Department of Computer Science and Engineering, University of Connecticut, Institute of System Genomics, Boston, MA, USA.
Dana-Farber Cancer Institute, Boston, MA, USA.
BMC Cancer. 2020 Mar 12;20(1):197. doi: 10.1186/s12885-020-6605-1.
BRCA1/2 germline mutation related cancers are candidates for new immune therapeutic interventions. This study was a hypothesis generating exploration of genomic data collected at diagnosis for 19 patients. The prominent tumor mutation burden (TMB) in hereditary breast and ovarian cancers in this cohort was not correlated with high global immune activity in their microenvironments. More information is needed about the relationship between genomic instability, phenotypes and immune microenvironments of these hereditary tumors in order to find appropriate markers of immune activity and the most effective anticancer immune strategies.
Mining and statistical analyses of the original DNA and RNA sequencing data and The Cancer Genome Atlas data were performed. To interpret the data, we have used published literature and web available resources such as Gene Ontology, The Cancer immunome Atlas and the Cancer Research Institute iAtlas.
We found that BRCA1/2 germline related breast and ovarian cancers do not represent a unique phenotypic identity, but they express a range of phenotypes similar to sporadic cancers. All breast and ovarian BRCA1/2 related tumors are characterized by high homologous recombination deficiency (HRD) and low aneuploidy. Interestingly, all sporadic high grade serous ovarian cancers (HGSOC) and most of the subtypes of triple negative breast cancers (TNBC) also express a high degree of HRD.
TMB is not associated with the magnitude of the immune response in hereditary BRCA1/2 related breast and ovarian cancers or in sporadic TNBC and sporadic HGSOC. Hereditary tumors express phenotypes as heterogenous as sporadic tumors with various degree of "BRCAness" and various characteristics of the immune microenvironments. The subtyping criteria developed for sporadic tumors can be applied for the classification of hereditary tumors and possibly also characterization of their immune microenvironment. A high HRD score may be a good candidate biomarker for response to platinum, and potentially PARP-inhibition.
Phase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients With Recurrent TNBC or HGSOC (NCT01623349), first posted on June 20, 2012. The design and the outcome of the clinical trial is not in the scope of this study.
BRCA1/2 种系突变相关癌症是新免疫治疗干预的候选者。本研究对 19 名患者在诊断时收集的基因组数据进行了假设生成探索。在该队列中，遗传性乳腺癌和卵巢癌的突出肿瘤突变负担（TMB）与微环境中的高全局免疫活性不相关。为了找到适当的免疫活性标志物和最有效的抗癌免疫策略，需要更多关于这些遗传性肿瘤的基因组不稳定性、表型和免疫微环境之间关系的信息。
对原始 DNA 和 RNA 测序数据以及癌症基因组图谱（TCGA）数据进行挖掘和统计分析。为了解释数据，我们使用了已发表的文献和可在线获取的资源，如基因本体论、癌症免疫图谱和癌症研究协会 i 图谱。
我们发现 BRCA1/2 种系相关的乳腺和卵巢癌并不代表独特的表型特征，而是表达了一系列与散发性癌症相似的表型。所有的 BRCA1/2 相关的乳腺和卵巢癌均表现出高度同源重组缺陷（HRD）和低非整倍体。有趣的是，所有散发性高级别浆液性卵巢癌（HGSOC）和大多数三阴性乳腺癌（TNBC）亚型也表现出高度的 HRD。
TMB 与遗传性 BRCA1/2 相关的乳腺和卵巢癌或散发性 TNBC 和散发性 HGSOC 中免疫反应的强度无关。遗传性肿瘤表达的表型与散发性肿瘤一样具有异质性，具有不同程度的“BRCA 样”和不同的免疫微环境特征。为散发性肿瘤开发的分型标准可用于遗传性肿瘤的分类，并可能用于其免疫微环境的特征描述。高 HRD 评分可能是对铂类药物和潜在 PARP 抑制剂反应的良好候选生物标志物。
口服 PI3 激酶抑制剂 BKM120 或 BYL719 联合口服 PARP 抑制剂奥拉帕利治疗复发性三阴性乳腺癌或高级别浆液性卵巢癌患者的 I 期研究（NCT01623349），于 2012 年 6 月 20 日首次发布。本研究不在临床试验的设计和结果范围内。
