Department of Oncology, Vejle Hospital, Vejle, Denmark
Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
Int J Gynecol Cancer. 2019 Jan;29(1):166-173. doi: 10.1136/ijgc-2018-000017.
Germline mutations in genes predict improved survival and sensitivity to treatment with poly(adenosine-diphosphate-ribose) polymerase inhibitors in epithelial ovarian carcinoma. The prognostic importance of other genetic alterations leading to homologous recombination deficiency, collectively BRCAness phenotype, is unresolved. The aim was to analyze the distribution of homologous recombination deficiency in epithelial ovarian carcinoma caused by mutations in a panel of homologous recombination genes (including ) or epigenetic alterations. A further aim was to investigate the prognostic importance of homologous recombination deficiency, the BRCAness phenotype.
We assessed 380 patient specimens from a Danish population-based epithelial ovarian carcinoma cohort for germline and somatic mutations in 18 different homologous recombination genes, including and , using next generation sequencing. Epigenetic alteration due to hypermethylation was assessed by pyrosequencing and BRCA1 protein expression was evaluated by immunohistochemistry.
Seventeen percent of patients with epithelial ovarian carcinoma carried a germline (9.8%) and/or somatic (6.3%) mutation in 12 (, , , , , , , , , , ) of 18 sequenced homologous recombination genes. The homologous recombination mutation rate was similar among the different histologic subtypes, however the type of mutation ( and other homologous recombination mutations) differed, p=4×10. hypermethylation was present in 7.4% of patient specimens for a total BRCAness phenotype of 23.9%. The BRCAness phenotype was associated with improved overall survival in the high-grade serous carcinoma subgroup with a median overall survival of 4.4 years (95% CI 3.0 to 5.3) versus 2.2 years (95% CI 1.9 to 2.4) in BRCAness wildtype, p=0.0002. Multivariate analysis confirmed an independent prognostic value of the BRCAness phenotype among the high-grade serous carcinoma subgroup, hazard ratio 0.65 (95% CI 0.47 to 0.92), p=0.014.
The BRCAness phenotype is present in almost one-fourth of epithelial ovarian carcinoma and holds important prognostic information. The implications of our findings in relation to poly(adenosine-diphosphate-ribose) polymerase inhibitor treatment call for further investigation.
基因中的种系突变可预测上皮性卵巢癌患者的生存改善和对聚（腺苷二磷酸核糖）聚合酶抑制剂治疗的敏感性。导致同源重组缺陷的其他遗传改变的预后重要性，即 BRCA 样表型，尚未得到解决。目的是分析由一组同源重组基因（包括和）中的突变或表观遗传改变导致的上皮性卵巢癌中同源重组缺陷的分布。另一个目的是研究同源重组缺陷、BRCA 样表型的预后意义。
我们使用下一代测序技术，评估了来自丹麦基于人群的上皮性卵巢癌队列的 380 名患者标本中 18 种不同同源重组基因（包括和）的种系和体细胞突变。通过焦磷酸测序评估由于 过度甲基化引起的表观遗传改变，并通过免疫组织化学评估 BRCA1 蛋白表达。
上皮性卵巢癌患者中有 17%（9.8%为种系和 6.3%为体细胞）携带 18 个测序同源重组基因中的 12 个（、、、、、、、、、）的种系和/或体细胞突变。不同组织学亚型的同源重组突变率相似，但突变类型（和其他同源重组突变）不同，p=4×10。患者标本中有 7.4%存在 过度甲基化，总 BRCA 样表型为 23.9%。BRCA 样表型与高级别浆液性癌亚组的总生存率改善相关，中位总生存率为 4.4 年（95%CI 3.0 至 5.3），而 BRCA 样野生型为 2.2 年（95%CI 1.9 至 2.4），p=0.0002。多变量分析证实 BRCA 样表型在高级别浆液性癌亚组中具有独立的预后价值，风险比为 0.65（95%CI 0.47 至 0.92），p=0.014。
BRCA 样表型存在于近四分之一的上皮性卵巢癌中，具有重要的预后信息。我们的发现对聚（腺苷二磷酸核糖）聚合酶抑制剂治疗的影响需要进一步研究。
