Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
Genes Chromosomes Cancer. 2010 Aug;49(8):711-25. doi: 10.1002/gcc.20784.
To identify a novel amplified cancer gene a systematic screen of 975 human cancer DNA samples, 750 cell lines and 225 primary tumors, using the Affymetrix 10K SNP microarray was undertaken. The screen identified 193 amplicons. A previously uncharacterized amplicon located on 6p21.2 whose 1 Mb minimal common amplified region contained eight genes (GLO1, DNAH8, GLP1R, C6orf64, KCNK5, KCNK17, KCNK16, and C6orf102) was further investigated to determine which gene(s) are the biological targets of this amplicon. Real time quantitative PCR (qPCR) analysis of all amplicon 6p21.2 genes in 618 human cancer cell lines identified GLO1, encoding glyoxalase 1, to be the most frequently amplified gene [twofold or greater amplification in 8.4% (49/536) of cancers]. Also the association between amplification and overexpression was greatest for GLO1. RNAi knockdown of GLO1 had the greatest and most consistent impact on cell accumulation and apoptosis. Cell lines with GLO1 amplification were more sensitive to inhibition of GLO1 by bromobenzylglutathione cyclopentyl diester (BBGC). Subsequent qPCR of 520 primary tumor samples identified twofold and greater amplification of GLO1 in 8/37 (22%) of breast, 12/71 (17%) of sarcomas, 6/53 (11.3%) of nonsmall cell lung, 2/23 (8.7%) of bladder, 6/93 (6.5%) of renal and 5/83 (6%) of gastric cancers. Amplification of GLO1 was rare in colon cancer (1/35) and glioma (1/94). Collectively the results indicate that GLO1 is at least one of the targets of gene amplification on 6p21.2 and may represent a useful target for therapy in cancers with GLO1 amplification.
为了鉴定一种新型的扩增癌症基因，我们对 975 个人类癌症 DNA 样本、750 个细胞系和 225 个原发性肿瘤进行了系统的筛查，使用的是 Affymetrix 10K SNP 微阵列。该筛查发现了 193 个扩增子。在 6p21.2 上发现了一个以前未被描述的扩增子，其 1Mb 的最小共同扩增区域包含八个基因（GLO1、DNAH8、GLP1R、C6orf64、KCNK5、KCNK17、KCNK16 和 C6orf102），我们进一步研究了该扩增子的哪个基因是其生物靶标。对 618 个人类癌细胞系中 6p21.2 所有扩增子基因的实时定量 PCR（qPCR）分析表明，编码乙醛酸酶 1 的 GLO1 是最常扩增的基因[在 536 个癌症中有 8.4%（49/536）存在两倍或更高的扩增]。扩增与过表达之间的关联也与 GLO1 最为密切。GLO1 的 RNAi 敲低对细胞积聚和凋亡的影响最大且最一致。GLO1 扩增的细胞系对溴苄基谷胱甘肽环戊基二酯（BBGC）抑制 GLO1 更为敏感。随后对 520 个原发性肿瘤样本的 qPCR 分析表明，在 37 个乳腺癌中有 8 个（22%）、71 个肉瘤中有 12 个（17%）、53 个非小细胞肺癌中有 6 个（11.3%）、23 个膀胱癌中有 2 个（8.7%）、93 个肾癌中有 6 个（6.5%）和 83 个胃癌中有 5 个（6%）存在 GLO1 的两倍或更高的扩增。在结肠癌（1/35）和神经胶质瘤（1/94）中，GLO1 的扩增很少见。总的来说，这些结果表明，GLO1 至少是 6p21.2 上基因扩增的靶标之一，并且可能代表了具有 GLO1 扩增的癌症的一种有用的治疗靶标。
