神經膠質瘤高突變機制及其治療意義
作者：
小柯機器人發布時間：2020/4/17 9:19:16
美國哈佛醫學院David M. Meredith等課題組的最新研究發現神經膠質瘤高突變的機制及其治療意。2020年4月15日出版的《自然》雜誌發表了該項成果。
他們全面分析10294膠質瘤的突變負荷和特徵的分子決定因素。他們描述了超突變的兩個主要途徑：與DNA聚合酶和錯配修復（MMR）基因的結構缺陷相關的從頭途徑；以及與化療敏感性神經膠質瘤中，MMR缺陷驅動的獲得性耐藥相關的更常見的後處理途徑，這種膠質瘤中化療藥物替莫唑胺治療後復發。
實驗上，替莫唑胺對MMR缺乏的細胞造成的損傷可以概括治療後高突變神經膠質瘤的突變特徵。MMR缺陷型神經膠質瘤的特點是：缺乏突出的T細胞浸潤，廣泛的腫瘤內異質性，患者存活率差以及對PD-1阻斷的反應率低。
此外，儘管大量分析未檢測到MMR缺陷型神經膠質瘤中的微衛星不穩定性，但對治療後突變的神經膠質瘤細胞進行單細胞全基因組測序分析，發現了微衛星突變。這些結果表明，化療可以驅動超突變群體的獲得，而不會促進對PD-1阻滯的反應，並支持對癌症中突變負荷和特徵的診斷使用。
據了解，在某些神經膠質瘤中觀察到很高的腫瘤突變負荷（高突變）；然而，人們對超突變發展的機制及其是否預測免疫療法的反應知之甚少。
附：英文原文
Title: Mechanisms and therapeutic implications of hypermutation in gliomas
Author: Mehdi Touat, Yvonne Y. Li, Adam N. Boynton, Liam F. Spurr, J. Bryan Iorgulescu, Craig L. Bohrson, Isidro Cortes-Ciriano, Cristina Birzu, Jack E. Geduldig, Kristine Pelton, Mary Jane Lim-Fat, Sangita Pal, Ruben Ferrer-Luna, Shakti H. Ramkissoon, Frank Dubois, Charlotte Bellamy, Naomi Currimjee, Juliana Bonardi, Kenin Qian, Patricia Ho, Seth Malinowski, Leon Taquet, Robert E. Jones, Aniket Shetty, Kin-Hoe Chow, Radwa Sharaf, Dean Pavlick, Lee A. Albacker, Nadia Younan, Capucine Baldini, Mat Verreault, Marine Giry, Erell Guillerm, Samy Ammari, Frdric Beuvon, Karima Mokhtari, Agusti Alentorn, Caroline Dehais, Caroline Houillier, Florence Laigle-Donadey, Dimitri Psimaras, Eudocia Q. Lee, Lakshmi Nayak, J. Ricardo McFaline-Figueroa, Alexandre Carpentier, Philippe Cornu, Laurent Capelle, Bertrand Mathon, Jill S. Barnholtz-Sloan, Arnab Chakravarti, Wenya Linda Bi, E. Antonio Chiocca, Katie Pricola Fehnel, Sanda Alexandrescu, Susan N. Chi, Daphne Haas-Kogan, Tracy T. Batchelor, Garrett M. Frampton, Brian M. Alexander, Raymond Y. Huang, Azra H. Ligon, Florence Coulet, Jean-Yves Delattre, Kh Hoang-Xuan, David M. Meredith
Issue&Volume: 2020-04-15
Abstract: A high tumour mutational burden (hypermutation) is observed in some gliomas1,2,3,4,5; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.
DOI: 10.1038/s41586-020-2209-9
Source: https://www.nature.com/articles/s41586-020-2209-9