Genomic and Transcriptomic Characterization of Relapsed SCLC Through Rapid Research Autopsy.
Genomic and Transcriptomic Characterization of Relapsed SCLC Through Rapid Research Autopsy.
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DOI：
10.1016/j.jtocrr.2021.100164
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发表时间：
2021-04
影响因子：
--
通讯作者：
Roychowdhury S
中科院分区：
文献类型：
--
作者：
Chen HZ;Bonneville R;Paruchuri A;Reeser JW;Wing MR;Samorodnitsky E;Krook MA;Smith AM;Dao T;Miya J;Wang W;Yu L;Freud AG;Allenby P;Cole S;Otterson G;Shields P;Carbone DP;Roychowdhury S
复发性SCLC的特点是治疗耐药和高死亡率。尽管经过了几十年的研究，但由于可用于分子研究的组织有限，导致治疗耐药性的机制仍然难以捉摸。因此，对复发小细胞肺癌分子特征的研究仍是一个未被满足的需求，以促进有效治疗的发展。我们对5例复发SCLC患者的研究尸检中获得的转移性肿瘤样本进行了全外显子组和转录组测序。我们使用生物信息学工具来推断亚克隆系统发育和识别复发性基因组改变。我们对来自尸检的肿瘤和正常转录组数据以及其他原发性和复发性SCLC数据集进行了免疫细胞特征和单样本基因集富集分析。此外，我们评估了T细胞炎症基因在神经内分泌（ASCL1, NEUROD1）和非神经内分泌（YAP1, POU2F3） SCLC亚型中的表达谱。外显子组测序揭示了分支进化引起的克隆异质性（肿瘤间和肿瘤内），并确定了复发SCLC中与耐药相关的截尾和亚克隆改变。转录组分析进一步显示，神经内分泌SCLC亚型（ASCL1、NEUROD1）的非炎症表型与参与适应性抗肿瘤免疫的基因表达降低相关，而非神经内分泌亚型（YAP1、POU2F3）的炎症表型更为明显。我们的研究结果揭示了复发SCLC中存在的肿瘤异质性和复杂的克隆进化。此外，我们报道神经内分泌SCLC亚型在免疫上是冷的，从而解释了对免疫检查点阻断的反应性降低。这些结果表明，SCLC的先天和获得性治疗耐药机制是亚型特异性的，并强调需要继续研究以支持这种癌症的治疗选择和发展。
Relapsed SCLC is characterized by therapeutic resistance and high mortality rate. Despite decades of research, mechanisms responsible for therapeutic resistance have remained elusive owing to limited tissues available for molecular studies. Thus, an unmet need remains for molecular characterization of relapsed SCLC to facilitate development of effective therapies. We performed whole-exome and transcriptome sequencing of metastatic tumor samples procured from research autopsies of five patients with relapsed SCLC. We implemented bioinformatics tools to infer subclonal phylogeny and identify recurrent genomic alterations. We implemented immune cell signature and single-sample gene set enrichment analyses on tumor and normal transcriptome data from autopsy and additional primary and relapsed SCLC data sets. Furthermore, we evaluated T cell-inflamed gene expression profiles in neuroendocrine (ASCL1, NEUROD1) and non-neuroendocrine (YAP1, POU2F3) SCLC subtypes. Exome sequencing revealed clonal heterogeneity (intertumor and intratumor) arising from branched evolution and identified resistance-associated truncal and subclonal alterations in relapsed SCLC. Transcriptome analyses further revealed a noninflamed phenotype in neuroendocrine SCLC subtypes (ASCL1, NEUROD1) associated with decreased expression of genes involved in adaptive antitumor immunity whereas non-neuroendocrine subtypes (YAP1, POU2F3) revealed a more inflamed phenotype. Our results reveal substantial tumor heterogeneity and complex clonal evolution in relapsed SCLC. Furthermore, we report that neuroendocrine SCLC subtypes are immunologically cold, thus explaining decreased responsiveness to immune checkpoint blockade. These results suggest that the mechanisms of innate and acquired therapeutic resistances are subtype-specific in SCLC and highlight the need for continued investigation to bolster therapy selection and development for this cancer.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
20.4
作者：
Best, Sarah A.;Hess, Jonas B.;Sutherland, Kate D.
通讯作者：
Sutherland, Kate D.
影响因子：
9.3
作者：
Griffith, Malachi;Miller, Christopher A.;Wilson, Richard K.
通讯作者：
Wilson, Richard K.
影响因子：
11.2
作者：
Carter H;Chen S;Isik L;Tyekucheva S;Velculescu VE;Kinzler KW;Vogelstein B;Karchin R
通讯作者：
Karchin R
DOI：
10.1126/science.aar3593
发表时间：
2018-10-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cristescu R;Mogg R;Ayers M;Albright A;Murphy E;Yearley J;Sher X;Liu XQ;Lu H;Nebozhyn M;Zhang C;Lunceford JK;Joe A;Cheng J;Webber AL;Ibrahim N;Plimack ER;Ott PA;Seiwert TY;Ribas A;McClanahan TK;Tomassini JE;Loboda A;Kaufman D
通讯作者：
Kaufman D