Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Am J Hum Genet. 2022 Aug 4;109(8):1520-1533. doi: 10.1016/j.ajhg.2022.07.005.
Germline PTEN variants (PTEN hamartoma tumor syndrome [PHTS]) confer up to 85% lifetime risk of female breast cancer (BC). BCs arising in PHTS are clinically distinct from sporadic BCs, including younger age of onset, multifocality, and an increased risk of second primary BCs. Yet, there is no previous investigation into the underlying genomic landscape of this entity. We sought to address the hypothesis that BCs arising in PHTS have a distinct genomic landscape compared to sporadic counterparts. We performed and analyzed exome sequencing data from 44 women with germline PTEN variants who developed BCs. The control cohort comprised of 497 women with sporadic BCs from The Cancer Genome Atlas (TCGA) dataset. We demonstrate that PHTS-derived BCs have a distinct somatic mutational landscape compared to the sporadic counterparts, namely second somatic hits in PTEN, distinct mutational signatures, and increased genomic instability. The PHTS group had a significantly higher frequency of somatic PTEN variants compared to TCGA (22.7% versus 5.6%; odds ratio [OR] 4.93; 95% confidence interval [CI] 2.21 to 10.98; p < 0.001) and a lower mutational frequency in PIK3CA (22.7% versus 33.4%; OR 0.59; 95% CI 0.28 to 1.22; p = 0.15). Somatic variants in PTEN and PIK3CA were mutually exclusive in PHTS (p = 0.01) but not in TCGA. Our findings have important implications for the personalized management of PTEN-related BCs, especially in the context of more accessible genetic testing.
胚系 PTEN 变异（PTEN 错构瘤肿瘤综合征 [PHTS]）使女性乳腺癌（BC）的终生风险增加高达 85%。源自 PHTS 的 BC 在临床上与散发性 BC 不同，包括发病年龄更小、多灶性和第二原发 BC 的风险增加。然而，此前尚未对该实体的潜在基因组景观进行调查。我们试图验证这样一个假设，即源自 PHTS 的 BC 与散发性 BC 相比具有独特的基因组景观。我们对 44 名携带胚系 PTEN 变异并发生 BC 的女性进行了外显子组测序数据分析。对照组由来自癌症基因组图谱（TCGA）数据集的 497 名患有散发性 BC 的女性组成。我们证明，源自 PHTS 的 BC 与散发性 BC 相比具有独特的体细胞突变景观，即 PTEN 的第二个体细胞突变、独特的突变特征和增加的基因组不稳定性。与 TCGA 相比，PHTS 组的体细胞 PTEN 变异频率显著更高（22.7%比 5.6%；优势比 [OR] 4.93；95%置信区间 [CI] 2.21 至 10.98；p < 0.001），PIK3CA 的突变频率更低（22.7%比 33.4%；OR 0.59；95%CI 0.28 至 1.22；p = 0.15）。源自 PHTS 的 PTEN 和 PIK3CA 的体细胞变异是相互排斥的（p = 0.01），但在 TCGA 中并非如此。我们的发现对 PTEN 相关 BC 的个体化管理具有重要意义，特别是在更易获得遗传检测的情况下。
