central  Google Scholar 

  12. Callahan MJ, Crum CP, Medeiros F, Kindelberger DW, Elvin JA, Garber JE, et al. Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction. J Clin Oncol. 2007;25(25):3985–90.

    PubMed  Google Scholar 

  13. Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship. Am J Surg Pathol. 2007;31(2):161–9.

    PubMed  Google Scholar 

  14. Viganó P, Somigliana E, Chiodo I, Abbiati A, Vercellini P. Molecular mechanisms and biological plausibility underlying the malignant transformation of endometriosis: a critical analysis. Hum Reprod Update. 2006;12(1):77–89.

    PubMed  Google Scholar 

  15. Ness RB. Endometriosis and ovarian cancer: thoughts on shared pathophysiology. Am J Obstet Gynecol. 2003;189(1):280–94.

    PubMed  Google Scholar 

  16. Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 2010;363(16):1532–43.

    PubMed  CAS  PubMed Central  Google Scholar 

  17. Jones S, Wang T-L, Shih I-M, Mao T-L, Nakayama K, Roden R, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science. 2010;330(6001):228–31.

    PubMed  CAS  PubMed Central  Google Scholar 

  18. Yamamoto S, Tsuda H, Takano M, Iwaya K, Tamai S, Matsubara O. PIK3CA mutation is an early event in the development of endometriosis-associated ovarian clear cell adenocarcinoma. J Pathol. 2011;225(2):189–94. Epub 2011/07/08.

    PubMed  CAS  Google Scholar 

  19. Wilson BG, Roberts CW. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer. 2011;11(7):481–92. Epub 2011/06/10.

    PubMed  CAS  Google Scholar 

  20. Tavassoli FA, Devilee P. Pathology and genetics of tumours of the breast and female genital tract. Lyon, PA: IARC; 2003. 432 p.

    Google Scholar 

  21. Köbel M, Kalloger SE, Baker PM, Ewanowich CA, Arseneau J, Zherebitskiy V, et al. Diagnosis of ovarian carcinoma cell type is highly reproducible: a transcanadian study. Am J Surg Pathol. 2010;34(7):984–93.

    PubMed  Google Scholar 

  22. Köbel M, Kalloger SE, Boyd N, McKinney S, Mehl E, Palmer C, et al. Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med. 2008;5(12):e232.

    PubMed  PubMed Central  Google Scholar 

  23. Singh N, Ayhan A, Menon U, Chin Aleong JA, Faruqi AZ, Gayther SA, et al. Grading of serous ovarian carcinoma: further evidence of a lack of agreement between conventional grading systems. Histopathology. 2008;52(3):393–5.

    PubMed  CAS  Google Scholar 

  24. Gilks CB, Ionescu DN, Kalloger SE, Köbel M, Irving J, Clarke B, et al. Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma. Hum Pathol. 2008;39(8):1239–51.

    PubMed  CAS  Google Scholar 

  25. Kommoss S, Schmidt D, Kommoss F, Hedderich J, Harter P, Pfisterer J, et al. Histological grading in a large series of advanced stage ovarian carcinomas by three widely used grading systems: consistent lack of prognostic significance. A translational research subprotocol of a prospective randomized phase III study (AGO-OVAR 3 protocol). Virchows Arch. 2009;454(3):249–56.

    PubMed  Google Scholar 

  26. Köbel M, Kalloger SE, Santos JL, Huntsman DG, Gilks CB, Swenerton KD. Tumor type and substage predict survival in stage I and II ovarian carcinoma: insights and implications. Gynecol Oncol. 2010;116(1):50–6.

    PubMed  Google Scholar 

  27. Bell J, Brady MF, Young RC, Lage J, Walker JL, Look KY, et al. Randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2006;102(3):432–9.

    PubMed  CAS  Google Scholar 

  28. Kalloger SE, Kobel M, Leung S, Mehl E, Gao D, Marcon KM, et al. Calculator for ovarian carcinoma subtype prediction. Mod Pathol. 2011;24(4):512–21. Epub 2010/12/07.

