Specific cancer types and prognosis in patients with variations in the KEAP1-NRF2 system: A retrospective cohort study

IF 4.5 2区 医学 Q1 ONCOLOGY
Cancer Science Pub Date : 2024-09-26 DOI:10.1111/cas.16355
Tomoyuki Iwasaki, Hidekazu Shirota, Keiju Sasaki, Kota Ouchi, Yuki Nakayama, Hiroyuki Oshikiri, Akihito Otsuki, Takafumi Suzuki, Masayuki Yamamoto, Chikashi Ishioka
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引用次数: 0

Abstract

The KEAP1–NRF2 system induces the expression of antioxidant genes in response to various types of oxidative stress. Some cancer cells activate this system, which increases their malignancy through genetic mutations. We performed a retrospective cohort study using the C-CAT database, which contains the gene-panel sequence data from 60,056 cases of diagnosed solid tumors. We analyzed somatic mutations in NRF2 and KEAP1 genes and their associations with clinical outcomes. Variants in the NRF2 gene were clustered in exon 2, which encodes the DLG and ETGE motifs essential for KEAP1 interaction. The NRF2 variants were frequently observed in esophageal and lung squamous cell carcinoma with frequencies of 35.9% and 19.6%, respectively. Among these mutations, the NRF2 variants in the ETGE motif were indicators of a worse prognosis. KEAP1 variants were found in 2.5% of all cases. The variants were frequent in lung cancer and showed a worse prognosis in lung and other types of adenocarcinomas. We then conducted gene expression analysis using TCGA data. While cancers with DLG and ETGE variants were similar in terms of gene expression profiles, there were significant differences between cancers with KEAP1 and NRF2 variants. Our results indicate that genetic alteration of the KEAP1–NRF2 pathway is a major factor in patient prognosis for each cancer type and its genetic variant. Variants in NRF2 and KEAP1 genes can characterize the biological basis of each cancer type and are involved in carcinogenesis, resistance to therapy, and other biological differences.

Abstract Image

KEAP1-NRF2系统变异患者的特定癌症类型和预后:一项回顾性队列研究。
KEAP1-NRF2 系统会诱导抗氧化基因的表达,以应对各种类型的氧化应激。一些癌细胞会激活这一系统,从而通过基因突变增加其恶性程度。我们利用 C-CAT 数据库进行了一项回顾性队列研究,该数据库包含 60,056 例确诊实体瘤患者的基因组序列数据。我们分析了 NRF2 和 KEAP1 基因的体细胞突变及其与临床结果的关系。NRF2 基因的变异集中在第 2 号外显子,该外显子编码 KEAP1 相互作用所必需的 DLG 和 ETGE 基序。NRF2基因变异在食管癌和肺鳞癌中出现频率分别为35.9%和19.6%。在这些变异中,ETGE基序的NRF2变异是预后较差的指标。2.5%的病例中发现了KEAP1变异。这种变异在肺癌中很常见,并显示肺癌和其他类型腺癌的预后较差。随后,我们利用 TCGA 数据进行了基因表达分析。虽然具有 DLG 和 ETGE 变异的癌症在基因表达谱方面相似,但具有 KEAP1 和 NRF2 变异的癌症之间存在显著差异。我们的研究结果表明,KEAP1-NRF2通路的基因改变是影响每种癌症类型及其基因变异患者预后的主要因素。NRF2和KEAP1基因的变异可以描述每种癌症类型的生物学基础,并参与致癌、抗药性和其他生物学差异。
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来源期刊
Cancer Science
Cancer Science 医学-肿瘤学
自引率
3.50%
发文量
406
审稿时长
2 months
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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