Oncopathological aspects of BRCA1 and BRCA2 genes inactivation in tumors of ovary, fallopian tube and pelvic peritoneum
Authors:
Petr Škapa 1; Pavel Dundr 2
Authors‘ workplace:
Ústav patologie a molekulární medicíny 2. LF UK a FN Motol, Praha
1; Ústav patologie 1. LF UK a VFN, Praha
2
Published in:
Čes.-slov. Patol., 52, 2016, No. 4, p. 199-204
Category:
Reviews Article
Overview
Ovarian carcinoma represents a heterogeneous group of malignant epithelial tumors which could be divided into two fundamental groups: Type I (endometrioid carcinoma, clear cell carcinoma, low grade serous carcinoma, mucinous carcinoma and more rare seromucinous carcinoma and malignant Brenner tumor) and type II (high grade serous carcinoma – HGSC). HGSC is the most frequent ovarian carcinoma which may be etiologically linked to inactivation of tumor suppressor genes BRCA1/2 and TP53 and differs from type I carcinomas by higher aggressiveness, tendency to peritoneal spread and worse prognosis. A precursor lesion of HGSC was described as a serous tubal intraepithelial carcinoma (STIC) which is usually localized in fimbria of the fallopian tube from where tumor cells are capable to implant on ovary and pelvic peritoneum. Therefore, HGSC may present itself not only as a tuboovarian tumor but also as a primary peritoneal carcinoma. HGSC constitutes a dominant group within hereditary ovarian carcinomas as a manifestation of hereditary breast and ovarian cancer or site-specific ovarian cancer syndromes which are associated with germinal mutations of BRCA1/2 genes. BRCA1 deficient HGSC show characteristic histological appearance which encompasses SET features (Solid-pseudoEndometrioid-Transitional), significant nuclear atypia and mitotic activity, geographic necrosis, marked lymphocytic infiltration and abnormalities in TP53 expression. Use of immunohistochemistry as a screening method for BRCA1/2 inactivation is questionable at this time. Bilateral adnexectomy is considered to be a standard prophylactic treatment of women affected by germinal BRCA1/2 mutation. In that case, fallopian tubes should be submitted completely for the histological evaluation according to the SEE-FIM protocol (Sectioning and Extensively Examining the FIMbria) due to the risk of STIC or occult HGSC. Tumors with BRCA1/2 inactivation show a better therapeutic response to platinum-based chemotherapeutic compounds and a more favorable prognosis. Inhibitors of poly(ADP-ribose) polymerase (PARP) are the next generation of antitumor agents comprising olaparib which is implemented in clinical practice currently. Germinal or somatic inactivation of BRCA1/2 serves as a predictor for targeted oncologic therapy by PARP inhibitors, therefore evaluation of these genes in ovarian carcinoma patients will be carried out by departments of pathology and clinical genetics. Next generation sequencing seems to be an ideal method for the reduction of the time factor and optimization of BRCA1/2 analysis. Unfortunately, a routine test for the evaluation of homologous recombination functionality and detection of “BRCAness” in sporadic tumors is still not available.
Keywords:
BRCA1 – BRCA2 – hereditary breast and ovarian cancer syndrome – high grade serous carcinoma – SEE-FIM protocol – PARP inhibitors
Sources
1. Prat J. Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features. Virchows Arch 2012; 460: 237-249.
2. Shih Ie M, Kurman RJ. Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol 2004; 164: 1511-1518.
3. McCluggage WG. Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis. Pathology 2011; 43: 420-432.
4. Kurman RJ, Shih Ie M. The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am J Pathol 2016; 186: 733-747.
5. Shaw PA. Hereditary carcinomas of the ovary, fallopian tube, and peritoneum. Surg Pathol Clin 2011; 4: 461-478.
6. Boyd J. Specific keynote: hereditary ovarian cancer: what we know. Gynecol Oncol 2003; 88: S8-10; discussion S11-13.
7. Prat J, Ribe A, Gallardo A. Hereditary ovarian cancer. Hum Pathol 2005; 36: 861-870.
8. Risch HA, McLaughlin JR, Cole DE, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 2001; 68: 700-710.
9. Shaw PA, McLaughlin JR, Zweemer RP, et al. Histopathologic features of genetically determined ovarian cancer. Int J Gynecol Pathol 2002; 21: 407-411.
10. Werness BA, Ramus SJ, Whittemore AS, et al. Histopathology of familial ovarian tumors in women from families with and without germline BRCA1 mutations. Hum Pathol 2000; 31: 1420-1424.
11. Lynch HT, Casey MJ, Snyder CL, et al. Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management. Mol Oncol 2009; 3: 97-137.
