APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response.
APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response.
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DOI：
10.18632/oncotarget.23344
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发表时间：
2018-01-12
期刊：
影响因子：
--
通讯作者：
Meeks JJ
中科院分区：
文献类型：
--
作者：
Glaser AP;Fantini D;Wang Y;Yu Y;Rimar KJ;Podojil JR;Miller SD;Meeks JJ
APOBEC酶负责涉及多种肿瘤的突变特征（TCW>T/G）。我们使用来自The Cancer Genome Atlas（n = 395），Beijing Genomics Institute（n = 99）和Cancer Cell Line Encyclopedia的测序数据探索膀胱癌中的APOBEC突变特征及其与特定突变，分子亚型，基因表达和生存的关系。基于APOBEC富集将肿瘤分为“APOBEC-高”和“APOBEC-低”。与APOBEC-低肿瘤患者相比，APOBEC-高肿瘤患者的总生存期更好（38.2 vs. 18.5个月，p = 0.005）。高APOBEC肿瘤更可能在DNA损伤反应基因（TP 53，ATR，BRCA 2）和染色质调节基因（ARID 1A，MLL，MLL 3）中发生突变，而低APOBEC肿瘤更可能在FGFR 3和KRAS中发生突变。APOBEC 3A和APOBEC 3B表达与突变负荷相关，与膀胱肿瘤分子亚型无关。APOBEC诱变与免疫特征（包括干扰素信号传导）的表达增加相关，并且在用IFNγ刺激APOBEC高膀胱癌细胞系后，APOBEC 3B的表达增加。总之，高APOBEC肿瘤更可能在DNA损伤反应和染色质调节基因中发生突变，可能为APOBEC酶提供更多底物，导致超突变表型和随后增强的免疫反应。
APOBEC enzymes are responsible for a mutation signature (TCW>T/G) implicated in a wide variety of tumors. We explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival using sequencing data from The Cancer Genome Atlas (n = 395), Beijing Genomics Institute (n = 99), and Cancer Cell Line Encyclopedia. Tumors were split into “APOBEC-high” and “APOBEC-low” based on APOBEC enrichment. Patients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs. 18.5 months, p = 0.005). APOBEC-high tumors are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2) and chromatin regulatory genes (ARID1A, MLL, MLL3), while APOBEC-low tumors are more likely to have mutations in FGFR3 and KRAS. APOBEC3A and APOBEC3B expression correlates with mutation burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis is associated with increased expression of immune signatures, including interferon signaling, and expression of APOBEC3B is increased after stimulation of APOBEC-high bladder cancer cell lines with IFNγ. In summary, APOBEC-high tumors are more likely to have mutations in DNA damage response and chromatin regulatory genes, potentially providing more substrate for APOBEC enzymes, leading to a hypermutational phenotype and the subsequent enhanced immune response.
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影响因子：
30.8
作者：
Burns, Michael B.;Temiz, Nuri A.;Harris, Reuben S.
通讯作者：
Harris, Reuben S.
DOI：
10.1016/j.jtho.2017.03.010
发表时间：
2017-06
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Faruki H;Mayhew GM;Serody JS;Hayes DN;Perou CM;Lai-Goldman M
通讯作者：
Lai-Goldman M
影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
DOI：
10.1080/07391102.2016.1231082
发表时间：
2017-01-01
影响因子：
4.4
作者：
Kumar, D. Thirumal;Doss, C. George Priya
通讯作者：
Doss, C. George Priya