Department of Woman, Child and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
Molecular and Genomic Diagnostics Laboratory, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
Gynecol Oncol. 2020 Sep;158(3):740-746. doi: 10.1016/j.ygyno.2020.06.479. Epub 2020 Jun 15.
For many years, BRCA mutational status has only been considered as a predictor of ovarian cancer susceptibility and as a prognostic factor. Nonetheless, in the era of precision medicine, it has also become a predictive biomarker of response to platinum-based-chemotherapy and, more recently, to PARP-inhibitors, also in the frontline setting. We assessed the feasibility of a fresh frozen tissue-based-BRCA-screening workflow in a tertiary referral center.
We consecutively enrolled a series of 456 newly diagnosed FIGO-Stage IIIC-IV, high grade serous-ovarian cancer patients. All patients receiving tumor-biopsy underwent tBRCA-testing.
Clinically relevant tissue-BRCA (tBRCA) variants were observed in 145 women (31.8%), particularly we recognized 89 (61.4%) patients with BRCA1-pathogenetic variants (PVs) and 56 women (38.6%) with BRCA2-PVs. Among 292 tBRCA wild-type (wt) patients, 88 cases were germline BRCA tested (gBRCA) and 86 (97.8%) were confirmed as gBRCAwt, while 1 (1.1%) had gBRCA variant of uncertain significance and 1 had gBRCA mutation (1.1%). The concordance of tumor test versus germline BRCA test was 86.3% (209/242). Large genomic rearrangements (LGRs) were suspected in 13/292 tBRCAwt patients (4.5%) by using bioinformatic algorithm and multiplex ligation-dependent probe amplification (MLPA) was performed, with evidence of PVs in only 1 case.
Fresh-frozen tissue-based BRCA screening workflow is feasible and reliable. It allows to enlarge the BRCA mutated population that might receive PARPi with the greatest benefit, without missing cascade testing for family members and therefore, maintaining its preventive role.
多年来，BRCA 突变状态仅被认为是卵巢癌易感性的预测因子和预后因素。然而，在精准医学时代，它也成为了铂类化疗和最近 PARP 抑制剂反应的预测生物标志物，也可用于一线治疗。我们评估了在三级转诊中心进行基于新鲜冷冻组织的 BRCA 筛查工作流程的可行性。
我们连续入组了 456 例新诊断的 IIIC-IV 期，高级别浆液性卵巢癌患者。所有接受肿瘤活检的患者均进行 tBRCA 检测。
在 145 名女性（31.8%）中观察到临床相关的组织 BRCA（tBRCA）变异，特别是我们发现 89 名（61.4%）患者存在 BRCA1 致病性变异（PVs），56 名（38.6%）患者存在 BRCA2-PVs。在 292 例 tBRCA 野生型（wt）患者中，88 例进行了种系 BRCA 检测（gBRCA），其中 86 例（97.8%）被证实为 gBRCAwt，1 例（1.1%）为意义未明的种系 BRCA 变异，1 例（1.1%）为种系 BRCA 突变。肿瘤检测与种系 BRCA 检测的一致性为 86.3%（209/242）。通过生物信息学算法怀疑 13/292 例 tBRCAwt 患者存在大片段基因重排（LGRs），并进行了多重连接依赖性探针扩增（MLPA），仅在 1 例中发现了 PVs。
基于新鲜冷冻组织的 BRCA 筛查工作流程是可行且可靠的。它可以扩大可能受益于 PARPi 的 BRCA 突变人群，而不会遗漏对家庭成员的级联检测，从而保持其预防作用。
