Buckingham Lela, Mitchell Rachel, Maienschein-Cline Mark, Green Stefan, Hu Vincent Hong, Cobleigh Melody, Rotmensch Jacob, Burgess Kelly, Usha Lydia
1Department of Pathology, Rush University Medical Center, Chicago, IL USA.
3Tennessee Oncology, Shelbyville, TN USA.
Hered Cancer Clin Pract. 2019 Jul 16;17:21. doi: 10.1186/s13053-019-0117-5. eCollection 2019.
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 or 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 ( non-carriers). At this time, 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 non-carriers is due to alterations (germline, somatic or epigenetic) in other cancer-associated genes which were not analyzed during analysis.
To assess the nature and potential clinical significance of somatic variants in phenocopy tumors, DNA from 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.
None of the familial mutations were found in the tumor samples tested. The most frequently occurring somatic gene variants were (6/11 cases) and (5/11 cases). somatic variants were found in 2/6 phenocopies, but 0/5 phenocopies. Variants of uncertain significance were found in other DNA repair genes (), one mismatch repair gene (), a DNA demethylation enzyme (), and two histone modifiers ().
Although limited by a small sample size, these results support a role of selected somatic variants and epigenetic mechanisms in the development of tumors in phenocopies.
拟表型个体与其患病亲属具有相同的表型（即符合遗传性乳腺癌和卵巢癌综合征的癌症 = HBOC），但通过血液种系检测评估的基因型不同（即他们不携带种系或 突变）。有证据表明，种系变异携带者的亲属患 HBOC 相关癌症的风险增加，即使他们自己的家族变异检测呈阴性（非携带者）。目前，建议拟表型个体接受与普通人群相同的癌症监测。这就提出了一个问题，即非携带者患癌风险增加是否是由于在 分析过程中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）。
为了评估拟表型肿瘤中体细胞变异的性质和潜在临床意义，使用 572 个癌症基因的下一代测序分析了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 FreeBayes 基因变异检测器调用变异。使用 Annovar 对变异进行注释，以了解其对蛋白质序列、预测功能、来自千人基因组计划的不同人群中的频率以及变异数据库 COSMIC 和 ClinVar 中的存在情况的影响。
在测试的肿瘤样本中未发现家族性 突变。最常见的体细胞基因变异是 （6/11 例）和 （5/11 例）。在 2/6 的拟表型中发现了体细胞变异，但在 0/5 的拟表型中未发现。在其他 DNA 修复基因（）、一个错配修复基因（）、一种 DNA 去甲基化酶（）和两种组蛋白修饰剂（）中发现了意义不确定的变异。
尽管受样本量小的限制，但这些结果支持特定体细胞变异和表观遗传机制在拟表型肿瘤发生中的作用。
