BackgroundBRCA phenocopies are individuals with the same phenotype (i.e. cancer consistent with Hereditary Breast and Ovarian Cancer syndrome = HBOC) as their affected relatives, but not the same genotype as assessed by blood germline testing (i.e. they do not carry a germline BRCA1 or BRCA2 mutation). There is some evidence of increased risk for HBOC-related cancers in relatives of germline variant carriers even though they themselves test negative for the familial variant (BRCA non-carriers). At this time, BRCA phenocopies are recommended to undergo the same cancer surveillance as individuals in the general population. This raises the question of whether the increased cancer risk in BRCA non-carriers is due to alterations (germline, somatic or epigenetic) in other cancer-associated genes which were not analyzed during BRCA analysis.MethodsTo assess the nature and potential clinical significance of somatic variants in BRCA phenocopy tumors, DNA from BRCA non-carrier tumor tissue was analyzed using next generation sequencing of 572 cancer genes. Tumor diagnoses of the 11 subjects included breast, ovarian, endometrial and primary peritoneal carcinoma. Variants were called using FreeBayes genetic variant detector. Variants were annotated for effect on protein sequence, predicted function, and frequency in different populations from the 1000 genomes project, and presence in variant databases COSMIC and ClinVar using Annovar.ResultsNone of the familial BRCA1/2 mutations were found in the tumor samples tested. The most frequently occurring somatic gene variants were ROS1(6/11 cases) and NUP98 (5/11 cases). BRCA2 somatic variants were found in 2/6 BRCA1 phenocopies, but 0/5 BRCA2 phenocopies. Variants of uncertain significance were found in other DNA repair genes (ERCC1, ERCC3, ERCC4, FANCD2, PALB2), one mismatch repair gene (PMS2), a DNA demethylation enzyme (TET2), and two histone modifiers (EZH2, SUZ12).ConclusionsAlthough limited by a small sample size, these results support a role of selected somatic variants and epigenetic mechanisms in the development of tumors in BRCA phenocopies.

中文翻译：

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BRCA表型肿瘤中具有潜在临床意义的体细胞变异


背景BRCA表型是指与其受影响的亲属具有相同表型（即与遗传性乳腺癌和卵巢癌综合征= HBOC一致的癌症）的个体，但与血液种系测试评估的基因型不同（即他们不携带种系BRCA1或BRCA2突变）。有一些证据表明，种系变异携带者的亲属患 HBOC 相关癌症的风险增加，即使他们本身的家族变异检测呈阴性（BRCA 非携带者）。目前，建议对 BRCA 表型进行与普通人群相同的癌症监测。这就提出了一个问题：BRCA 非携带者的癌症风险增加是否是由于 BRCA 分析期间未分析的其他癌症相关基因的改变（种系、体细胞或表观遗传）所致。方法评估体细胞的性质和潜在临床意义针对 BRCA 表型肿瘤中的变异，使用 572 个癌症基因的下一代测序分析了 BRCA 非携带者肿瘤组织的 DNA。 11 名受试者的肿瘤诊断包括乳腺癌、卵巢癌、子宫内膜癌和原发性腹膜癌。使用 FreeeBayes 遗传变异检测器来检测变异。对来自 1000 个基因组计划的不同人群中的蛋白质序列、预测功能和频率的影响以及变异数据库 COSMIC 和 ClinVar 中存在的变异进行了注释。结果在测试的肿瘤样本中没有发现家族性 BRCA1/2 突变。最常见的体细胞基因变异是ROS1（6/11例）和NUP98（5/11例）。 BRCA2 体细胞变异在 2/6 BRCA1 表型中发现，但在 0/5 BRCA2 表型中发现。 在其他 DNA 修复基因（ERCC1、ERCC3、ERCC4、FANCD2、PALB2）、一种错配修复基因（PMS2）、一种 DNA 去甲基化酶（TET2）和两种组蛋白修饰剂（EZH2、SUZ12）中发现了不确定意义的变异。由于样本量较小，这些结果支持了 BRCA 表型中选定的体细胞变异和表观遗传机制在肿瘤发展中的作用。