City of Hope Cancer Center, Duarte, California.
Dana-Farber Cancer Institute, Boston, Massachusetts.
Cancer Epidemiol Biomarkers Prev. 2022 Aug 2;31(8):1621-1629. doi: 10.1158/1055-9965.EPI-21-1296.
Though germline TP53 pathogenic/likely pathogenic variants (PV) are associated with Li-Fraumeni syndrome, many detected by multigene panels represent aberrant clonal expansion (ACE), most due to clonal hematopoiesis (CH). Discerning ACE/CH from germline variants and postzygotic mosaicism (PZM) is critically needed for risk assessment and management.
Participants in the Li-Fraumeni & TP53 Understanding & Progress (LiFT UP) study with a TP53 PV were eligible. Demographics, personal/family cancer history, and clinical laboratory test reports were obtained. DNA from multiple tissues was analyzed using a custom QIAseq assay (ACE panel) that included TP53 and other CH-associated genes; the ACE panel and eyebrow follicles were assessed in a workflow to discern TP53 PV clinical categories.
Among 134 participants there was a significant difference for the age at diagnosis (P < 0.001), component cancers (P = 0.007), and clinical testing criteria (P < 0.001), comparing germline with PZM or ACE. ACE panel analysis of DNA from 55 sets of eyebrow follicles (mean 1.4 ug) and 36 formalin-fixed, paraffin imbedded tissues demonstrated low variance (SE, 3%; P = 0.993) for TP53 variant allele fraction, with no significant difference (P = 0.965) between tissue types, and detected CH gene PVs. Of 55 multi-tissue cases, germline status was confirmed for 20, PZM in seven, ACE for 25, and three were indeterminate. Additional CH variants were detected in six ACE and two germline cases.
We demonstrated an effective approach and tools for discerning germline TP53 status.
Discernment of PZM and TP53-driven CH increases diagnostic accuracy and enables risk-appropriate care.
尽管种系 TP53 致病性/可能致病性变异（PV）与 Li-Fraumeni 综合征相关，但许多通过多基因panel 检测到的变异代表异常克隆性扩增（ACE），大多数归因于克隆性造血（CH）。区分种系变异与合子后嵌合体（PZM）和体细胞嵌合（CH）对于风险评估和管理至关重要。
Li-Fraumeni & TP53 理解与进展（LiFT UP）研究中具有 TP53 PV 的参与者符合条件。获取人口统计学、个人/家族癌症史和临床实验室检测报告。使用包括 TP53 和其他 CH 相关基因的定制 QIAseq 检测方法（ACE panel）分析来自多个组织的 DNA；在工作流程中评估 ACE panel 和眉毛毛囊，以辨别 TP53 PV 的临床分类。
在 134 名参与者中，种系与 PZM 或 ACE 相比，在诊断年龄（P < 0.001）、组成癌症（P = 0.007）和临床检测标准（P < 0.001）方面存在显著差异。55 对眉毛毛囊（平均 1.4ug）和 36 份福尔马林固定、石蜡包埋组织的 DNA 的 ACE panel 分析显示 TP53 变异等位基因分数的方差较小（SE，3%；P = 0.993），组织类型之间无显著差异（P = 0.965），并检测到 CH 基因 PV。在 55 例多组织病例中，20 例为种系状态，7 例为 PZM，25 例为 ACE，3 例为不确定。在 6 例 ACE 和 2 例种系病例中还检测到其他 CH 变体。
我们展示了一种有效区分种系 TP53 状态的方法和工具。
区分 PZM 和 TP53 驱动的 CH 可提高诊断准确性，并实现风险适当的护理。
