Isolated BAP1 Genomic Alteration in Malignant Pleural Mesothelioma Predicts Distinct Immunogenicity with Implications for Immunotherapeutic Response.
Isolated BAP1 Genomic Alteration in Malignant Pleural Mesothelioma Predicts Distinct Immunogenicity with Implications for Immunotherapeutic Response.
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作者：
恶性胸膜间皮瘤（MPM）是一种高度侵袭性，治疗耐药的癌症，具有明确的炎症病因，目前尚无治愈方法。免疫检查点抑制（ICI）疗法已经改变了许多类型癌症的治疗模式，最近的临床数据显示有希望改善MPM治疗。然而，对ICI治疗的反应既不统一也不可预测。MPM的基因组图谱主要以肿瘤抑制基因（TSGs）（约70%）的基因组改变为特征，特别是BAP1、CDKN2A/B和NF2。孤立的TSG基因组改变与多个并发的TSG改变对临床结果、治疗反应、MPM生物学和免疫肿瘤微环境的影响尚不清楚。在这里，我们展示了TSG改变组合对MPM临床结局、治疗反应和分子通路的影响。例如，与有或没有BAP1的CDKN2A/B和/或NF2改变的肿瘤相比，仅BAP1改变的肿瘤(a)与更长的总体患者生存率相关，(B)包含具有改变的转录因子和途径活性模式的独特免疫原性亚型。恶性胸膜间皮瘤（MPM）是一种侵袭性的胸膜腔间皮细胞癌，缺乏有效的治疗方法。肿瘤抑制基因（TSGs） BAP1、CDKN2A/B和NF2的多体细胞突变和拷贝数丢失通常与MPM相关。TSG的单个和多个基因组改变对MPM生物学、免疫肿瘤微环境、临床结果和治疗反应的影响尚不清楚。与有或没有BAP1的CDKN2A/B和/或NF2改变的肿瘤相比，仅BAP1基因组改变的肿瘤患者的总体生存率更长，并且形成了一种独特的免疫原性亚型，其转录因子和途径活性模式发生了改变。CDKN2A/B基因组改变一直导致不良的临床结果。由于只有BAP1的基因组改变与PD-1治疗反应特征和更高的LAG3和VISTA基因表达相关，因此它可能是免疫检查点阻断治疗的候选标记物。我们关于TSG基因型对MPM的影响以及TSG改变与分子通路之间的相关性的研究结果为开发个体化MPM治疗提供了基础。
Malignant Pleural Mesothelioma (MPM) is a highly aggressive, therapy-resistant cancer with a well-established inflammatory etiology and has no cure. Immune checkpoint inhibition (ICI) therapy has shifted treatment paradigms in many types of cancers, and recent clinical data have shown promise for improving MPM treatment. However, response to ICI therapy has been neither uniform nor predictable. The genomic landscape of MPM is primarily characterized by genomic alterations in tumor suppressor genes (TSGs) (~70%), particularly BAP1, CDKN2A/B and NF2. The impact of an isolated TSG genomic alteration versus multiple concurrent TSG alterations on clinical outcome, treatment response and MPM biology and the immune tumor microenvironment are unclear. Here, we showed the effect of TSG alteration combinations on clinical outcome, therapeutic response, and molecular pathways in MPM. For example, tumors with alterations in BAP1 alone were (a) associated with a longer overall patient survival rate compared to tumors with CDKN2A/B and/or NF2 alterations with or without BAP1 and (b) comprised a distinct immunogenic subtype with altered transcription factor and pathway activity patterns. Malignant pleural mesothelioma (MPM), an aggressive cancer of the mesothelial cells lining the pleural cavity, lacks effective treatments. Multiple somatic mutations and copy number losses in tumor suppressor genes (TSGs) BAP1, CDKN2A/B, and NF2 are frequently associated with MPM. The impact of single versus multiple genomic alterations of TSG on MPM biology, the immune tumor microenvironment, clinical outcomes, and treatment responses are unknown. Tumors with genomic alterations in BAP1 alone were associated with a longer overall patient survival rate compared to tumors with CDKN2A/B and/or NF2 alterations with or without BAP1 and formed a distinct immunogenic subtype with altered transcription factor and pathway activity patterns. CDKN2A/B genomic alterations consistently contributed to an adverse clinical outcome. Since the genomic alterations of only BAP1 was associated with the PD-1 therapy response signature and higher LAG3 and VISTA gene expression, it might be a candidate marker for immune checkpoint blockade therapy. Our results on the impact of TSG genotypes on MPM and the correlations between TSG alterations and molecular pathways provide a foundation for developing individualized MPM therapies.
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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：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
影响因子：
4.7
作者：
Budhwani M;Mazzieri R;Dolcetti R
通讯作者：
Dolcetti R
抑制细胞周期蛋白依赖性激酶 4/6 可克服恶性间皮瘤中对程序性细胞死亡 1 阻断的主要耐药性。
DOI：
10.1016/j.athoracsur.2021.08.054
发表时间：
2022-11
期刊：
The Annals of thoracic surgery
影响因子：
--
作者：
Jang HJ;Truong CY;Lo EM;Holmes HM;Ramos D;Ramineni M;Lee JS;Wang DY;Pietropaolo M;Ripley RT;Burt BM;Lee HS
通讯作者：
Lee HS
影响因子：
7.5
作者：
Asciak, Rachelle;George, Vineeth;Rahman, Najiib M.
通讯作者：
Rahman, Najiib M.