    PubMed  CAS  Google Scholar 

  29. Kobel M, Kalloger SE, Lee S, Duggan MA, Kelemen LE, Prentice L, et al. Biomarker-based ovarian carcinoma typing: a histologic investigation in the ovarian tumor tissue analysis consortium. Cancer Epidemiol Biomarkers Prev. 2013;22(10):1677–86. Epub 2013/07/25.

    PubMed  Google Scholar 

  30. McCluggage WG, Lyness RW, Atkinson RJ, Dobbs SP, Harley I, McClelland HR, et al. Morphological effects of chemotherapy on ovarian carcinoma. J Clin Pathol. 2002;55(1):27–31.

    PubMed  CAS  PubMed Central  Google Scholar 

  31. Spentzos D, Levine DA, Ramoni MF, Joseph M, Gu X, Boyd J, et al. Gene expression signature with independent prognostic significance in epithelial ovarian cancer. J Clin Oncol. 2004;22(23):4700–10.

    PubMed  Google Scholar 

  32. Selvanayagam ZE, Cheung TH, Wei N, Vittal R, Lo KWK, Yeo W, et al. Prediction of chemotherapeutic response in ovarian cancer with DNA microarray expression profiling. Cancer Genet Cytogenet. 2004;154(1):63–6.

    PubMed  CAS  Google Scholar 

  33. Spentzos D, Levine DA, Kolia S, Otu H, Boyd J, Libermann TA, et al. Unique gene expression profile based on pathologic response in epithelial ovarian cancer. J Clin Oncol. 2005;23(31):7911–8.

    PubMed  CAS  Google Scholar 

  34. Berchuck A, Iversen ES, Lancaster JM, Pittman J, Luo J, Lee P, et al. Patterns of gene expression that characterize long-term survival in advanced stage serous ovarian cancers. Clin Cancer Res. 2005;11(10):3686–96.

    PubMed  CAS  Google Scholar 

  35. Hartmann LC, Lu KH, Linette GP, Cliby WA, Kalli KR, Gershenson D, et al. Gene expression profiles predict early relapse in ovarian cancer after platinum-paclitaxel chemotherapy. Clin Cancer Res. 2005;11(6):2149–55.

    PubMed  CAS  Google Scholar 

  36. Bernardini M, Lee C-H, Beheshti B, Prasad M, Albert M, Marrano P, et al. High-resolution mapping of genomic imbalance and identification of gene expression profiles associated with differential chemotherapy response in serous epithelial ovarian cancer. Neoplasia. 2005;7(6):603–13.

    PubMed  CAS  PubMed Central  Google Scholar 

  37. Jazaeri AA, Awtrey CS, Chandramouli GVR, Chuang YE, Khan J, Sotiriou C, et al. Gene expression profiles associated with response to chemotherapy in epithelial ovarian cancers. Clin Cancer Res. 2005;11(17):6300–10.

    PubMed  CAS  Google Scholar 

  38. Helleman J, Jansen MPHM, Span PN, van Staveren IL, Massuger LFAG, Meijer-van Gelder ME, et al. Molecular profiling of platinum resistant ovarian cancer. Int J Cancer. 2006;118(8):1963–71.

    PubMed  CAS  Google Scholar 

  39. Dressman HK, Berchuck A, Chan G, Zhai J, Bild A, Sayer R, et al. An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer. J Clin Oncol. 2007;25(5):517–25.

    PubMed  CAS  Google Scholar 

  40. Crijns APG, Fehrmann RSN, de Jong S, Gerbens F, Meersma GJ, Klip HG, et al. Survival-related profile, pathways, and transcription factors in ovarian cancer. PLoS Med. 2009;6(2):e24.

    PubMed  Google Scholar 

  41. Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S, et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res. 2008;14(16):5198–208.

