PO.BCS01.02 · 生物信息与计算
应激反应性基因组改变揭示了PTSD生物学与乳腺癌侵袭性之间的双向关系
Stress-responsive genomic alterations reveal a bi-directional relationship between PTSD biology and breast cancer aggressiveness
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摘要 Abstract
中文摘要
背景：乳腺癌(BrCa)与创伤后应激障碍(PTSD)之间存在复杂的双向关系。虽然癌症诊断和治疗可诱发PTSD，但新出现的流行病学数据表明，既存的心理应激或PTSD也可能升高罹患乳腺癌的风险或加速肿瘤进展。这一相互作用背后的生物学机制仍不清楚。我们假设肿瘤内在的应激反应性基因改变可能为这一关联提供分子层面的洞见。
方法：我们使用cBioPortal/TCGA数据集分析了17,605例乳腺肿瘤，并将其与一个95,474样本的泛癌参考进行比较。从已发表文献中整理出六十余个PTSD和应激相关基因，包括：TG、CYP11B1、CYP11B2、CRH、NR3C1、SLC6A4、PRKCA、CHRNA6、RGS2、DRD2、BDNF、FKBP5、SLC6A2、TPH2等。评估了拷贝数改变、共扩增模式和临床结局（包括转移进展）。
结果：与泛癌参考队列相比，应激相关基因在乳腺癌中表现出显著富集的拷贝数扩增。在17,605例BrCa肿瘤中，六十余个PTSD、情绪和应激-内分泌相关基因显示出复发性CNA。关键改变包括TG(19%)、CYP11B1/CYP11B2(16%)、RGS2(12%)、CRH(10%)、PRKCA(9%)和CHRNA6(8%)，在BrCa中的频率明显高于其在所有癌症类型的95,474例肿瘤中的频率(2-5%)。TG扩增的肿瘤表现出协调的共扩增，涉及8q24(MYC/PVT1)和1q32，并伴有特征性的8p22缺失，这些基因组特征与侵袭性疾病生物学强相关。探索性临床注释进一步显示，TG或CYP11B门控的BrCa队列表现出快速的转移进展，转移中位时间<10个月。总之，这些发现鉴定出乳腺癌中稳健的应激-肿瘤基因组轴，并突显甲状腺球蛋白(TG)和促肾上腺皮质激素释放激素(CRH)作为可开发为客观、无创血清生物标志物的高优先级候选物。
结论：大规模平民肿瘤基因组分析揭示，应激反应性和PTSD相关基因在乳腺癌中反复扩增，并与高风险致癌区域共聚集。这些发现支持一种生物学模型，即慢性应激/PTSD与乳腺癌侵袭性通过共享的神经内分泌和GPCR相关分子通路交汇。这一应激/肿瘤轴可能有助于解释乳腺癌诊断后出现的PTSD以及应激相关的乳腺癌风险或进展升高。这些见解为开发客观生物标志物以及探索PTSD-BrCa界面的机制研究奠定了基础。
查看英文原文 English abstract
Background: Breast cancer (BrCa) and post-traumatic stress disorder (PTSD) exhibit a complex, bidirectional relationship. While cancer diagnosis and treatment can induce PTSD, emerging epidemiologic data indicate that pre-existing psychological stress or PTSD may also elevate the risk of developing breast cancer or accelerate tumor progression. The biological mechanisms underlying this interaction remain unclear. We hypothesized that tumor-intrinsic alterations in stress-responsive genes may provide molecular insight into this connection.
Methods: We analyzed 17,605 breast tumors using cBioPortal/TCGA datasets and compared them with a 95,474-sample pan-cancer reference. PTSD- and stress-related over sixty genes were curated from published literature and included: TG, CYP11B1, CYP11B2, CRH, NR3C1, SLC6A4, PRKCA, CHRNA6, RGS2, DRD2, BDNF, FKBP5, SLC6A2, TPH2, and others. Copy number alterations, co-amplification patterns, and clinical outcomes (including metastatic progression) were evaluated.
Results: Stress-related genes exhibited significantly enriched copy number amplifications in breast cancer compared with a pan-cancer reference cohort. Across 17,605 BrCa tumors, more than sixty PTSD-, mood-, and stress-endocrine-associated genes showed recurrent CNAs. Key alterations included TG (19%), CYP11B1/CYP11B2 (16%), RGS2 (12%), CRH (10%), PRKCA (9%), and CHRNA6 (8%), markedly higher BrCa than their frequency across 95,474 tumors from all cancer types (2-5%). TG-amplified tumors demonstrated coordinated co-amplifications involving 8q24 (MYC/PVT1) and 1q32, along with characteristic 8p22 deletions, genomic features strongly associated with aggressive disease biology. Exploratory clinical annotation further showed that TG- or CYP11B-gated BrCa cohorts exhibited rapid metastatic progression, with a median time to metastasis <10 months. Together, these findings identify a robust stress-tumor genomic axis in breast cancer and highlight Thyroglobulin (TG) and Corticotropin-Releasing Hormone (CRH) as high-priority candidates for development as objective, noninvasive serum biomarkers.
Conclusion: Large-scale civilian tumor genomic analyses reveal that stress-responsive and PTSD-linked genes are recurrently amplified in breast cancer and co-cluster with high-risk oncogenic regions. These findings support a biological model in which chronic stress/PTSD and breast cancer aggressiveness intersect through shared neuroendocrine and GPCR-linked molecular pathways. This stress/tumor axis may help explain both PTSD arising after a breast cancer diagnosis and stress-associated increases in breast cancer risk or progression. These insights establish a foundation for developing objective biomarkers and mechanistic studies exploring the PTSD-BrCa interface.
利益披露 Disclosure
A. Bera, None..
M. Srivastava, None.