Mechanisms and therapeutic implications of hypermutation in gliomas.
Mechanisms and therapeutic implications of hypermutation in gliomas.
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DOI：
10.1038/s41586-020-2209-9
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发表时间：
2020-04
期刊：
影响因子：
64.8
通讯作者：
Ligon KL
中科院分区：
文献类型：
--
作者：
Touat M;Li YY;Boynton AN;Spurr LF;Iorgulescu JB;Bohrson CL;Cortes-Ciriano I;Birzu C;Geduldig JE;Pelton K;Lim-Fat MJ;Pal S;Ferrer-Luna R;Ramkissoon SH;Dubois F;Bellamy C;Currimjee N;Bonardi J;Qian K;Ho P;Malinowski S;Taquet L;Jones RE;Shetty A;Chow KH;Sharaf R;Pavlick D;Albacker LA;Younan N;Baldini C;Verreault M;Giry M;Guillerm E;Ammari S;Beuvon F;Mokhtari K;Alentorn A;Dehais C;Houillier C;Laigle-Donadey F;Psimaras D;Lee EQ;Nayak L;McFaline-Figueroa JR;Carpentier A;Cornu P;Capelle L;Mathon B;Barnholtz-Sloan JS;Chakravarti A;Bi WL;Chiocca EA;Fehnel KP;Alexandrescu S;Chi SN;Haas-Kogan D;Batchelor TT;Frampton GM;Alexander BM;Huang RY;Ligon AH;Coulet F;Delattre JY;Hoang-Xuan K;Meredith DM;Santagata S;Duval A;Sanson M;Cherniack AD;Wen PY;Reardon DA;Marabelle A;Park PJ;Idbaih A;Beroukhim R;Bandopadhayay P;Bielle F;Ligon KL
在一些胶质瘤中观察到高肿瘤突变负担（超突变）;然而，超突变发生的机制以及它是否预测对免疫治疗的反应还知之甚少。在这里，我们全面分析了10,294个胶质瘤中突变负荷和特征的分子决定因素。我们描述了两种主要的超突变途径：一种是与DNA聚合酶和错配修复（MMR）基因的结构缺陷相关的从头途径，另一种是更常见的治疗后途径，与化疗敏感性胶质瘤中MMR缺陷驱动的获得性耐药相关，化疗药物替莫唑胺治疗后复发。在实验上，治疗后高度突变的神经胶质瘤的突变特征被MMR缺陷细胞中替莫唑胺诱导的损伤所概括。MMR缺陷型胶质瘤的特征在于缺乏显著的T细胞浸润、广泛的瘤内异质性、患者存活率低和对PD-1阻断的应答率低。此外，尽管批量分析没有检测到MMR缺陷胶质瘤中的微卫星不稳定性，但治疗后高度突变的胶质瘤细胞的单细胞全基因组测序分析确定了微卫星突变。这些结果表明，化疗可以驱动超突变群体的获得，而不会促进对PD-1阻断的反应，并支持突变负荷和特征在癌症中的诊断用途。
A high tumour mutational burden (hypermutation) is observed in some gliomas ; 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.
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免疫原性肿瘤克隆的排斥受到克隆分数的限制。
影响因子：
7.7
作者：
Gejman RS;Chang AY;Jones HF;DiKun K;Hakimi AA;Schietinger A;Scheinberg DA
通讯作者：
Scheinberg DA
影响因子：
16.6
作者：
Cortes-Ciriano I;Lee S;Park WY;Kim TM;Park PJ
通讯作者：
Park PJ
影响因子：
28.2
作者：
Francis JM;Zhang CZ;Maire CL;Jung J;Manzo VE;Adalsteinsson VA;Homer H;Haidar S;Blumenstiel B;Pedamallu CS;Ligon AH;Love JC;Meyerson M;Ligon KL
通讯作者：
Ligon KL
影响因子：
9.8
作者：
Berends, MJW;Wu, Y;Kleibeuker, JH
通讯作者：
Kleibeuker, JH
DOI：
10.1093/bioinformatics/btv408
发表时间：
2015-11-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Gehring JS;Fischer B;Lawrence M;Huber W
通讯作者：
Huber W