Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
J Natl Cancer Inst. 2021 Nov 29;113(12):1751-1760. doi: 10.1093/jnci/djab117.
Genetic testing for Li-Fraumeni syndrome (LFS) is performed by using blood specimens from patients selected based on phenotype-dependent guidelines. This approach is problematic for understanding the LFS clinical spectrum because patients with nonclassical presentations are missed, clonal hematopoiesis-related somatic blood alterations cannot be distinguished from germline variants, and unrelated tumors cannot be differentiated from those driven by germline TP53 defects.
To provide insights into the LFS-related cancer spectrum, we analyzed paired tumor-blood DNA sequencing results in 17 922 patients with cancer and distinguished clonal hematopoiesis-related, mosaic, and germline TP53 variants. Loss of heterozygosity and TP53 mutational status were assessed in tumors, followed by immunohistochemistry for p53 expression on a subset to identify those lacking biallelic TP53 inactivation.
Pathogenic/likely pathogenic TP53 variants were identified in 50 patients, 12 (24.0%) of which were clonal hematopoiesis related and 4 (8.0%) of which were mosaic. Twelve (35.3%) of 34 patients with germline TP53 variants did not meet LFS testing criteria. Loss of heterozygosity of germline TP53 variant was observed in 96.0% (95% confidence interval [CI] = 79.7% to 99.9%) of core LFS spectrum-type tumors vs 45.5% (95% CI = 16.8% to 76.6%) of other tumors and 91.3% (95% CI = 72.0% to 98.9%) of tumors from patients who met LFS testing criteria vs 61.5% (95% CI = 31.6% to 86.1%) of tumors from patients who did not. Tumors retaining the wild-type TP53 allele exhibited wild-type p53 expression.
Our results indicate that some TP53 variants identified in blood-only sequencing are not germline and a substantial proportion of patients with LFS are missed based on current testing guidelines. Additionally, a subset of tumors from patients with LFS do not have biallelic TP53 inactivation and may represent cancers unrelated to their germline TP53 defect.
Li-Fraumeni 综合征（LFS）的基因检测是通过使用基于表型依赖性指南选择的患者的血液标本进行的。这种方法在了解 LFS 临床谱方面存在问题，因为错过了非典型表现的患者，不能区分与克隆性造血相关的体细胞血液改变与种系变体，也不能区分无关肿瘤与由种系 TP53 缺陷驱动的肿瘤。
为了深入了解 LFS 相关癌症谱，我们分析了 17922 名癌症患者的配对肿瘤 - 血液 DNA 测序结果，并区分了与克隆性造血相关的、镶嵌的和种系 TP53 变体。评估了肿瘤中的杂合性丢失和 TP53 突变状态，随后对一小部分肿瘤进行 p53 表达的免疫组织化学染色，以确定那些缺乏双等位基因 TP53 失活的肿瘤。
在 50 名患者中发现了致病性/可能致病性 TP53 变体，其中 12 名（24.0%）与克隆性造血相关，4 名（8.0%）为镶嵌型。34 名种系 TP53 变体患者中有 12 名（35.3%）不符合 LFS 检测标准。在核心 LFS 谱型肿瘤中，96.0%（95%置信区间 [CI] = 79.7% 至 99.9%）观察到种系 TP53 变体的杂合性丢失，而在其他肿瘤中为 45.5%（95% CI = 16.8% 至 76.6%），在符合 LFS 检测标准的患者的肿瘤中为 91.3%（95% CI = 72.0% 至 98.9%），而在不符合 LFS 检测标准的患者的肿瘤中为 61.5%（95% CI = 31.6% 至 86.1%）。保留野生型 TP53 等位基因的肿瘤表现出野生型 p53 表达。
我们的结果表明，在血液测序中发现的一些 TP53 变体并非种系，并且根据当前检测标准，相当一部分 LFS 患者被遗漏。此外，一部分 LFS 患者的肿瘤没有双等位基因 TP53 失活，可能代表与种系 TP53 缺陷无关的癌症。