    PubMed  CAS  Google Scholar 

  42. Fehrmann RSN, Li X-Y, van der Zee AGJ, de Jong S, Te Meerman GJ, de Vries EGE, et al. Profiling studies in ovarian cancer: a review. Oncologist. 2007;12(8):960–6.

    PubMed  Google Scholar 

  43. Agarwal R, Kaye SB. Expression profiling and individualisation of treatment for ovarian cancer. Curr Opin Pharmacol. 2006;6(4):345–9.

    PubMed  CAS  Google Scholar 

  44. Na Y-J, Farley J, Zeh A, del Carmen M, Penson R, Birrer MJ. Ovarian cancer: markers of response. Int J Gynecol Cancer. 2009;19 Suppl 2:S21–9.

    PubMed  Google Scholar 

  45. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98(19):10869–74.

    PubMed  CAS  PubMed Central  Google Scholar 

  46. Sotiriou C, Neo S-Y, McShane LM, Korn EL, Long PM, Jazaeri A, et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A. 2003;100(18):10393–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  47. The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–15. Epub 2011/07/02.

    PubMed Central  Google Scholar 

  48. Sieh W, Kobel M, Longacre TA, Bowtell DD, deFazio A, Goodman MT, et al. Hormone-receptor expression and ovarian cancer survival: an ovarian tumor tissue analysis consortium study. Lancet Oncol. 2013;14(9):853–62. Epub 2013/07/13.

    PubMed  CAS  PubMed Central  Google Scholar 

  49. Verhaak RG, Tamayo P, Yang JY, Hubbard D, Zhang H, Creighton CJ, et al. Prognostically relevant gene signatures of high-grade serous ovarian carcinoma. J Clin Invest. 2013;123(1):517–25. Epub 2012/12/22.

    PubMed  CAS  PubMed Central  Google Scholar 

  50. Yang JY, Yoshihara K, Tanaka K, Hatae M, Masuzaki H, Itamochi H, et al. Predicting time to ovarian carcinoma recurrence using protein markers. J Clin Invest. 2013;123(9):3740–50. Epub 2013/08/16.

    PubMed  CAS  PubMed Central  Google Scholar 

  51. Matulonis UA, Hirsch M, Palescandolo E, Kim E, Liu J, van Hummelen P, et al. High throughput interrogation of somatic mutations in high grade serous cancer of the ovary. PLoS One. 2011;6(9):e24433. Epub 2011/09/21.

    PubMed  CAS  PubMed Central  Google Scholar 

  52. Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, et al. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989;342(6250):705–8.

    PubMed  CAS  Google Scholar 

  53. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10(8):789–99.

    PubMed  CAS  Google Scholar 

  54. de Graeff P, Crijns APG, de Jong S, Boezen M, Post WJ, de Vries EGE, et al. Modest effect of p53, EGFR and HER-2/neu on prognosis in epithelial ovarian cancer: a meta-analysis. Br J Cancer. 2009;101(1):149–59.

    PubMed  PubMed Central  Google Scholar 

  55. Stewart RL, Royds JA, Burton JL, Heatley MK, Wells M. Direct sequencing of the p53 gene shows absence of mutations in endometrioid endometrial adenocarcinomas expressing p53 protein. Histopathology. 1998;33(5):440–5.

    PubMed  CAS  Google Scholar 

  56. Singer G, Stöhr R, Cope L, Dehari R, Hartmann A, Cao DF, et al. Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation. Am J Surg Pathol. 2005;29(2):218–24.

    PubMed  Google Scholar 

  57. Kuo K-T, Mao T-L, Jones S, Veras E, Ayhan A, et al. Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. Am J Pathol. 2009;174(5):1597–601.

    PubMed  CAS  PubMed Central  Google Scholar 

  58. Ahmed AA, Etemadmoghadam D, Temple J, Lynch AG, Riad M, Sharma R, et al. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J Pathol. 2010;221(1):49–56.

