MGZ - Medical Genetics Center, Germany; Arbeitsgruppe Erbliche Gastrointestinale Tumore, Medizinische Klinik und Poliklinik IV - Campus Innenstadt, Klinikum der Universität München, Germany.
Center for Medical Genetics, Ghent University Hospital, Belgium.
Eur J Med Genet. 2021 Dec;64(12):104360. doi: 10.1016/j.ejmg.2021.104360. Epub 2021 Oct 13.
Historically, it is estimated that 5-10% of cancer patients carry a causative genetic variant for a tumor predisposition syndrome. These conditions have high clinical relevance as they are actionable regarding risk-specific surveillance, predictive genetic testing, reproductive options, and - in some cases - risk reducing surgery or targeted therapy. Every individual is born with on average 0.5-1 exonic mosaic variants prevalent in single or multiple tissues. Depending on the tissues affected, mosaic conditions can abrogate the clinical phenotype of a tumor predisposition syndrome and can even go unrecognized, because it can be impossible or difficult to detect them with routine genetic testing in blood/leucocytes. On the other hand, it is estimated that at least 4% of presumed de novo variants are the result of low-level mosaicism (variant allele frequency <10%) in a parent, while around 7% are true mosaic variants with a higher variant allele frequency, which can sometimes be confused for heterozygous variants. Clonal hematopoiesis however can simulate a mosaic tumor predisposition in genetic diagnostics and has to be taken into account, especially for TP53 variants. Depending on the technique, variant allele frequencies of 2-3% can be detected for single nucleotide variants by next generation sequencing, copy number variants with variant allele frequencies of 5-30% can be detected by array-based technologies or MLPA. Mosaic tumor predisposition syndromes are more common than previously thought and may often remain undiagnosed. The clinical suspicion and diagnostic procedure for several cases with mosaic tumor predisposition syndromes are presented.
从历史上看，估计有 5-10%的癌症患者携带有肿瘤易感性综合征的致病遗传变异。这些情况具有重要的临床意义，因为它们可以针对特定风险的监测、预测性基因检测、生殖选择进行操作，并且在某些情况下可以进行降低风险的手术或靶向治疗。每个人出生时平均带有 0.5-1 个外显子镶嵌变异，存在于单个或多个组织中。根据受影响的组织，镶嵌情况可能会消除肿瘤易感性综合征的临床表型，甚至可能未被识别，因为在血液/白细胞中使用常规基因检测可能无法或难以检测到它们。另一方面，估计至少有 4%的假定新发变异是父母中低水平镶嵌（变异等位基因频率<10%）的结果，而大约 7%是真正具有较高变异等位基因频率的镶嵌变异，这有时可能会与杂合变异混淆。然而，克隆性造血可以在遗传诊断中模拟镶嵌性肿瘤易感性，必须加以考虑，尤其是对于 TP53 变异。根据技术的不同，通过下一代测序可以检测到 2-3%的单核苷酸变异的变异等位基因频率，通过基于阵列的技术或 MLPA 可以检测到变异等位基因频率为 5-30%的拷贝数变异。镶嵌性肿瘤易感性综合征比以前认为的更为常见，并且可能经常未被诊断。呈现了几个镶嵌性肿瘤易感性综合征病例的临床怀疑和诊断程序。
