Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Histopathology. 2012 May;60(6):943-52. doi: 10.1111/j.1365-2559.2012.04178.x. Epub 2012 Feb 20.
KEAP1 inhibits nuclear factor erythroid 2-related factor 2 (NRF2)-induced cytoprotection, and is considered to be a candidate tumour suppressor. Somatic mutation of NRF2 has been analysed in a wide variety of human cancers, whereas somatic mutation of KEAP1 has been reported only in lung and gall bladder cancers. The aim of our study was to investigate whether KEAP1 mutations are widespread in human cancers.
We analysed 499 cancer tissues from lung, breast, colon, stomach, liver, larynx and prostate, and leukaemias, by single-strand conformation polymorphism analysis. We detected somatic mutations of KEAP1 in gastric (11.1%), hepatocellular (8.9%), colorectal (7.8%), lung (4.6%), breast (2.0%) and prostate (1.3%) carcinomas. Allelic losses of the KEAP1 locus were identified in 42.9% of cancers with KEAP1 mutations, but no NRF2 mutations were detected in these cancers. The NRF2-activated cytoprotective proteins (NAD(P)H dehydrogenase quinone 1 and glutamine-cysteine ligase catalytic subunit) were expressed in all of the cancers with KEAP1 mutations.
Our data show that KEAP1 mutations occur widely in solid cancers, irrespective of histological type. Biallelic inactivation of KEAP1 and increased levels of cytoprotective proteins in the cancers suggest that KEAP1 mutations might protect cancer cells from oxidative insults and play a role in the development of solid cancers.
KEAP1 抑制红细胞生成素 2 相关因子 2（NRF2）诱导的细胞保护作用，被认为是候选肿瘤抑制因子。已对各种人类癌症中的 NRF2 体细胞突变进行了分析，而仅在肺癌和胆囊癌中报道了 KEAP1 的体细胞突变。我们研究的目的是调查 KEAP1 突变是否广泛存在于人类癌症中。
我们通过单链构象多态性分析，分析了来自肺、乳腺、结肠、胃、肝、喉和前列腺以及白血病的 499 种癌症组织。我们在胃癌（11.1%）、肝细胞癌（8.9%）、结直肠癌（7.8%）、肺癌（4.6%）、乳腺癌（2.0%）和前列腺癌（1.3%）中检测到 KEAP1 的体细胞突变。在具有 KEAP1 突变的癌症中，KEAP1 基因座的等位基因缺失率为 42.9%，但这些癌症中未检测到 NRF2 突变。NRF2 激活的细胞保护蛋白（NAD（P）H 脱氢酶醌 1 和谷氨酰胺半胱氨酸连接酶催化亚基）在所有具有 KEAP1 突变的癌症中均有表达。
我们的数据表明，KEAP1 突变广泛存在于实体瘤中，与组织学类型无关。KEAP1 的双等位基因失活和癌症中细胞保护蛋白水平的增加表明，KEAP1 突变可能使癌细胞免受氧化应激的影响，并在实体瘤的发生中发挥作用。
