Department of Gynecology and Obstetrics, University Hospital Klinikum Rechts der Isar, Technical University Munich (TUM), Munich, Germany.
Institute of Pathology, Technical University Munich (TUM), Munich, Germany.
Arch Gynecol Obstet. 2021 Jun;303(6):1557-1567. doi: 10.1007/s00404-020-05883-x. Epub 2020 Nov 27.
TP53germline (g) mutations, associated with the Li-Fraumeni syndrome (LFS), have rarely been reported in the context of hereditary breast and ovarian cancer (HBOC). The prevalence and cancer risks in this target group are unknown and counseling remains challenging. Notably an extensive high-risk surveillance program is implemented, which evokes substantial psychological discomfort. Emphasizing the lack of consensus about clinical implications, we aim to further characterize TP53g mutations in HBOC families.
Next-generation sequencing was conducted on 1876 breast cancer (BC) patients who fulfilled the inclusion criteria for HBOC.
(Likely) pathogenic variants in TP53 gene were present in 0.6% of the BC cohort with higher occurrence in early onset BC < 36 years. (1.1%) and bilateral vs. unilateral BC (1.1% vs. 0.3%). Two out of eleven patients with a (likely) pathogenic TP53g variant (c.542G > A; c.375G > A) did not comply with classic LFS/Chompret criteria. Albeit located in the DNA-binding domain of the p53-protein and therefore revealing no difference to LFS-related variants, they only displayed a medium transactivity reduction constituting a retainment of wildtype-like anti-proliferative functionality.
Among our cohort of HBOC families, we were able to describe a clinical subgroup, which is distinct from the classic LFS-families. Strikingly, two families did not adhere to the LFS criteria, and functional analysis revealed a reduced impact on TP53 activity, which may suit to the attenuated phenotype. This is an approach that could be useful in developing individualized screening efforts for TP53g mutation carrier in HBOC families. Due to the low incidence, national/international cooperation is necessary to further explore clinical implications. This might allow providing directions for clinical recommendations in the future.
与 Li-Fraumeni 综合征（LFS）相关的 TP53 种系（g）突变在遗传性乳腺癌和卵巢癌（HBOC）中很少见。该目标群体中的患病率和癌症风险尚不清楚，咨询仍然具有挑战性。值得注意的是，实施了广泛的高危监测计划，这引起了相当大的心理不适。强调缺乏关于临床意义的共识，我们旨在进一步描述 HBOC 家族中的 TP53g 突变。
对符合 HBOC 纳入标准的 1876 名乳腺癌（BC）患者进行下一代测序。
BC 队列中存在 TP53 基因（可能）致病性变异，在早发性 BC<36 岁时发生率较高。（1.1%）和双侧 vs. 单侧 BC（1.1% vs. 0.3%）。11 名具有（可能）致病性 TP53g 变异的患者中的 2 名（c.542G> A；c.375G> A）不符合经典 LFS/Chompret 标准。虽然它们位于 p53 蛋白的 DNA 结合域中，因此与 LFS 相关的变异没有区别，但它们仅显示出中等的转录活性降低，保留了野生型样的抗增殖功能。
在我们的 HBOC 家族队列中，我们能够描述一个与经典 LFS 家族不同的临床亚组。引人注目的是，有两个家族不符合 LFS 标准，功能分析显示 TP53 活性的影响降低，这可能适合于减弱的表型。这是一种在 HBOC 家族中对 TP53g 突变携带者进行个体化筛查的有用方法。由于发病率低，需要国家/国际合作来进一步探索临床意义。这可能为未来提供临床建议提供方向。
