Oncology Center, Hospital Sírio-Libanês, São Paulo, SP, Brazil.
Molecular Oncology Center, Hospital Sírio-Libanês, São Paulo, SP, Brazil.
Oncologist. 2023 Jul 5;28(7):624-627. doi: 10.1093/oncolo/oyad105.
Li-Fraumeni syndrome (LFS) is a pan-cancer predisposition syndrome caused by germline pathogenic variants in the gene TP53. The interpretation of TP53 variants in clinical scenarios outside the classic LFS criteria may be challenging. Here, we report a patient affected by 2 primary cancers at later ages, who harbored a likely pathogenic TP53 at low allele frequency detected in a blood sample.
The Molecular Tumor Board committee at our institution revisited the case of a patient who was enrolled in a research protocol for the investigation of genetic conditions associated with neuroendocrine tumors. Clinical, familial, and molecular data were reviewed. The patient received germline testing using a next generation sequencing multi-gene panel and was incidentally found to harbor a TP53 likely pathogenic variant, with 22% of variant allele fraction. Additional samples, including a second blood sample, oral swab, and saliva, were collected for DNA analysis. A new TP53 sequencing round was performed with the attempt to distinguish between a true constitutional germline variant and a somatically acquired variant due to aberrant clonal expansion of bone marrow precursors.
Patient's personal and familial history of cancer did not meet classic nor Chompret LFS criteria. Environmental risk factors for cancer were identified, such as alcohol abuse and tobacco exposure. The TP53 variant initially found in the next-generation sequencing was confirmed by Sanger sequencing in the previous DNA sample extracted from blood for the first analysis and in a second blood sample collected 6 years later. The TP53 variant was not detected in the DNA extracted from the oral swab and saliva samples.
Considering the low TP53 variant allele fraction in blood, absence of variant detection in oral swab and saliva samples, the lack of LFS clinical criteria, and history of exposure to environmental risk factors for cancer, the main hypothesis for this case was aberrant clonal expansion due to clonal hematopoiesis. Oncologists should interpret TP53 findings during germline testing with caution.
李-佛美尼综合征（Li-Fraumeni syndrome，LFS）是一种泛癌种易患综合征，由 TP53 基因种系致病性变异引起。在经典 LFS 标准之外的临床情况下，对 TP53 变异的解读可能具有挑战性。在这里，我们报告了一例年龄较大时发生两种原发性癌症的患者，其血液样本中检测到低频等位的疑似致病性 TP53。
我们机构的分子肿瘤委员会重新审议了一名参加与神经内分泌肿瘤相关遗传条件研究方案的患者病例。回顾了临床、家族和分子数据。对患者进行了使用下一代测序多基因panel 的种系检测，偶然发现其携带 TP53 疑似致病性变异，变异等位基因分数为 22%。收集了包括第二份血样、口腔拭子和唾液在内的其他样本进行 DNA 分析。进行了新的 TP53 测序回合，以尝试区分真正的种系突变和由于骨髓前体细胞异常克隆扩增导致的体细胞获得性变异。
患者的个人和家族癌症史既不符合经典 LFS 标准，也不符合 Chompret LFS 标准。确定了癌症的环境危险因素，如酗酒和吸烟。最初在下一代测序中发现的 TP53 变异在第一次分析中从血液中提取的先前 DNA 样本以及 6 年后采集的第二份血液样本中通过 Sanger 测序得到了证实。口腔拭子和唾液样本中未检测到 TP53 变异。
考虑到血液中 TP53 变异等位基因分数低、口腔拭子和唾液样本中未检测到变异、缺乏 LFS 临床标准以及癌症环境危险因素暴露史，该病例的主要假设是克隆性造血导致的异常克隆扩增。肿瘤学家在种系检测中应谨慎解读 TP53 结果。
