Resource-efficient pooled sequencing expands translational impact in solid tumors.
Resource-efficient pooled sequencing expands translational impact in solid tumors.
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DOI：
10.52733/kcj18n2.a1
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Hakimi AA
中科院分区：
文献类型：
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作者：
DiNatale RG;Mano R;Makarov V;Rusk N;Drill E;Winer A;Sankin A;Yoo A;Freeman BA;Hsieh JJ;Chen YB;Coleman JA;Berger M;Ostrovnaya I;Chan TA;Russo P;Reznik E;Hakimi AA
肿瘤内遗传异质性（ITH）对利用测序进行癌症管理决策提出了重大挑战。虽然多个肿瘤区域的测序可以解决ITH的缺陷，但它会显著增加成本和资源利用率。我们提出了一种合并的多区域测序策略，即在测序前将来自多个肿瘤区域的DNA等分试样混合，作为一种具有成本效益的策略，通过解决ITH来提高翻译价值，同时保留有价值的残留组织用于二次分析。聚焦于肾癌，我们证明了来自两个区域的DNA池显著增加了突变检测，同时减少了克隆性错误归因。这导致具有治疗上可行的突变的患者的比例增加，改善患者风险分层，并改善进化轨迹的推断，其准确性与真正的多区域测序相当。应用于非小细胞肺癌数据的相同方法大大改善了肿瘤突变负荷（TMB）检测。我们的研究结果表明，合并的DNA测序策略是一种具有成本效益的替代方案，以解决内在的遗传异质性在临床环境中。
Intratumoral genetic heterogeneity (ITH) poses a significant challenge to utilizing sequencing for decision making in the management of cancer. Although sequencing of multiple tumor regions can address the pitfalls of ITH, it does so at a significant increase in cost and resource utilization. We propose a pooled multiregional sequencing strategy, whereby DNA aliquots from multiple tumor regions are mixed prior to sequencing, as a cost-effective strategy to boost translational value by addressing ITH while preserving valuable residual tissue for secondary analysis. Focusing on kidney cancer, we demonstrate that DNA pooling from as few as two regions significantly increases mutation detection while reducing clonality misattribution. This leads to an increased fraction of patients identified with therapeutically actionable mutations, improved patient risk stratification, and improved inference of evolutionary trajectories with an accuracy comparable to bona fide multiregional sequencing. The same approach applied to non-small-cell lung cancer data substantially improves tumor mutational burden (TMB) detection. Our findings demonstrate that pooled DNA sequencing strategies are a cost-effective alternative to address intrinsic genetic heterogeneity in clinical settings.