The impact of ARID1A mutation on molecular characteristics in colorectal cancer.
The impact of ARID1A mutation on molecular characteristics in colorectal cancer.
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DOI：
10.1016/j.ejca.2020.09.006
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Lenz HJ
中科院分区：
文献类型：
--
作者：
Tokunaga R;Xiu J;Goldberg RM;Philip PA;Seeber A;Battaglin F;Arai H;Lo JH;Naseem M;Puccini A;Berger MD;Soni S;Zhang W;Chen S;Hwang JJ;Shields AF;Marshall JL;Baba H;Korn WM;Lenz HJ
ARID1A是SWI/SNF复合体的一个关键亚单位，它调节核小体的动态重新定位以修复DNA损伤。只有小型先导性研究评估了ARID1A突变在结直肠癌(CRC)中的作用。本研究的目的是探讨ARID1A突变对结直肠癌临床病理和分子特征的潜在影响。我们使用了7978个CRC病例的综合数据集(一个来自CLIA认证的实验室的数据集和三个独立发布的数据集)。应用下一代测序、RNA测序和免疫组织化学方法分析ARID1A突变与免疫表型[微卫星不稳定状态(MSI)、肿瘤突变负荷(TMB)、程序性死亡配体1(PD-L1)和估计浸润性免疫细胞]、临床病理特征和相关途径等分子特征的关系。在发现和验证队列中，与ARID1A野生型样本相比，ARID1A突变样本具有更多基因组不稳定的肿瘤特征(MSI高和TMB高)，并表现出更多T细胞炎症微环境[PD-L1表达和高估计浸润性细胞毒性T淋巴细胞(CTL)]的特征。即使没有MSI高状态的ARID1A突变样本也是TMB高状态，有高水平的PD-L1表达，以及高估计的浸润性CTL。ARID1A突变在右侧原发肿瘤和早期肿瘤中更为常见。ARID1A突变主要存在与染色质修饰、DNA修复、WNT信号和EGFR抑制剂耐药途径相关的基因突变，ARID1A突变强烈调控DNA修复途径。在ARID1A突变样本中，化疗/放射治疗敏感性的关键基因被抑制。我们的发现可能为开发基于ARID1A突变状态的结直肠癌个体化治疗方法提供新的见解。
ARID1A is a key subunit of the SWI/SNF complex which regulates dynamic repositioning of nucleosomes to repair DNA damage. Only small pilot studies have evaluated the role of ARID1A mutation in colorectal cancer (CRC). The aim of present study was to explore the potential impact of ARID1A mutation on clinicopathological and molecular characteristics in CRC. We used integrated datasets of 7,978 CRC cases (one data set from a CLIA-certified laboratory and three independent published data sets). The associations of ARID1A mutation with molecular characteristics including immune profile [the status of microsatellite instability (MSI), tumor mutational burden (TMB), programmed death ligand 1 (PD-L1), and estimated-infiltrating immune cells], clinicopathological features, and related pathways were analyzed using next-generation sequencing, RNA-sequencing, and immunohistochemistry. ARID1A mutant samples had more genomically unstable tumor features (MSI-high and TMB-high) and exhibited more characteristics of a T-cell-inflamed microenvironment [PD-L1 expression, and high estimated-infiltrating cytotoxic T lymphocytes (CTLs)] than ARID1A wild-type samples in the discovery and validation cohorts. Even ARID1A mutant samples without MSI-high status were TMB-high, had high levels of PD-L1 expression, and high estimated-infiltrating CTLs. ARID1A mutations were more common with right-sided primary and earlier stage tumors. ARID1A mutant tumors mainly had co-occurring gene mutations related to Chromatin modifying, DNA repair, WNT signaling, and EGFR inhibitor resistance pathways, and ARID1A mutations strongly regulated DNA repair pathways. Key genes for chemo/radio-therapy sensitivity were suppressed in ARID1A mutant samples. Our findings may provide novel insight to develop individualized approaches for treatment of CRC based on ARID1A mutation status.
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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：
8
作者：
Berns K;Caumanns JJ;Hijmans EM;Gennissen AMC;Severson TM;Evers B;Wisman GBA;Jan Meersma G;Lieftink C;Beijersbergen RL;Itamochi H;van der Zee AGJ;de Jong S;Bernards R
通讯作者：
Bernards R
SWI/SNF成分ARID1A限制胰腺肿瘤形成。
影响因子：
24.5
作者：
Wang SC;Nassour I;Xiao S;Zhang S;Luo X;Lee J;Li L;Sun X;Nguyen LH;Chuang JC;Peng L;Daigle S;Shen J;Zhu H
通讯作者：
Zhu H
影响因子：
30.8
作者：
Mathur R;Alver BH;San Roman AK;Wilson BG;Wang X;Agoston AT;Park PJ;Shivdasani RA;Roberts CW
通讯作者：
Roberts CW
影响因子：
28.2
作者：
Grasso CS;Giannakis M;Wells DK;Hamada T;Mu XJ;Quist M;Nowak JA;Nishihara R;Qian ZR;Inamura K;Morikawa T;Nosho K;Abril-Rodriguez G;Connolly C;Escuin-Ordinas H;Geybels MS;Grady WM;Hsu L;Hu-Lieskovan S;Huyghe JR;Kim YJ;Krystofinski P;Leiserson MDM;Montoya DJ;Nadel BB;Pellegrini M;Pritchard CC;Puig-Saus C;Quist EH;Raphael BJ;Salipante SJ;Shin DS;Shinbrot E;Shirts B;Shukla S;Stanford JL;Sun W;Tsoi J;Upfill-Brown A;Wheeler DA;Wu CJ;Yu M;Zaidi SH;Zaretsky JM;Gabriel SB;Lander ES;Garraway LA;Hudson TJ;Fuchs CS;Ribas A;Ogino S;Peters U
通讯作者：
Peters U