    PubMed  CAS  PubMed Central  Google Scholar 

  59. Köbel M, Reuss A, Bois AD, Kommoss S, Kommoss F, Gao D, et al. The biological and clinical value of p53 expression in pelvic high-grade serous carcinomas. J Pathol. 2010;222(2):191–8.

    PubMed  Google Scholar 

  60. Shahin MS, Hughes JH, Sood AK, Buller RE. The prognostic significance of p53 tumor suppressor gene alterations in ovarian carcinoma. Cancer. 2000;89(9):2006–17.

    PubMed  CAS  Google Scholar 

  61. Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer. 2009;9(12):862–73.

    PubMed  CAS  Google Scholar 

  62. Cheok CF, Verma CS, Je B, Lane DP. Translating p53 into the clinic. Nat Rev Clin Oncol. 2011;8(1):25–37.

    PubMed  CAS  Google Scholar 

  63. Carrassa L, Chila R, Lupi M, Ricci F, Celenza C, Mazzoletti M, et al. Combined inhibition of Chk1 and Wee1: in vitro synergistic effect translates to tumor growth inhibition in vivo. Cell Cycle. 2012;11(13):2507–17. Epub 2012/06/21.

    PubMed  CAS  Google Scholar 

  64. Emerling BM, Hurov JB, Poulogiannis G, Tsukazawa KS, Choo-Wing R, Wulf GM, et al. Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors. Cell. 2013;155(4):844–57. Epub 2013/11/12.

    PubMed  CAS  PubMed Central  Google Scholar 

  65. Nakayama K, Nakayama N, Jinawath N, Salani R, Kurman RJ, Shih I-M, et al. Amplicon profiles in ovarian serous carcinomas. Int J Cancer. 2007;120(12):2613–7.

    PubMed  CAS  Google Scholar 

  66. Farley J, Smith LM, Darcy KM, Sobel E, O’Connor D, Henderson B, et al. Cyclin E expression is a significant predictor of survival in advanced, suboptimally debulked ovarian epithelial cancers: a Gynecologic Oncology Group study. Cancer Res. 2003;63(6):1235–41.

    PubMed  CAS  Google Scholar 

  67. Etemadmoghadam D, deFazio A, Beroukhim R, Mermel C, George J, Getz G, et al. Integrated genome-wide DNA copy number and expression analysis identifies distinct mechanisms of primary chemoresistance in ovarian carcinomas. Clin Cancer Res. 2009;15(4):1417–27.

    PubMed  CAS  PubMed Central  Google Scholar 

  68. Etemadmoghadam D, George J, Cowin PA, Cullinane C, Kansara M, Group AOCS, et al. Amplicon-dependent CCNE1 expression is critical for clonogenic survival after cisplatin treatment and is correlated with 20q11 gain in ovarian cancer. PLoS One. 2010;5(11):e15498.

    PubMed  PubMed Central  Google Scholar 

  69. Theurillat JP, Metzler SC, Henzi N, Djouder N, Helbling M, Zimmermann AK, et al. URI is an oncogene amplified in ovarian cancer cells and is required for their survival. Cancer Cell. 2011;19(3):317–32. Epub 2011/03/15.

    PubMed  CAS  Google Scholar 

  70. Etemadmoghadam D, Weir BA, Au-Yeung G, Alsop K, Mitchell G, George J, et al. Synthetic lethality between CCNE1 amplification and loss of BRCA1. Proc Natl Acad Sci U S A. 2013;110:19489–94. Epub 2013/11/13.

    PubMed  CAS  PubMed Central  Google Scholar 

  71. Etemadmoghadam D, Au-Yeung G, Wall M, Mitchell C, Kansara M, Loehrer E, et al. Resistance to CDK2 inhibitors is associated with selection of polyploid cells in CCNE1-amplified ovarian cancer. Clin Cancer Res. 2013;19(21):5960–71. Epub 2013/09/06.

    PubMed  CAS  Google Scholar 

  72. Markman M, Rothman R, Hakes T, Reichman B, Hoskins W, Rubin S, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol. 1991;9(3):389–93.

