非-B DNA相关突变负荷作为癌症治疗反应和预后的标志
Non-B DNA-informed mutation burden as a marker of treatment response and outcome in cancer
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影响因子:6.8
分区:医学2区 Top / 肿瘤学2区
发表日期:2024 Dec
作者:
Qi Xu, Jeanne Kowalski
DOI:
10.1038/s41416-024-02873-7
摘要
基因组不稳定性在肿瘤发生中起关键作用，肿瘤突变负荷（TMB）是评估免疫治疗疗效的重要生物标志物，但其预测能力有限，且存在异质性。非-B DNA易于突变，且在癌症发展中扮演重要角色，结合突变信息可能提供更具潜力的癌症生物标志物。我们评估了突变与非-B DNA的相互作用，采用量化肿瘤突变及其与非-B DNA的共定位情况，结合生存分析和药物敏感性评估，探索其临床意义。我们提出两个新型标志物：‘nbTMB’（非-B DNA信息的肿瘤突变负荷）和‘mlTNB’（突变定位的肿瘤非-B DNA负荷）。在病例研究中：(1) nbTMB能区分免疫治疗中TMB高患者的生存异质性，而TMB本身则不能；(2) nbTMB能反映卵巢癌细胞系顺铂敏感性变化，而TMB则不能；(3) mlTNB能区分早期胰腺癌患者的生存异质性，而其他基因组不稳定性标志物难以识别。这些新颖标志物为理解癌症治疗反应和预后提供了细腻的视角，强调需要全面探索非-B与B-DNA特征的相互作用。
Abstract
Genomic instability is crucial in tumorigenesis, with Tumour Mutation Burden (TMB) being a biomarker to indicate therapeutic effectiveness, particularly in immunotherapy. However, TMB is not always a reliable predictor and displays heterogeneity. Non-B DNA, susceptible to mutations, play a significant role in cancer development, indicating their potential merit when combined with mutation for enhanced markers in cancer.We assessed mutations and non-B DNA interplay as biomarkers. Our methodology quantifies tumour mutations and their co-localization with non-B DNA, using survival and drug sensitivity assessments for clinical relevance.We introduce two novel markers, 'nbTMB' (non-B-informed tumour mutation burden) and 'mlTNB' (mutation-localised tumour non-B burden). In case studies: (1) nbTMB informs on survival heterogeneity among TMB-high patients undergoing immunotherapy whereas TMB is unable to further differentiate; (2) nbTMB informs on altered cisplatin sensitivity among ovarian cancer cell lines whereas TMB is unable to differentiate; and (3) mlTNB informs on survival heterogeneity among early-stage pancreatic cancer progressors in whom other markers of genomic instability fail to differentiate.These novel markers offer a nuanced approach to enhance our understanding of treatment responses and outcomes in cancer, underscoring the need for a comprehensive exploration of the interplay between non-B and B-DNA features.