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KRAS mutation in primary ovarian serous borderline tumors correlates with tumor recurrence

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Abstract

Oncogenic activation of the mitogen-activated protein kinase (MAPK) pathway due to KRAS or BRAF gain-of-function mutation is frequently found in ovarian serous borderline tumor (SBT) and their extraovarian implants. We investigated mutational status of KRAS and BRAF of the primary ovarian SBTs that had a high stage presentation in correlation with clinical outcome. Among 39 consecutive primary SBTs with either invasive implants (20 cases) or non-invasive implants (19 cases), KRAS and BRAF mutational analysis was informative in 34 cases. Sixteen cases (47%) harbored a KRAS mutation, while 5 cases (15%) had a BRAF V600E mutation. High-stage disease (IIIC) was seen in 31% (5/16) of patients with a KRAS mutation and 39% (7/18) of patients without a KRAS mutation (p = 0.64). KRAS mutations were present in 9/16 (56%) tumors with invasive implants/LGSC versus 7/18 (39%) tumors with non-invasive implants (p = 0.31). BRAF mutation was seen in 5 cases with non-invasive implants. Tumor recurrence was seen in 31% (5/16) of patients with a KRAS mutation, compared to 6% (1/18) of patients without a KRAS mutation (p = 0.04). A KRAS mutation predicted an adverse disease-free survival (31% survival at 160 months) compared to those with wild-type KRAS (94% at 160 months; log-rank test, p = 0.037; HR 4.47). In conclusion, KRAS mutation in primary ovarian SBTs is significantly associated with a worse disease-free survival, independent of the high tumor stage or histological subtypes of extraovarian implant. KRAS mutation testing of primary ovarian SBT may servce as a useful biomarker for tumor recurrence.

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References

  1. Bell KA, Smith Sehdev AE, Kurman RJ (2001) Refined diagnostic criteria for implants associated with ovarian atypical proliferative serous tumors (borderline) and micropapillary serous carcinomas. Am J Surg Pathol 25:419–432

    Article  CAS  PubMed  Google Scholar 

  2. Ahn G, Folkins AK, McKenney JK et al (2016) Low-grade serous carcinoma of the ovary: clinicopathologic analysis of 52 invasive cases and identification of a possible noninvasive intermediate lesion. Am J Surg Pathol 40:1165–1176

    Article  PubMed  Google Scholar 

  3. Ayhan A, Guvendag Guven ES, Guven S et al (2005) Recurrence and prognostic factors in borderline ovarian tumors. Gynecol Oncol 98:439–445

    Article  PubMed  Google Scholar 

  4. Park JY, Kim DY, Kim JH et al (2009) Surgical management of borderline ovarian tumors: the role of fertility-sparing surgery. Gynecol Oncol 113:75–82

    Article  PubMed  Google Scholar 

  5. Hannibal CG, Vang R, Junge J et al (2014) A nationwide study of serous “borderline” ovarian tumors in Denmark 1978–2002: centralized pathology review and overall survival compared with the general population. Gynecol Oncol 134:267–273

    Article  PubMed  PubMed Central  Google Scholar 

  6. Longacre TA, McKenney JK, Tazelaar HD et al (2005) Ovarian serous tumors of low malignant potential (borderline tumors): outcome-based study of 276 patients with long-term (> or =5-year) follow-up. Am J Surg Pathol 29:707–723

    Article  PubMed  Google Scholar 

  7. Vang R, Hannibal CG, Junge J et al (2017) Long-term behavior of serous borderline tumors subdivided into atypical proliferative tumors and noninvasive low-grade carcinomas: a population-based clinicopathologic study of 942 cases. Am J Surg Pathol 41:725–737

    Article  PubMed  PubMed Central  Google Scholar 

  8. McKenney JK, Balzer BL, Longacre TA (2006) Lymph node involvement in ovarian serous tumors of low malignant potential (borderline tumors): pathology, prognosis, and proposed classification. Am J Surg Pathol 30:614–624

    Article  PubMed  Google Scholar 

  9. Seidman JD, Kurman RJ (2000) Ovarian serous borderline tumors: a critical review of the literature with emphasis on prognostic indicators. Hum Pathol 31:539–557

    Article  CAS  PubMed  Google Scholar 

  10. Prat J, De Nictolis M (2002) Serous borderline tumors of the ovary: a long-term follow-up study of 137 cases, including 18 with a micropapillary pattern and 20 with microinvasion. Am J Surg Pathol 26:1111–1128

    Article  PubMed  Google Scholar 

  11. Bell DA, Longacre TA, Prat J et al (2004) Serous borderline (low malignant potential, atypical proliferative) ovarian tumors: workshop perspectives. Hum Pathol 35:934–948

    Article  PubMed  Google Scholar 

  12. Hannibal CG, Vang R, Junge J et al (2017) A nationwide study of ovarian serous borderline tumors in Denmark 1978–2002. Risk of recurrence, and development of ovarian serous carcinoma. Gynecol Oncol 144:174–180

    Article  PubMed  Google Scholar 

  13. Chui MH, Xing D, Zeppernick F et al (2019) Clinicopathologic and molecular features of paired cases of metachronous ovarian serous borderline tumor and subsequent serous carcinoma. Am J Surg Pathol 43:1462–1472

    Article  PubMed  PubMed Central  Google Scholar 

  14. Singer G, Oldt R 3rd, Cohen Y et al (2003) Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 95:484–486

    Article  CAS  PubMed  Google Scholar 

  15. Ho CL, Kurman RJ, Dehari R et al (2004) Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors. Cancer Res 64:6915–6918