    PubMed  CAS  Google Scholar 

  73. Borst P, Rottenberg S, Jonkers J. How do real tumors become resistant to cisplatin? Cell Cycle. 2008;7(10):1353–9.

    PubMed  CAS  Google Scholar 

  74. Trainer AH, Meiser B, Watts K, Mitchell G, Tucker K, Friedlander M. Moving toward personalized medicine: treatment-focused genetic testing of women newly diagnosed with ovarian cancer. Int J Gynecol Cancer. 2010;20(5):704–16.

    PubMed  Google Scholar 

  75. Hennessy BTJ, Timms KM, Carey MS, Gutin A, Meyer LA, Flake N, Darl D, et al. Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol. 2010;28(22):3570–6.

    PubMed  PubMed Central  Google Scholar 

  76. Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30(21):2654–63. Epub 2012/06/20.

    PubMed  CAS  PubMed Central  Google Scholar 

  77. Chetrit A, Hirsh-Yechezkel G, Ben-David Y, Lubin F, Friedman E, Sadetzki S. Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer. J Clin Oncol. 2008;26(1):20–5.

    PubMed  Google Scholar 

  78. Tan DSP, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, et al. “BRCAness” syndrome in ovarian cancer: a case–control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol. 2008;26(34):5530–6.

    PubMed  Google Scholar 

  79. Yang D, Khan S, Sun Y, Hess K, Shmulevich I, Sood AK, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. 2011;306(14):1557–65. Epub 2011/10/13.

    PubMed  CAS  PubMed Central  Google Scholar 

  80. Bolton KL, Chenevix-Trench G, Goh C, Sadetzki S, Ramus SJ, Karlan BY, et al. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA. 2012;307(4):382–90. Epub 2012/01/26.

    PubMed  CAS  PubMed Central  Google Scholar 

  81. Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet. 2010;42(5):410–4. Epub 2010/04/20.

    PubMed  CAS  Google Scholar 

  82. Pelttari LM, Heikkinen T, Thompson D, Kallioniemi A, Schleutker J, Holli K, et al. RAD51C is a susceptibility gene for ovarian cancer. Hum Mol Genet. 2011;20(16):3278–88. Epub 2011/05/28.

    PubMed  CAS  Google Scholar 

  83. Loveday C, Turnbull C, Ramsay E, Hughes D, Ruark E, Frankum JR, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet. 2011;43(9):879–82. Epub 2011/08/09.

    PubMed  CAS  Google Scholar 

  84. Rafnar T, Gudbjartsson DF, Sulem P, Jonasdottir A, Sigurdsson A, Jonasdottir A, et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat Genet. 2011;43(11):1104–7. Epub 2011/10/04.

    PubMed  CAS  Google Scholar 

  85. Mukhopadhyay A, Elattar A, Cerbinskaite A, Wilkinson SJ, Drew Y, Kyle S, et al. Development of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to poly(ADP-ribose) polymerase inhibitors. Clin Cancer Res. 2010;16(8):2344–51.

    PubMed  CAS  Google Scholar 

  86. Norquist B, Wurz KA, Pennil CC, Garcia R, Gross J, Sakai W, et al. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol. 2011;29(22):3008–15. Epub 2011/06/29.

    PubMed  CAS  PubMed Central  Google Scholar 

  87. Sakai W, Swisher EM, Jacquemont C, Chandramohan KV, Couch FJ, Langdon SP, et al. Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma. Cancer Res. 2009;69(16):6381–6. Epub 2009/08/06.

    PubMed  CAS  PubMed Central  Google Scholar 

  88. Swisher EM, Sakai W, Karlan BY, Wurz K, Urban N, Taniguchi T. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res. 2008;68(8):2581–6.

    PubMed  CAS  PubMed Central  Google Scholar 

  89. Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature. 2008;451(7182):1116–20.

    PubMed  CAS  PubMed Central  Google Scholar 

  90. Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature. 2008;451(7182):1111–5. Epub 2008/02/12.

