Premetastatic shifts of endogenous and exogenous mutational processes support consolidative therapy in EGFR-driven lung adenocarcinoma
Premetastatic shifts of endogenous and exogenous mutational processes support consolidative therapy in EGFR-driven lung adenocarcinoma
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DOI：
10.1016/j.canlet.2021.11.011in
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发表时间：
2022-02-01
期刊：
影响因子：
9.7
通讯作者：
Townsend, Jeffrey P.
中科院分区：
文献类型：
--
作者：
Fisk, J. Nicholas;Mahal, Amandeep R.;Townsend, Jeffrey P.
癌症的进展是一个进化过程，在采样时间点之间进行评估具有挑战性。然而，在特定的时间段内癌症演变的调查是至关重要的关键事件，如获得治疗耐药性和随后的致命转移扩散的治疗耐药细胞群的阐明。在这里，我们在临床注释的癌症时序图中应用突变特征分析，以检测和描述肿瘤采样时间点之间由内源性（例如增变基因突变）和外源性（例如诱变治疗）因素引起的转移突变过程。在一名患者中，我们发现顺铂治疗可以引入突变，从而对随后的厄洛替尼靶向治疗产生遗传抗性。在另一名患者中，我们将缺陷性错配修复相关突变标签SBS 3的检测追溯到已知驱动突变CTNNB 1 S37 C的出现。在这两例患者中，转移性谱系来自于治疗过程中出现的单一祖先谱系-这一发现为EGFR阳性非小细胞肺癌的局部巩固治疗优于其他治疗方法提供了依据。概括地说，这些结果证明了系统发育分析的实用性，该系统发育分析结合了临床时间进程和突变特征去卷积，以告知治疗决策和疾病病因的回顾性评估。
The progression of cancer is an evolutionary process that is challenging to assess between sampling timepoints. However, investigation of cancer evolution over specific time periods is crucial to the elucidation of key events such as the acquisition of therapeutic resistance and subsequent fatal metastatic spread of therapy-resistant cell populations. Here we apply mutational signature analyses within clinically annotated cancer chronograms to detect and describe the shifting mutational processes caused by both endogenous (e.g. mutator gene mutation) and exogenous (e.g. mutagenic therapeutics) factors between tumor sampling timepoints. In one patient, we find that cisplatin therapy can introduce mutations that confer genetic resistance to subsequent targeted therapy with Erlotinib. In another patient, we trace detection of defective mismatch-repair associated mutational signature SBS3 to the emergence of known driver mutation CTNNB1 S37C. In both of these patients, metastatic lineages emerged from a single ancestral lineage that arose during therapy-a finding that argues for the consideration of local consolidative therapy over other therapeutic approaches in EGFR-positive non-small cell lung cancer. Broadly, these results demonstrate the utility of phylogenetic analysis that incorporates clinical time course and mutational signature deconvolution to inform therapeutic decision making and retrospective assessment of disease etiology.