Frequency of Mutations and Polymorphisms in Borderline Ovarian Tumors of Known Cancer Genes

Overview

Journal Mod Pathol

Specialty Pathology

Date 2012 Nov 24

PMID 23174937

Citations 11

Authors

Katherine Stemke-Hale

Kristy Shipman

Isidora Kitsou-Mylona

David G de Castro

Vicky Hird

Robert Brown

James Flanagan

Hani Gabra

Gordon B Mills

Roshan Agarwal

Mona El-Bahrawy

Affiliations

Soon will be listed here.

Abstract

Borderline ovarian tumors represent an understudied subset of ovarian tumors. Most studies investigating aberrations in borderline tumors have focused on KRAS/BRAF mutations. In this study, we conducted an extensive analysis of mutations and single-nucleotide polymorphisms (SNPs) in borderline ovarian tumors. Using the Sequenom MassArray platform, we investigated 160 mutations/polymorphisms in 33 genes involved in cell signaling, apoptosis, angiogenesis, cell cycle regulation and cellular senescence. Of 52 tumors analyzed, 33 were serous, 18 mucinous and 1 endometrioid. KRAS c.35G>A p.Gly12Asp mutations were detected in eight tumors (six serous and two mucinous), BRAF V600E mutations in two serous tumors, and PIK3CA H1047Y and PIK3CA E542K mutations in a serous and an endometrioid BOT, respectively. CTNNB1 mutation was detected in a serous tumor. Potentially functional polymorphisms were found in vascular endothelial growth factor (VEGF), ABCB1, FGFR2 and PHLPP2. VEGF polymorphisms were the most common and detected at four loci. PHLPP2 polymorphisms were more frequent in mucinous as compared with serous tumors (P=0.04), with allelic imbalance in one case. This study represents the largest and most comprehensive analysis of mutations and functional SNPs in borderline ovarian tumors to date. At least 25% of borderline ovarian tumors harbor somatic mutations associated with potential response to targeted therapeutics.

Citing Articles

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References

Morice P, Uzan C, Fauvet R, Gouy S, Duvillard P, Darai E . Borderline ovarian tumour: pathological diagnostic dilemma and risk factors for invasive or lethal recurrence. Lancet Oncol. 2012; 13(3):e103-15. DOI: 10.1016/S1470-2045(11)70288-1. View

Oliva E, Sarrio D, Brachtel E, Sanchez-Estevez C, Soslow R, Moreno-Bueno G . High frequency of beta-catenin mutations in borderline endometrioid tumours of the ovary. J Pathol. 2006; 208(5):708-13. DOI: 10.1002/path.1923. View

Wong H, Low J, Chua Y, Busmanis I, Tay E, Ho T . Ovarian tumors of borderline malignancy: a review of 247 patients from 1991 to 2004. Int J Gynecol Cancer. 2007; 17(2):342-9. DOI: 10.1111/j.1525-1438.2007.00864.x. View

Brognard J, Niederst M, Reyes G, Warfel N, Newton A . Common polymorphism in the phosphatase PHLPP2 results in reduced regulation of Akt and protein kinase C. J Biol Chem. 2009; 284(22):15215-23. PMC: 2685702. DOI: 10.1074/jbc.M901468200. View

Mayr D, Kanitz V, Amann G, Engel J, Burges A, Lohrs U . HER-2/neu gene amplification in ovarian tumours: a comprehensive immunohistochemical and FISH analysis on tissue microarrays. Histopathology. 2006; 48(2):149-56. DOI: 10.1111/j.1365-2559.2005.02306.x. View

Gao T, Brognard J, Newton A . The phosphatase PHLPP controls the cellular levels of protein kinase C. J Biol Chem. 2007; 283(10):6300-11. DOI: 10.1074/jbc.M707319200. View

Diebold J, Seemuller F, Lohrs U . K-RAS mutations in ovarian and extraovarian lesions of serous tumors of borderline malignancy. Lab Invest. 2003; 83(2):251-8. DOI: 10.1097/01.lab.0000056994.81259.32. View

Kennedy A, HART W . Ovarian papillary serous tumors of low malignant potential (serous borderline tumors). A long-term follow-up study, including patients with microinvasion, lymph node metastasis, and transformation to invasive serous carcinoma. Cancer. 1996; 78(2):278-86. DOI: 10.1002/(SICI)1097-0142(19960715)78:2<278::AID-CNCR14>3.0.CO;2-T. View

McKenney J, Balzer B, Longacre T . Patterns of stromal invasion in ovarian serous tumors of low malignant potential (borderline tumors): a reevaluation of the concept of stromal microinvasion. Am J Surg Pathol. 2006; 30(10):1209-21. DOI: 10.1097/01.pas.0000213299.11649.fa. View

10.

Seidman J, Kurman R . Ovarian serous borderline tumors: a critical review of the literature with emphasis on prognostic indicators. Hum Pathol. 2000; 31(5):539-57. DOI: 10.1053/hp.2000.8048. View

11.

Mok S, Bell D, Knapp R, Fishbaugh P, Welch W, Muto M . Mutation of K-ras protooncogene in human ovarian epithelial tumors of borderline malignancy. Cancer Res. 1993; 53(7):1489-92. View

12.

Bellacosa A, De Feo D, Godwin A, BELL D, Cheng J, Altomare D . Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer. 1995; 64(4):280-5. DOI: 10.1002/ijc.2910640412. View

13.

Cuatrecasas M, Erill N, Musulen E, Costa I, Matias-Guiu X, Prat J . K-ras mutations in nonmucinous ovarian epithelial tumors: a molecular analysis and clinicopathologic study of 144 patients. Cancer. 1998; 82(6):1088-95. View

14.

Kupryjanczyk J, Bell D, Dimeo D, Beauchamp R, Thor A, Yandell D . p53 gene analysis of ovarian borderline tumors and stage I carcinomas. Hum Pathol. 1995; 26(4):387-92. DOI: 10.1016/0046-8177(95)90138-8. View

15.

Jurinke C, Denissenko M, Oeth P, Ehrich M, Van Den Boom D, Cantor C . A single nucleotide polymorphism based approach for the identification and characterization of gene expression modulation using MassARRAY. Mutat Res. 2005; 573(1-2):83-95. DOI: 10.1016/j.mrfmmm.2005.01.007. View

16.

Catasus L, Gallardo A, Cuatrecasas M, Prat J . PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters. Mod Pathol. 2007; 21(2):131-9. DOI: 10.1038/modpathol.3800992. View

17.

Lakhani S, Manek S, Penault-Llorca F, Flanagan A, Arnout L, Merrett S . Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin Cancer Res. 2004; 10(7):2473-81. DOI: 10.1158/1078-0432.ccr-1029-3. View

18.

Schultheis A, Lurje G, Rhodes K, Zhang W, Yang D, Garcia A . Polymorphisms and clinical outcome in recurrent ovarian cancer treated with cyclophosphamide and bevacizumab. Clin Cancer Res. 2008; 14(22):7554-63. PMC: 2586993. DOI: 10.1158/1078-0432.CCR-08-0351. View

19.

Ho C, Kurman R, Dehari R, Wang T, Shih I . Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors. Cancer Res. 2004; 64(19):6915-8. DOI: 10.1158/0008-5472.CAN-04-2067. View

20.

Sieben N, Macropoulos P, Roemen G, Kolkman-Uljee S, Fleuren G, Houmadi R . In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours. J Pathol. 2004; 202(3):336-40. DOI: 10.1002/path.1521. View