Germline 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 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 , distinct mutational signatures, and increased genomic instability. The PHTS group had a significantly higher frequency of somatic 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 (22.7% versus 33.4%; OR 0.59; 95% CI 0.28 to 1.22; p = 0.15). Somatic variants in and were mutually exclusive in PHTS (p = 0.01) but not in TCGA. Our findings have important implications for the personalized management of -related BCs, especially in the context of more accessible genetic testing.

中文翻译：

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外显子组测序揭示了具有种系 PTEN 变异的女性乳腺癌中独特的体细胞基因组景观


种系变异（PTEN 错构瘤肿瘤综合征 [PHTS]）导致女性终生罹患乳腺癌 (BC) 的风险高达 85%。 PHTS 中出现的 BC 在临床上与散发性 BC 不同，包括发病年龄较小、多灶性以及第二原发性 BC 的风险增加。然而，之前没有对该实体的潜在基因组景观进行过调查。我们试图解决这样的假设：与零星的对应物相比，PHTS 中出现的 BC 具有独特的基因组景观。我们对 44 名患有 BC 的生殖系变异女性的外显子组测序数据进行了分析。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，与散发的对应物相比，PHTS 衍生的 BC 具有独特的体细胞突变景观，即 中的第二次体细胞命中、独特的突变特征和增加的基因组不稳定性。与 TCGA 相比，PHTS 组的体细胞变异频率显着更高（22.7% 对比 5.6%；比值比 [OR] 4.93；95% 置信区间 [CI] 2.21 至 10.98；p < 0.001），并且 ( 22.7% 与 33.4%；OR 0.59；95% CI 0.28 至 1.22；p = 0.15）。 PHTS 中的体细胞变异和 PHTS 中的体细胞变异是相互排斥的 (p = 0.01)，但在 TCGA 中则不然。我们的研究结果对于相关 BC 的个性化管理具有重要意义，特别是在更容易进行基因检测的背景下。