Dai Jiawei, Rozenblit Mariya, Li Xiaoyue, Shan Naing Lin, Wang Yueyue, Mane Shrikant, Marczyk Michal, Pusztai Lajos
Yale Cancer Center, Yale School of Medicine, Suite 120, Rm 133, 300 George Street, New Haven, CT, 06511, USA.
Yale Center for Genome Analysis, West Haven, CT, USA.
Breast Cancer Res. 2025 Apr 22;27(1):60. doi: 10.1186/s13058-025-02018-5.
Normal breast tissues adjacent to cancer often harbor many of the same genomic alterations as the cancer itself. However, it remains unclear whether histologically normal breast tissues carry genomic changes related to cancer development years before a cancer diagnosis.
Whole exome sequencing was performed to examine germline and somatic alterations in histologically normal breast tissues from women who subsequently developed breast cancer (n = 79, pre-diagnosis tissues) and compared these with results from breast tissues of women who did not (n = 81). No patient had germline mutations in cancer predisposition genes.
The pre-diagnosis tissues had significantly more high functional impact germline variants per sample than the healthy controls (P = 0.034), 36.5% of affected genes were cancer hallmark genes, among these 62.4% were involved with evading growth suppressors and 5.7% with genome instability. The average number of somatic mutations were similar between the two cohorts. Mutation signature analysis revealed COSMIC signatures 3 (associated with impaired homologous recombination) as a dominant signature more frequent in pre-diagnosis tissues. At gene and variant level, nine common germline polymorphisms in two immune regulatory genes, FCGBP and TPSBP2, and along with three somatic mutations in F13A1, FRY and TMLHE, were significantly more frequently mutated in the pre-diagnosis samples.
Individuals who develop breast cancer have a higher germline variant burden in normal breast tissues leading to subtle deficiencies in DNA repair that in the context of other germline and somatic mutations could facilitate malignant transformation.
癌旁正常乳腺组织通常存在许多与癌组织本身相同的基因组改变。然而，目前尚不清楚组织学上正常的乳腺组织在癌症诊断前数年是否携带与癌症发生相关的基因组变化。
对随后发生乳腺癌的女性（n = 79，诊断前组织）的组织学正常乳腺组织进行全外显子测序，以检测种系和体细胞改变，并将这些结果与未患乳腺癌女性（n = 81）的乳腺组织结果进行比较。所有患者的癌症易感基因均无种系突变。
与健康对照相比，诊断前组织每个样本具有高功能影响的种系变异显著更多（P = 0.034），36.5%的受影响基因是癌症标志基因，其中62.4%与逃避生长抑制有关，5.7%与基因组不稳定有关。两个队列的体细胞突变平均数相似。突变特征分析显示，COSMIC特征3（与同源重组受损相关）是诊断前组织中更常见的主要特征。在基因和变异水平上，两个免疫调节基因FCGBP和TPSBP2中的九个常见种系多态性，以及F13A1、FRY和TMLHE中的三个体细胞突变，在诊断前样本中的突变频率显著更高。
患乳腺癌的个体正常乳腺组织中的种系变异负担更高，导致DNA修复存在细微缺陷，在其他种系和体细胞突变的背景下，可能促进恶性转化。
