Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers

Abstract

Background: Pathogenic variants in homologous recombination repair (HRR) genes other than BRCA1/2 have been associated with a high risk of ovarian cancer (OC). In current clinical practice, genetic testing is generally limited to BRCA1/2. Herein, we investigated the mutational status of both BRCA1/2 and 5 HRR genes in 69 unselected OC, evaluating the advantage of multigene panel testing in everyday clinical practice. Methods: We analyzed 69 epithelial OC samples using an NGS custom multigene panel of the 5 HRR pathways genes, beyond the genetic screening routine of BRCA1/2 testing. Results: Overall, 19 pathogenic variants (27.5%) were detected. The majority (21.7%) of patients displayed a deleterious mutation in BRCA1/2, whereas 5.8% harbored a pathogenic variant in one of the HRR genes. Additionally, there were 14 (20.3%) uncertain significant variants (VUS). The assessment of germline mutational status showed that a small number of variants (five) were not detected in the corresponding blood sample. Notably, we detected one BRIP1 and four BRCA1/2 deleterious variants in the low-grade serous and endometrioid histology OC, respectively. Conclusion: We demonstrate that using a multigene panel beyond BRCA1/2 improves the diagnostic yield in OC testing, and it could produce clinically relevant results.

Tumor BRCA Testing in Epithelial Ovarian Cancers: Past and Future—Five-Years’ Single-Institution Experience of 762 Consecutive Patients

“…We confirmed the feasibility of tumor BRCA testing in the routine clinical setting, with a very low failure rate (less than 1%) and a turnaround time consistent with clinical need (median TAT less than two weeks), strengthening our previous results [ 21 ] and in line with the recently reported experience of other Italian groups [ 19 , 23 , 29 ]. However, both the studies of Marchetti [ 23 ] and Turchiano [ 29 ] were based on a fresh-frozen tissue approach, which was a very promising strategy to overcome the degradation and chemical modification of DNA resulting from formalin fixation and paraffin embedding, but it required framework and facilities (i.e., biobanking) not always available in hospitals. In the present study, according to the results presented by the Ligurian BRCA working group [ 19 ], we reported a workflow based on the analysis of FFPE specimens, available in every Pathology Division.…”

“…To date, methods for HRD detection are limited to genetic profiling of homologous recombination repair genes or genomic assays evaluating HRD-induced genomic scar, even if emerging evidence supports the evaluation of RAD51 foci formation [ 56 , 57 , 58 ]. As recently reported, an NGS profiling including HR genes ( BARD1 , BRIP1 , PALB2 , RAD51C , and RAD51D ) could improve the rate of tumor with HRD by 5–6%, identifying patients who may mostly benefit from PARPi therapy [ 29 ]. In our cohort, a comprehensive tumor profile including homologous recombination genes (i.e., ATM , PALB2 , RAD50 , RAD51 , RAD51B , RAD51C , RAD51D , …) was performed for 100 cases, finding pathogenic alterations in four tumor samples, as previously reported [ 59 ].…”

Molecular Management of High-Grade Serous Ovarian Carcinoma

“…Germline mutations in the BRCA1 and BRCA2 genes, present in 13-22% of HGSOC cases [184][185][186], are tightly correlated with the onset of OC, given their detection in patients who developed HG-SOC from precancerous FTE lesions [97]. Other reported germline mutations include RAD51, BRIP1, PALB2, CHEK2, MRE11A, RAD50, and ATM, which belong to the Fanconi anemia-BRCA pathway and play crucial roles in the HRR system for double-stranded DNA breaks [187][188][189][190]. Mutations affecting genes involved in HRR may also trigger HRR pathway deficiency (HRD), thereby increasing DNA errors, genomic instability, and the risk of HGSOC [82,191,192].…”

Insights into the Oncogenic, Prognostic, and Immunological Role of BRIP1 in Pan-Cancer: A Comprehensive Data-Mining-Based Study

“…Te National Comprehensive Cancer Network (NCCN) guidelines identifed BRIP1 as a potential risk factor for breast cancer, especially for triple negative breast cancers [5]. In ovarian cancer, a deleterious mutation of BRIP1 was associated with low-grade histology and led to an increased risk of the disease [6]. In endometrial cancer, BRIP1 correlated to tumor recurrence and patients with mutations in BRIP1 might beneft from poly ADP-ribose polymerase (PARP) inhibitors [7].…”