    PubMed  CAS  Google Scholar 

  91. Cooke SL, Temple J, Macarthur S, Zahra MA, Tan LT, Crawford RAF, et al. Intra-tumour genetic heterogeneity and poor chemoradiotherapy response in cervical cancer. Br J Cancer. 2011;104(2):361–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  92. Cooke SL, Ng CKY, Melnyk N, Garcia MJ, Hardcastle T, Temple J, et al. Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma. Oncogene. 2010;29(35):4905–13.

    PubMed  CAS  PubMed Central  Google Scholar 

  93. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23–8.

    PubMed  CAS  Google Scholar 

  94. Dexter DL, Kowalski HM, Blazar BA, Fligiel Z, Vogel R, Heppner GH. Heterogeneity of tumor cells from a single mouse mammary tumor. Cancer Res. 1978;38(10):3174–81.

    PubMed  CAS  Google Scholar 

  95. Khalique L, Ayhan A, Weale ME, Jacobs IJ, Ramus SJ, Gayther SA. Genetic intra-tumour heterogeneity in epithelial ovarian cancer and its implications for molecular diagnosis of tumours. J Pathol. 2007;211(3):286–95.

    PubMed  CAS  Google Scholar 

  96. Khalique L, Ayhan A, Whittaker JC, Singh N, Jacobs IJ, Gayther SA, et al. The clonal evolution of metastases from primary serous epithelial ovarian cancers. Int J Cancer. 2009;124(7):1579–86.

    PubMed  CAS  Google Scholar 

  97. Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, et al. Tumour evolution inferred by single-cell sequencing. Nature. 2011;472(7341):90–4. Epub 2011/03/15.

    PubMed  CAS  Google Scholar 

  98. Navin N, Krasnitz A, Rodgers L, Cook K, Meth J, Kendall J, et al. Inferring tumor progression from genomic heterogeneity. Genome Res. 2010;20(1):68–80.

    PubMed  CAS  PubMed Central  Google Scholar 

  99. Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009;461(7265):809–13.

    PubMed  CAS  Google Scholar 

  100. Wu X, Northcott PA, Dubuc A, Dupuy AJ, Shih DJ, Witt H, et al. Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature. 2012;482(7386):529–33. Epub 2012/02/22.

    PubMed  CAS  PubMed Central  Google Scholar 

  101. Vermaat JS, Nijman IJ, Koudijs MJ, Gerritse FL, Scherer SJ, Mokry M, et al. Primary colorectal cancers and their subsequent hepatic metastases are genetically different: implications for selection of patients for targeted treatment. Clin Cancer Res. 2012;18(3):688–99. Epub 2011/12/17.

    PubMed  CAS  Google Scholar 

  102. Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T, et al. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol. 2012;30(5):413–21. Epub 2012/05/01.

    PubMed  CAS  Google Scholar 

  103. Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;486(7403):395–9. Epub 2012/04/13.

    PubMed  CAS  Google Scholar 

  104. Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA, et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010;467(7319):1109–13. Epub 2010/10/29.

    PubMed  CAS  PubMed Central  Google Scholar 

  105. Choi S, Henderson MJ, Kwan E, Beesley AH, Sutton R, Bahar AY, et al. Relapse in children with acute lymphoblastic leukemia involving selection of a preexisting drug-resistant subclone. Blood. 2007;110(2):632–9.

    PubMed  CAS  Google Scholar 

  106. Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002;2(2):117–25.

    PubMed  CAS  Google Scholar 

  107. Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, Laï JL, Grardel-Duflos N, Philippe N, Facon T, Fenaux P, Preudhomme C. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood. 2002;100(3):1014–8.

    PubMed  CAS  Google Scholar 

  108. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–92. Epub 2012/03/09.

    PubMed  CAS  Google Scholar 

  109. Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004;305(5687):1163–7. Epub 2004/07/31.

    PubMed  CAS  Google Scholar 

  110. Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007;11(3):259–73.

