Current guidelines for referral to the British Columbia Cancer Agency Hereditary Cancer Program include the criterion of offering genetic counseling and testing to individuals with nonmucinous ovarian cancer diagnosed at any age. The importance of this criterion is evident, as even with a comprehensive family history obtained by a genetic counselor, germline BRCA1 and BRCA2 mutation carriers with high-grade serous histology and without a personal or family history suggestive of hereditary breast and ovarian cancer would not be identified. By showing the number of germline BRCA1 and BRCA2 mutation carriers with high-grade serous epithelial ovarian carcinoma meeting only the criterion of ovarian cancer in the proband, Figure 2 outlines which cases would be captured by family histories (by a genetic counselor or nongenetic counselor) as compared with histology-driven referral. Figure 2A–B shows the difference between family history ascertained by the gynecologic oncology surgeon (denoted as nongenetic counselor) and the genetic counselor. If the first family history was taken by another health care provider other than the gynecologic surgeon (eg, general practitioner), this was also recorded as a nongenetic counselor. Restricting BRCA1 and BRCA2 testing to women with family histories of hereditary breast and ovarian cancer, as ascertained by the surgeon, missed 14 mutation carriers, lowering detection rates to 9% (12/131) or 11.6% (12/103) if only considering the patients with high-grade serous histology. This improved to 16% (21/131) or 20.4% (21/103) when ascertained by the genetic counselor. Therefore, on reviewing the histories as obtained by the nongenetic counselor compared with those ascertained by the genetic counselor, it was apparent that 35% (9/26, 95% CI 17–56%) of BRCA1 and BRCA2 mutation carriers with high-grade serous epithelial ovarian carcinoma would have been missed if referrals for testing had only been based on having a family history suggestive of hereditary breast and ovarian cancer (Fig. 2). Even with the more extensive history obtained by a genetic counselor, 19% (5/26, 95% CI 6–39%) of mutation carriers did not meet the familial component of hereditary breast and ovarian cancer criteria and before the inclusion of the criterion addressing singleton cases of nonmucinous epithelial ovarian carcinoma in the proband would not have been offered testing. Capture of these probands was secondary to our research study protocol in which counseling and testing was offered to all patients and what was an emerging practice change to consider referral for all nonmucinous ovarian carcinomas. If considering only cases with high-grade serous epithelial ovarian carcinoma and without a family history of hereditary breast and ovarian cancer, 12% of women (5/42, 95% CI 4–26%) were germline BRCA1 and BRCA2 mutation carriers. Furthermore, the number of mutation-positive women without an apparent family history increased to 14 individuals when the family history was taken by a nongenetic counselor. The average age of ovarian cancer diagnoses in women with high-grade serous epithelial ovarian carcinoma who did not have a family history of hereditary breast and ovarian cancer was 47.4 years in mutation-positive cases (ranging from 42 to 54 years) and 62 years in mutation-negative cases (ranging from 37 to 84 years). This difference was significant when compared using a Mann-Whitney U test (P=.003). Of the two mutation carriers that harbored the recurrent c.185 delAG mutation, only one was reported to be of Ashkenazi Jewish descent. Two unrelated individuals carried exon 13 duplications.
1. Gilks CB, Prat J. Ovarian carcinoma pathology and genetics: recent advances. Hum Pathol 2009;40:1213–23.
2. Kobel 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:e232.
3. Kalloger SE, Kobel M, Leung S, Mehl E, Gao D, Marcon KM, et al.. Calculator for ovarian carcinoma subtype prediction. Mod Pathol 2011;24:512–21.
4. Gilks CB. Molecular abnormalities in ovarian cancer subtypes other than high-grade serous carcinoma. J Oncol 2010;2010:740968.
5. Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, 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;68:700–10.
6. Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, et al.. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: A kin-cohort study in Ontario, Canada. J Natl Cancer Inst 2006;98:1694–706.
7. Pal T, Permuth-Wey J, Betts JA, Krischer JP, Fiorica J, Arango H, et al.. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer 2005;104:2807–16.
8. Pharoah PD, Easton DF, Stockton DL, Gayther S, Ponder BA. Survival in familial, BRCA1-associated, and BRCA2-associated epithelial ovarian cancer. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group. Cancer Res 1999;59:868–71.
9. Werness BA, Ramus SJ, DiCioccio RA, Whittemore AS, Garlinghouse-Jones K, Oakley-Girvan I, et al.. Histopathology, FIGO stage, and BRCA mutation status of ovarian cancers from the Gilda Radner Familial Ovarian Cancer Registry. Int J Gynecol Pathol 2004;23:29–34.
10. Lakhani SR, Manek S, Penault-Llorca F, Flanagan A, Arnout L, Merrett S, et al.. Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin Cancer Res 2004;10:2473–81.
11. Zhang S, Royer R, Li S, McLaughlin JR, Rosen B, Risch HA, et al.. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol 2011;121:353–7.
12. Alsop K, Fereday S, Meldrum C, deFazio A, Webb P, Birrer MJ, et al.. Germ-line BRCA mutations in high-grade ovarian cancer: a case for routine BRCA mutation screening after a diagnosis of invasive ovarian cancer. J Clin Oncol 2011;29(Suppl):5026.
13. Press JZ, De Luca A, Boyd N, Young S, Troussard A, Ridge Y, et al.. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer 2008;8:17.
14. McAlpine JN, Porter H, Kobel M, Nelson BH, Prentice LM, Kalloger SE, et al.. BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian HGS carcinoma. Mod Pathol 2012;25:740–50.
15. Hennessy BT, Timms KM, Carey MS, Gutin A, Meyer LA, Flake DD 2nd, 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;28:3570–6.
16. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609–15.
17. Arnold AG, Bhatia J, Phillips MF, Gardner GJ, Bell-McGuinn KM, Aghajanian C, et al.. Feasibility and yield of offering genetic counseling to all patients with newly diagnosed high-grade epithelial ovarian cancer. J Clin Oncol 2011;29(Suppl):1509.
18. Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, et al.. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A 2011;108:18032–7.
19. Gilks CB, Ionescu DN, Kalloger SE, Kobel 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;39:1239–51.
20. Kobel 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;34:984–93.
22. Hereditary breast and ovarian cancer syndrome. Practice Bulletin No. 103. American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;113:957–66.