SH2D4A downregulation due to loss of chromosome 8p is associated with poor prognosis and low T cell infiltration in colorectal cancer
SH2D4A downregulation due to loss of chromosome 8p is associated with poor prognosis and low T cell infiltration in colorectal cancer
复制标题
由于 8p 染色体缺失导致的 SH2D4A 下调与结直肠癌预后不良和 T 细胞浸润低相关
DOI：
10.1038/s41416-021-01660-y
复制
发表时间：
2021
影响因子：
8.8
通讯作者：
Kono Koji
中科院分区：
文献类型：
--
作者：
Matsumoto Takuro;Okayama Hirokazu;Nakajima Shotaro;Saito Katsuharu;Ito Misato;Kaneta Akinao;Kanke Yasuyuki;Onozawa Hisashi;Hayase Suguru;Fujita Shotaro;Sakamoto Wataru;Saito Motonobu;Seze Zenichiro;Momma Tomoyuki;Mimura Kosaku;Kono Koji
背景结直肠癌（colorectal cancer，CRC）是通过错配修复缺陷（deficient mismatch-repair，dMMR）引起的染色体不稳定（chromosome instability，CIN）或微卫星不稳定（microsatellite instability，MSI）而发生的。我们的目的是寻找新的癌症相关基因，这些基因在微卫星稳定（MSS）CRC中恶性转化时下调，这些基因通常表现为CIN，具有熟练的错配修复（pMMR）。方法对腺瘤，MSI/MSS CRC和细胞系进行全面筛选，然后进行拷贝数分析，并在微阵列和RNA-seq队列中证实其遗传和预后相关性（共3262例）。对524例大肠腺瘤、原位癌和dMMR/pMMR大肠癌标本进行SH 2D 4A免疫组化染色。SH 2D 4A的功能作用进行了研究，使用CRC细胞line.ResultsA组的11个基因，包括SH 2D 4A，在腺瘤癌序列MSS/CIN CRCs，主要是由于染色体8 p缺失，下调，其负面的预后影响，在独立的队列验证。所有腺瘤均为SH 2D 4A阳性，但一部分CRC（5.3%）缺乏SH 2D 4A免疫组化染色，与预后不良和T细胞浸润稀少相关。SH 2D 4A耗竭没有影响细胞增殖或IL-6诱导的STAT 3 phosphorylation.ConclusionsOur研究结果表明，下调染色体8 p上的多个基因，包括SH 2D 4A，协同促进肿瘤发生，导致免疫冷肿瘤微环境和预后不良。
BackgroundColorectal cancer (CRC) develops through chromosomal instability (CIN) or microsatellite instability (MSI) due to deficient mismatch-repair (dMMR). We aimed to characterise novel cancer-associated genes that are downregulated upon malignant transformation in microsatellite stable (MSS) CRCs, which typically exhibit CIN with proficient mismatch-repair (pMMR).MethodsComprehensive screening was conducted on adenomas, MSI/MSS CRCs and cell lines, followed by copy number analysis, and their genetic and prognostic relevance was confirmed in microarray and RNA-seq cohorts (n= 3262, in total). Immunohistochemistry for SH2D4A was performed in 524 specimens of adenoma, carcinoma in situ and dMMR/pMMR CRC. The functional role of SH2D4A was investigated using CRC cell lines.ResultsA set of 11 genes, including SH2D4A, was downregulated during the adenoma-carcinoma sequence in MSS/CIN CRCs, mainly due to chromosome 8p deletions, and their negative prognostic impact was validated in independent cohorts. All adenomas were SH2D4A positive, but a subset of CRCs (5.3%) lacked SH2D4A immunohistochemical staining, correlating with poor prognosis and scarce T cell infiltration. SH2D4A depletion did not affect cell proliferation or IL-6-induced STAT3 phosphorylation.ConclusionsOur findings suggest that downregulation of multiple genes on chromosome 8p, including SH2D4A, cooperatively contribute to tumorigenesis, resulting in the immune cold tumour microenvironment and poor prognosis.
登录
查看更多内容
影响因子：
50.3
作者：
Taylor AM;Shih J;Ha G;Gao GF;Zhang X;Berger AC;Schumacher SE;Wang C;Hu H;Liu J;Lazar AJ;Cancer Genome Atlas Research Network;Cherniack AD;Beroukhim R;Meyerson M
通讯作者：
Meyerson M
影响因子：
13.5
作者：
Ploeger, Carolin;Waldburger, Nina;Fraas, Angelika;Goeppert, Benjamin;Pusch, Stefan;Breuhahn, Kai;Wang, Xin Wei;Schirmacher, Peter;Roessler, Stephanie
通讯作者：
Roessler, Stephanie
影响因子：
29.4
作者：
Pino MS;Chung DC
通讯作者：
Chung DC
影响因子：
29.4
作者：
Roessler S;Long EL;Budhu A;Chen Y;Zhao X;Ji J;Walker R;Jia HL;Ye QH;Qin LX;Tang ZY;He P;Hunter KW;Thorgeirsson SS;Meltzer PS;Wang XW
通讯作者：
Wang XW
影响因子：
50.3
作者：
Liu Y;Sethi NS;Hinoue T;Schneider BG;Cherniack AD;Sanchez-Vega F;Seoane JA;Farshidfar F;Bowlby R;Islam M;Kim J;Chatila W;Akbani R;Kanchi RS;Rabkin CS;Willis JE;Wang KK;McCall SJ;Mishra L;Ojesina AI;Bullman S;Pedamallu CS;Lazar AJ;Sakai R;Cancer Genome Atlas Research Network;Thorsson V;Bass AJ;Laird PW
通讯作者：
Laird PW