PO.PS01.12 · 人群科学
铅的生物蓄积驱动人类乳腺癌的基因组不稳定性和凋亡抵抗
Lead Bioaccumulation Drives Genomic Instability and Apoptotic Resistance in Human Breast Cancer
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摘要 Abstract
中文摘要
引言：铅（Pb）是一种广泛存在的环境毒性物质，被 IARC 列为可能的人类致癌物，但其在乳腺癌中的机制性作用仍不明确。流行病学研究提示 Pb 暴露与乳腺癌风险之间存在关联，但将 Pb 蓄积与分子癌症特征相联系的组织水平数据有限。了解 Pb 是否在乳腺肿瘤内生物蓄积并影响关键癌症标志，可能揭示被忽视的乳腺癌进展环境决定因素。
方法：来自 26 名女性患者的福尔马林固定石蜡包埋乳腺癌样本。使用电感耦合等离子体质谱（ICP-MS）定量铅浓度。对冷冻肿瘤等分试样（n = 21）进行全基因组测序和 RNA-seq，从而评估肿瘤突变负荷（TMB）、微卫星不稳定性（MSI）、突变特征和 PAM50 分子亚型。采用 Spearman 相关、自助法置信区间和非参数检验评估 Pb 浓度与临床病理或分子变量之间的关系。
结果：铅在 100% 的乳腺癌样本中被检出，平均浓度为 18.2 ± 16.2 mg/kg（范围：0.2-310 mg/kg）。铅水平与年龄或经典病理特征（包括组织学分级（p = 0.8）和淋巴结转移（p = 0.6））无关联。值得注意的是，Pb 浓度独立于 PAM50 亚型，提示 Pb 蓄积反映了一个与既有内在分类不同的生物学维度。Pb 蓄积与基因组不稳定性之间出现了显著关系。铅浓度与 TMB（ρ = 0.87；p < 0.0001）和 MSI（ρ = 0.79；p < 0.0001）强相关。Pb 水平最高的肿瘤还携带 TP53 错义突变和移码缺失，突显了 Pb 负荷与 DNA 修复通路失调之间的联系。这些发现支持一种模型，即 Pb 生物蓄积促进突变过程，可能通过破坏错配修复机制实现。Pb 浓度还与 BCL2（ρ = 0.66；p = 0.001）和 p53（ρ = 0.65；p = 0.002）的表达呈正相关，指向对调控性细胞死亡的抵抗增强。
结论：本文报告的数据突显了将环境金属负荷纳入乳腺癌风险评估的必要性，尤其是对于 TMB/MSI 升高、可能从免疫治疗中获益的患者。
查看英文原文 English abstract
Introduction: Lead (Pb) is a widespread environmental toxicant classified by IARC as a probable human carcinogen, yet its mechanistic involvement in breast cancer remains poorly defined. Epidemiological studies suggest an association between Pb exposure and breast cancer risk, but tissue-level data linking Pb accumulation to molecular cancer features are limited. Understanding whether Pb bioaccumulates within breast tumors and influences key cancer hallmarks may reveal overlooked environmental determinants of breast cancer progression.
Methods: Formalin-fixed paraffin-embedded breast cancer samples from 26 female patients. Lead concentration was quantified using inductively coupled plasma mass spectrometry (ICP-MS). Whole-genome sequencing and RNA-seq were performed on frozen tumor aliquots (n = 21), enabling assessment of Tumor Mutational Burden (TMB), Microsatellite Instability (MSI), mutational signatures, and PAM50 molecular subtypes. Spearman correlation, bootstrap confidence intervals, and non-parametric tests assessed relationships between Pb concentration and clinicopathological or molecular variables.
Results: Lead was detected in 100% of breast cancer samples, with a mean concentration of 18.2 ± 16.2 mg/kg (range: 0.2-310 mg/kg). Lead levels showed no association with age or classical pathological features, including histologic grade (p = 0.8) and lymph-node metastasis (p = 0.6). Notably, Pb concentration was independent of PAM50 subtypes, suggesting that Pb accumulation reflects a biological dimension distinct from established intrinsic classifications.A significant relationship emerged between Pb accumulation and genomic instability. Lead concentration strongly correlated with TMB (ρ = 0.87; p < 0.0001) and MSI (ρ = 0.79; p < 0.0001). Tumors with the highest Pb levels also harbored TP53 missense mutations and frameshift deletions, underscoring a link between Pb burden and DNA repair pathway dysregulation. These findings support a model in which Pb bioaccumulation promotes mutational processes, potentially via disruption of mismatch repair mechanisms.Pb concentration was also positively associated with expression of BCL2 (ρ = 0.66; p = 0.001) and p53 (ρ = 0.65; p = 0.002), pointing toward enhanced resistance to regulated cell death.
Conclusion: Data here reported highlighted the need to incorporate environmental metal burden into breast cancer risk assessment particularly for patients exhibiting elevated TMB/MSI who may benefit from immunotherapy.
利益披露 Disclosure
R. Bonfiglio, None..
M. Scimeca, None.