12. Soslow RA, Han G, Park KJ, et al. Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma. Mod Pathol 2012; 25: 625-636.
13. Schrader KA, Hurlburt J, Kalloger SE, et al. Germline BRCA1 and BRCA2 mutations in ovarian cancer: utility of a histology-based referral strategy. Obstet Gynecol 2012; 120: 235-240.
14. Press JZ, De Luca A, Boyd N, et al. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer 2008; 8: 17.
15. Husain A, He G, Venkatraman ES, Spriggs DR. BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II). Cancer Res 1998; 58: 1120-1123.
16. McAlpine JN, Porter H, Kobel M, et al. BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma. Mod Pathol 2012; 25: 740-750.
17. Seidman JD, Beil DA, Crum CP, et al. Serous tumours. In: Kurman RJ, Carcangiu ML, Herrington CS, Young RH, eds. WHO classification of tumours of female reproductive organs. Lyon, PA: IARC; 2014: 15-24.
18. Lim D, Murali R, Murray MP, Veras E, Park KJ, Soslow RA. Morphological and immunohistochemical reevaluation of tumors initially diagnosed as ovarian endometrioid carcinoma with emphasis on high-grade tumors. Am J Surg Pathol 2016; 40: 302-312.
19. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10: 942-949.
20. Clarke B, Tinker AV, Lee CH, et al. Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss. Mod Pathol 2009; 22: 393-402.
21. Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 2005; 102: 18538-18543.
22. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006; 354: 34-43.
23. Kwa M, Muggia F. Ovarian cancer: a brief historical overview of intraperitoneal trials. Ann Surg Oncol 2014; 21: 1429-1434.
24. Kwa M, Edwards S, Downey A, et al. Ovarian cancer in BRCA mutation carriers: improved outcome after intraperitoneal (IP) cisplatin. Ann Surg Oncol 2014; 21: 1468-1473.
25. Kim SH, Park WS, Yun SI, et al. Overexpression of BRCA1 or BRCA2 in prostatectomy specimens is predictive of biochemical recurrence after radical prostatectomy. Histopathology 2016; 68: 673-679.
26. Garg K, Levine DA, Olvera N, et al. BRCA1 immunohistochemistry in a molecularly characterized cohort of ovarian high-grade serous carcinomas. Am J Surg Pathol 2013; 37: 138-146.
27. Carser JE, Quinn JE, Michie CO, et al. BRCA1 is both a prognostic and predictive biomarker of response to chemotherapy in sporadic epithelial ovarian cancer. Gynecol Oncol 2011; 123: 492-498.
28. Radosa MP, Hafner N, Camara O, et al. Loss of BRCA1 protein expression as indicator of the BRCAness phenotype is associated with favorable overall survival after complete resection of sporadic ovarian cancer. Int J Gynecol Cancer 2011; 21: 1399-1406.
29. Foretová L, Macháčková E, Palacová M, Navrátilová M, Svoboda M, Petráková K. Doporučení rozšíření indikačních kriterií ke genetickému testování mutací v genech BRCA1 a BRCA2 u hereditárního syndromu nádorů prsu a ovarií. Klin Onkol 2016; 29 Suppl 1: S9-13.
30. Wang Y, Li L, Wang Y, Tang SN, Zheng W. Fallopian tube secretory cell expansion: a sensitive biomarker for ovarian serous carcinogenesis. Am J Transl Res 2016; 8: 230-238.
31. Zikán M. Gynekologická prevence a gynekologické aspekty péče u nosiček mutací genů BRCA1 a BRCA2. Klin Onkol 2016; 29 Suppl 1: S22-30.
32. Chang PS, Crum CP. The fallopian tube and broad ligament. In: Crum CP, Lee KR, eds. Diagnostic gynecologic and obstetric pathology. Philadelphia, PA: WB Saunders; 2006: 675-712.
33. Mingels MJ, van Ham MA, de Kievit IM, et al. Mullerian precursor lesions in serous ovarian cancer patients: using the SEE-Fim and SEE-End protocol. Mod Pathol 2014; 27: 1002-1013.
34. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361: 123-134.
35. Meehan RS, Chen AP. New treatment option for ovarian cancer: PARP inhibitors. Gynecol Oncol Res Pract 2016; 3: 3.
36. Bixel K, Hays JL. Olaparib in the management of ovarian cancer. Pharmgenomics Pers Med 2015; 8: 127-135.
37. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33: 244-250.
38. Kim G, Ison G, McKee AE, et al. FDA approval summary: Olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res 2015; 21: 4257-4261.
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Anatomical pathology Forensic medical examiner ToxicologyArticle was published in
Czecho-Slovak Pathology
2016 Issue 4
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