    Article  CAS  PubMed  Google Scholar 

  16. Jones S, Wang TL, Kurman RJ et al (2012) Low-grade serous carcinomas of the ovary contain very few point mutations. J Pathol 226:413–420

    Article  CAS  PubMed  Google Scholar 

  17. Hunter SM, Anglesio MS, Ryland GL et al (2015) Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes. Oncotarget 6:37663–37677

    Article  PubMed  PubMed Central  Google Scholar 

  18. Krzystyniak J, Ceppi L, Dizon DS et al (2016) Epithelial ovarian cancer: the molecular genetics of epithelial ovarian cancer. Ann Oncol 27(Suppl 1):i4–i10

    Article  PubMed  PubMed Central  Google Scholar 

  19. Anglesio MS, Arnold JM, George J et al (2008) Mutation of ERBB2 provides a novel alternative mechanism for the ubiquitous activation of RAS-MAPK in ovarian serous low malignant potential tumors. Mol Cancer Res 6:1678–1690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Xing D, Suryo Rahmanto Y, Zeppernick F et al (2017) Mutation of NRAS is a rare genetic event in ovarian low-grade serous carcinoma. Hum Pathol 68:87–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zuo T, Wong S, Buza N et al (2018) KRAS mutation of extraovarian implants of serous borderline tumor: prognostic indicator for adverse clinical outcome. Mod Pathol 31:350–357

    Article  CAS  PubMed  Google Scholar 

  22. Chui MH, Kjaer SK, Frederiksen K et al (2019) BRAF(V600E) -mutated ovarian serous borderline tumors are at relatively low risk for progression to serous carcinoma. Oncotarget 10:6870–6878

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tsang YT, Deavers MT, Sun CC et al (2013) KRAS (but not BRAF) mutations in ovarian serous borderline tumour are associated with recurrent low-grade serous carcinoma. J Pathol 231:449–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. WHO (2020) Classification of Tumours 5th Edition - Female Genital Tumours. (IARC Press, Lyon, France

  25. Zhong H, Liu Y, Talmor M et al (2013) Deparaffinization and lysis by hydrothermal pressure (pressure cooking) coupled with chaotropic salt column purification: a rapid and efficient method of DNA extraction from formalin-fixed paraffin-embedded tissue. Diagn Mol Pathol 22:52–58

    Article  CAS  PubMed  Google Scholar 

  26. Dillon DA, Johnson CC, Topazian MD et al (2000) The utility of Ki-ras mutation analysis in the cytologic diagnosis of pancreatobiliary neoplasma. Cancer J 6:294–301

    CAS  PubMed  Google Scholar 

  27. Metzker ML (2005) Emerging technologies in DNA sequencing. Genome Res 15:1767–1776

    Article  CAS  PubMed  Google Scholar 

  28. Mayr D, Hirschmann A, Löhrs U et al (2006) KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants. Gynecol Oncol 103:883–887

    Article  CAS  PubMed  Google Scholar 

  29. Ardighieri L, Zeppernick F, Hannibal CG et al (2014) Mutational analysis of BRAF and KRAS in ovarian serous borderline (atypical proliferative) tumours and associated peritoneal implants. J Pathol 232:16–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gershenson DM, Sun CC, Westin SN et al (2022) The genomic landscape of low-grade serous ovarian/peritoneal carcinoma and its impact on clinical outcomes. Gynecol Oncol 165:560–567

    Article  CAS  PubMed  Google Scholar 

  31. Malpica A, Wong KK (2016) The molecular pathology of ovarian serous borderline tumors. Ann Oncol 27(Suppl 1):i16–i19

    Article  PubMed  PubMed Central  Google Scholar 

  32. Silva EG, Tornos C, Zhuang Z et al (1998) Tumor recurrence in stage I ovarian serous neoplasms of low malignant potential. Int J Gynecol Pathol 17:1–6

    Article  CAS  PubMed  Google Scholar 

  33. Grisham RN, Iyer G, Garg K et al (2013) BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer. Cancer 119:548–554

    Article  CAS  PubMed  Google Scholar 

  34. Wong KK, Tsang YT, Deavers MT et al (2010) BRAF mutation is rare in advanced-stage low-grade ovarian serous carcinomas. Am J Pathol 177:1611–1617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zeppernick F, Ardighieri L, Hannibal CG et al (2014) BRAF mutation is associated with a specific cell type with features suggestive of senescence in ovarian serous borderline (atypical proliferative) tumors. Am J Surg Pathol 38:1603–1611

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA

    Austin McHenry, Natalia Buza & Pei Hui

  2. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    Douglas A. Rottmann

Authors
  1. Austin McHenry
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  2. Douglas A. Rottmann
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  3. Natalia Buza
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  4. Pei Hui
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Contributions

Dr. Austin McHenry conducted study case selection, data collection and analysis, and drafted the manuscript. Dr. Douglas Rottmann conducted initial study case selection and data collection. Dr. Natalia Buza conducted study data review and contributed to the writing of the manuscript. Dr. Pei Hui designed the study, conducted data review and analysis, and finilized the manucirpt.

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Correspondence to Pei Hui.

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McHenry, A., Rottmann, D.A., Buza, N. et al. KRAS mutation in primary ovarian serous borderline tumors correlates with tumor recurrence. Virchows Arch 483, 71–79 (2023). https://doi.org/10.1007/s00428-023-03564-z

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  • DOI: https://doi.org/10.1007/s00428-023-03564-z

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