Wheeler David A, Takebe Naoko, Hinoue Toshinori, Hoadley Katherine A, Cardenas Maria F, Hamilton Alina M, Laird Peter W, Wang Linghua, Johnson Adrienne, Dewal Ninad, Miller Vincent, Piñeyro David, Castro de Moura Manuel, Esteller Manel, Shen Hui, Zenklusen Jean Claude, Tarnuzzer Roy, McShane Lisa M, Tricoli James V, Williams Paul M, Lubensky Irina, O'Sullivan-Coyne Geraldine, Kohn Elise C, Little Richard F, White Jeffrey, Malik Shakun, Harris Lyndsay, Weil Carol, Chen Alice P, Karlovich Chris, Rodgers Brian, Shankar Lalitha, Jacobs Paula, Nolan Tracy, Hu Jianhong, Muzny Donna M, Doddapaneni Harshavardhan, Korchina Viktoriya, Gastier-Foster Julie, Bowen Jay, Leraas Kristen, Edmondson Elijah F, Doroshow James H, Conley Barbara A, Ivy S Percy, Staudt Louis M
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA.
Cancer Cell. 2021 Jan 11;39(1):38-53.e7. doi: 10.1016/j.ccell.2020.10.015. Epub 2020 Nov 19.
A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories-DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis-with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy.
一小部分晚期癌症患者的存活时间明显长于患有临床特征相似肿瘤的患者。通过对个体患者肿瘤活检样本进行基因组分析，已确定了对治疗产生特殊反应的分子机制。在此，我们使用多个平台对111名特殊反应患者的无偏队列的肿瘤活检样本进行了分析，以描绘遗传和表观遗传异常以及肿瘤微环境。综合分析揭示了近四分之一患者治疗反应的可能机制。这些机制可分为四大类——DNA损伤反应、细胞内信号传导、免疫参与以及预后良好的遗传改变——许多肿瘤属于多个类别。这些分析揭示了可能在治疗中加以利用的合成致死关系以及有利于治疗成功的罕见遗传病变，同时还提供了大量关于可能影响癌症治疗反应的致癌机制的可测试假设。