    PubMed  CAS  Google Scholar 

  111. Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA, et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science. 2008;322(5906):1377–80.

    PubMed  CAS  PubMed Central  Google Scholar 

  112. Micci F, Haugom L, Ahlquist T, Abeler VM, Trope CG, Lothe RA, et al. Tumor spreading to the contralateral ovary in bilateral ovarian carcinoma is a late event in clonal evolution. J Oncol. 2010;2010:646340.

    PubMed  PubMed Central  Google Scholar 

  113. McAlpine JN, Eisenkop SM, Spirtos NM. Tumor heterogeneity in ovarian cancer as demonstrated by in vitro chemoresistance assays. Gynecol Oncol. 2008;110(3):360–4.

    PubMed  CAS  Google Scholar 

  114. Griffin N, Grant LA, Freeman SJ, Jimenez-Linan M, Berman LH, Earl H, et al. Image-guided biopsy in patients with suspected ovarian carcinoma: a safe and effective technique? Eur Radiol. 2009;19(1):230–5. Epub 2008/08/16.

    PubMed  Google Scholar 

  115. Spencer JA, Weston MJ, Saidi SA, Wilkinson N, Hall GD. Clinical utility of image-guided peritoneal and omental biopsy. Nat Rev Clin Oncol. 2010;7(11):623–31.

    PubMed  Google Scholar 

  116. Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 1977;37(3):646–50. Epub 1977/03/01.

    PubMed  CAS  Google Scholar 

  117. Kamat AA, Baldwin M, Urbauer D, Dang D, Han LY, Godwin A, et al. Plasma cell-free DNA in ovarian cancer: an independent prognostic biomarker. Cancer. 2010;116(8):1918–25. Epub 2010/02/19.

    PubMed  CAS  PubMed Central  Google Scholar 

  118. Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985–90. Epub 2008/08/02.

    PubMed  CAS  PubMed Central  Google Scholar 

  119. Leary RJ, Kinde I, Diehl F, Schmidt K, Clouser C, Duncan C, et al. Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med. 2010;2(20):20. Epub 2010/04/08.

    Google Scholar 

  120. Yung TK, Chan KC, Mok TS, Tong J, To KF, Lo YM. Single-molecule detection of epidermal growth factor receptor mutations in plasma by microfluidics digital PCR in non-small cell lung cancer patients. Clin Cancer Res. 2009;15(6):2076–84. Epub 2009/03/12.

    PubMed  CAS  Google Scholar 

  121. Chen Z, Feng J, Buzin CH, Liu Q, Weiss L, Kernstine K, et al. Analysis of cancer mutation signatures in blood by a novel ultra-sensitive assay: monitoring of therapy or recurrence in non-metastatic breast cancer. PLoS One. 2009;4(9):e7220. Epub 2009/10/01.

    PubMed  PubMed Central  Google Scholar 

  122. Poveda A, Kaye SB, McCormack R, Wang S, Parekh T, Ricci D, et al. Circulating tumor cells predict progression free survival and overall survival in patients with relapsed/recurrent advanced ovarian cancer. Gynecol Oncol. 2011;122(3):567–72. Epub 2011/06/15.

    PubMed  Google Scholar 

  123. Forshew T, Murtaza M, Parkinson C, Gale D, Tsui DW, Kaper F, et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med. 2012;4(136):136ra68. Epub 2012/06/01.

    PubMed  Google Scholar 

  124. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486(7404):532–6. Epub 2012/06/23.

    PubMed  CAS  PubMed Central  Google Scholar 

  125. Diaz Jr LA, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486(7404):537–40. Epub 2012/06/23.

    PubMed  CAS  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this chapter

Cite this chapter

Brenton, J.D. (2015). Genomic Applications in Epithelial Ovarian Malignancies. In: Netto, G., Schrijver, I. (eds) Genomic Applications in Pathology. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0727-4_28

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-0727-4_28

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4939-0726-7

  • Online ISBN: 978-1-4939-0727-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics