Department of Pathology and Molecular Pathology, University Hospital Zurich, 8091, Zurich, Switzerland.
Department of Gynecology, University Hospital Zurich, Zurich, Switzerland.
J Cancer Res Clin Oncol. 2018 May;144(5):865-874. doi: 10.1007/s00432-018-2609-5. Epub 2018 Feb 17.
The role of somatic BRCA1/2 gene mutations in breast cancer is getting increasing attention in view of hereditary disease. The medullary phenotype and triple negative intrinsic subtypes are often, but not exclusively encountered in BRCA1 germline mutated breast cancer, whilst for BRCA2, no association to specific histological features are known. In this study, we addressed the relationship between morphological medullary phenotype and BRCA1/2 somatic mutations in breast cancer without known positive family anamnesis.
32 clinically sporadic breast cancers with medullary features were analyzed for somatic BRCA1/2 mutations (all coding exons) with next-generation sequencing technology. Paraffin-embedded formalin-fixed breast cancer samples from all patients were analyzed.
Three of 32 tumors (9%) had pathogenic (ARUP class-5) BRCA1 gene alterations. Two of these pathogenic variants exhibited deletions leading to frameshift mutations (p.Glu23fs, p.Val1234fs), and the remaining single-nucleotid-variant resulted in premature STOP codon (p.Glu60Ter). In one patient, the same pathogenic BRCA1 mutation was detected (p.Glu23fs) in normal breast tissue. Retrospective follow-up in two patients revealed a positive family history for breast cancer and consecutive germline mutation testing confirmed presence of BRCA1 mutations. No somatic pathogenic BRCA2 mutations were detected.
BRCA1 mutation testing may be useful in clinically sporadic breast cancer patients with medullary features to identify potential mutation carriers independently from intrinsic molecular subtype. Formalin-fixed paraffin-embedded cancer tissue can undergo testing within a routine molecular-diagnostic setting as a clinical BRCA1/2 mutation screening strategy.
鉴于遗传性疾病，BRCA1/2 种系基因突变在乳腺癌中的作用受到越来越多的关注。髓样表型和三阴性内在亚型在 BRCA1 种系突变乳腺癌中经常出现，但并非仅在 BRCA1 种系突变乳腺癌中出现，而对于 BRCA2，尚无与特定组织学特征相关的报道。在这项研究中，我们在无明确阳性家族史的情况下，研究了乳腺癌中形态学髓样表型与 BRCA1/2 种系突变之间的关系。
使用下一代测序技术分析了 32 例临床散发性具有髓样特征的乳腺癌患者的 BRCA1/2 种系突变（所有编码外显子）。对所有患者的石蜡包埋福尔马林固定乳腺癌样本进行分析。
32 例肿瘤中有 3 例（9%）存在致病性（ARUP 分级 5）BRCA1 基因突变。其中两种致病性变体导致移码突变（p.Glu23fs，p.Val1234fs），而其余单核苷酸变体导致提前终止密码子（p.Glu60Ter）。在一名患者中，在正常乳腺组织中发现了相同的致病性 BRCA1 突变（p.Glu23fs）。对两名患者的回顾性随访显示，她们有乳腺癌阳性家族史，随后进行的种系突变检测证实了 BRCA1 突变的存在。未检测到致病性 BRCA2 种系突变。
在具有髓样特征的临床散发性乳腺癌患者中，BRCA1 突变检测可能有助于识别潜在的突变携带者，而与内在分子亚型无关。福尔马林固定石蜡包埋的肿瘤组织可在常规分子诊断环境中进行检测，作为临床 BRCA1/2 突变筛查策略。
