Somatic mutations in BRCA1&2 in 201 unselected ovarian carcinoma samples – single institution study

Abstract

Ovarian cancer (OC) is the most lethal among gynecologic malignancies worldwide. Unfortunately, in around 70% of cases cancer is diagnosed in late stages (III-IV) which decreases the 5-year survival rate to 25%. The standard of care in ovarian cancer is debulking surgery followed by chemotherapy regimens based on platinum salts. Since 2014 PARP inhibitors became available for OC patients with germline or/and somatic mutations in BRCA1/2, including maintenance therapy. BRCA1/2 Next Generation Sequencing (NGS)-based analysis of formalin-fixed paraffin-embedded (FFPE) ovarian cancer samples becomes the standard of care. The aim of the present study was to evaluate the frequency of mutations in 201 unselected ovarian cancer tissues using the NGS method. In total, pathogenic mutations in both genes were detected in 24% (49/201) of the ovarian cancer cases tested. For 41 patients the results of testing of DNA isolated from blood sample revealed that 17% (35/201) mutations were germline origin, whereas 3% (6/201) mutations were somatic. In 4% (8/201) cases blood sample was inaccessible. The presence of pathogenic mutations was correlated with younger age at diagnosis and serous subtype. Close cooperation between many specialists (gynecologist, pathologist, oncologist, clinical genetics and molecular biologist) is indispensable for efficient and on-time BRCA1/2 ovarian tumor tissue testing.

Tumor and germline next generation sequencing in high grade serous cancer: experience from a large population‐based testing program

“…The overall prevalence of BRCA1/2 PV in 570 HGSC tumor samples was 16%. While consistent with the 17% reported in a recently published large cohort, [14] it is somewhat lower than the 24–30% reported by others [15,18,31,32]. This is potentially a reflection of the large‐scale, population‐based testing approach represented in our study compared with small, controlled research‐based settings.…”

“…[7,10,11] However, the introduction of PARPi in the treatment of HGSC is rapidly changing the landscape of BRCA1/2 testing. While the prevalence of germline BRCA1/2 PV is reported to be 10-20% in women with HGSC [12,13], BRCA1/2 PVs are identified in 15-30% of tumor samples [14][15][16][17][18][19]. The difference, representing individuals with somatic variants present only in tumor tissue, accounts for an important cohort of patients who could benefit from PARPi therapy, but who would not be identified by germline testing alone.…”

Year 1: Experiences of a tertiary cancer centre following implementation of reflex BRCA1 and BRCA2 tumor testing for all high-grade serous ovarian cancers in a universal healthcare system

“…When tumor testing is completed, follow-up genetic counseling and germline testing of patients with identified PVs is critical to clarify whether family members may be at risk. This is particularly important for HGSOC, as 57-85% of BRCA1/2 PVs identified in tumor tissues are germline in origin [25,[33][34][35]. In this study, 94% (16/17) of HGSOC patients with a BRCA1/2 PV in their tumor were referred for genetic counseling, all of whom provided a blood sample for germline testing.…”

BRCA1/2 Mutation Detection in the Tumor Tissue from Selected Polish Patients with Breast Cancer Using Next Generation Sequencing

“…In the present study, we identified one somatic variant in a tissue with 35% of tumor cells (Table 3), which is slightly lower but still in concordance with the data of other groups. Kowalik et al reported that the lowest percentage of tumor cells with detectable pathogenic variants was 40% in ovarian cancer tissue samples [51], while Ellison et al suggested that the starting material should contain at least 10% of tumor cells in order to detect low-frequency somatic variants [52].…”