Exome sequencing identifies somatic mutations in novel driver genes in non-small cell lung cancer

Zhang, Manman; Zhang, Lele; Li, Yan; Sun, Feng; Fang, Yun; Zhang, Ruijia; Wu, Jin; Zhou, Guanbiao; Song, Hwangjun; Xue, Lu; Han, Bing; Zheng, Cuixia

doi:10.18632/aging.103500

Cited by 11 publications

(12 citation statements)

References 45 publications

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“…Given its role in DNA damage responses and p53-mediated apoptotic cell death, it is possible that the abnormal expression of HECW1 may disrupt cell homeostasis and cause tumorigenesis [ 19 , 20 ]. Recently, mutations of HECW1 have been identified in non-small cell lung cancer and muscle-invasive transitional cell carcinoma [ 10 , 11 ]. Additionally, HECW1 has been found to negatively regulate ErbB4 protein expression via ubiquitin-mediated degradation in breast cancer [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

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Integrating HECW1 expression into the clinical indicators exhibits high accuracy in assessing the prognosis of patients with clear cell renal cell carcinoma

et al. 2021

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Abstracts Background Although many intratumoral biomarkers have been reported to predict clear cell renal cell carcinoma (ccRCC) patient prognosis, combining intratumoral and clinical indicators could predict ccRCC prognosis more accurately than any of these markers alone. This study mainly examined the prognostic value of HECT, C2 and WW domain-containing E3 ubiquitin protein ligase 1 (HECW1) expression in ccRCC patients in combination with established clinical indicators. Methods The expression level of HECW1 was screened out by data-independent acquisition mass spectrometry (DIA-MS) and analyzed in ccRCC patients from the The Cancer Genome Atlas (TCGA) database and our cohort. A total of 300 ccRCC patients were stochastically divided into a training cohort and a validation cohort, and real-time PCR, immunohistochemistry (IHC) and statistical analyses were employed to examine the prognostic value of HECW1 in ccRCC patients. Results The expression level of HECW1 usually decreased in human ccRCC specimens relative to control specimens in TCGA (p < 0.001). DIA-MS, Real-time PCR, and IHC analyses also showed that the majority of ccRCCs harbored decreased HECW1 expression compared with that in normal adjacent tissues (p < 0.001). Additionally, HECW1 expression was reduced in ccRCC cell lines compared with the normal renal cell line HK-2 (p < 0.001). Moreover, lower HECW1 expression was found in ccRCC patients with a higher tumor node metastasis (TNM) stage, bone metastasis, or first-line targeted drug resistance (p < 0.001). Low HECW1 expression indicated higher TNM stage, SSIGN (Stage, Size, Grade, and Necrosis) score and WHO/ISUP grade and poor prognosis in ccRCC patients (p < 0.05). Even after multivariable adjustment, HECW1, TNM stage, and SSIGN score served as independent risk factors. The c-index analysis showed that integrating intratumoral HECW1 expression into TNM stage or SSIGN score resulted in a higher c-index value than these indicators alone for predicting ccRCC patient prognosis. Conclusion HECW1 is a novel prognostic biomarker and therapeutic target in ccRCC, and integrating intratumoral HECW1 expression with established clinical indicators yields higher accuracy in assessing the postoperative prognosis of ccRCC patients.

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Section: Discussionmentioning

confidence: 99%

“…Furthermore, HECW1 has been described in some studies on malignant tumors. Exome sequencing studies have revealed somatic mutations in HECW1, along with other novel driver genes, in non-small cell lung cancer (NSCLC) [ 10 ]. In addition, the novel mutant gene HECW1 was identified in muscle-invasive transitional cell carcinoma [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Integrating HECW1 expression into the clinical indicators exhibits high accuracy in assessing the prognosis of patients with clear cell renal cell carcinoma

et al. 2021

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“…Many previous studies have shown that MTs in NRF2 play a role in cancer progression [ 31 , 32 , 33 ]. We summarize NRF2 MTs in different cancers and MTs in NRF2 involved with the overactivation of NRF2.…”

Section: Discussionmentioning

confidence: 99%

NRF2 DLG Domain Mutations Identified in Japanese Liver Cancer Patients Affect the Transcriptional Activity in HCC Cell Lines

Haque

Śmiech

Łuczyńska

et al. 2021

IJMS

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Geographically, East Asia had the highest liver cancer burden in 2017. Besides this, liver cancer-related deaths were high in Japan, accounting for 3.90% of total deaths. The development of liver cancer is influenced by several factors, and genetic alteration is one of the critical factors among them. Therefore, the detailed mechanism driving the oncogenic transformation of liver cells needs to be elucidated. Recently, many researchers have focused on investigating the liver cancer genome and identified somatic mutations (MTs) of several transcription factors. In this line, next-generation sequencing of the cancer genome identified that oxidative stress-related transcription factor NRF2 (NFE2L2) is mutated in different cancers, including hepatocellular carcinoma (HCC). Here, we demonstrated that NRF2 DLG motif mutations (NRF2 D29A and L30F), found in Japanese liver cancer patients, upregulate the transcriptional activity of NRF2 in HCC cell lines. Moreover, the transcriptional activity of NRF2 mutations is not suppressed by KEAP1, presumably because NRF2 MTs disturb proper NRF2-KEAP1 binding and block KEAP1-mediated degradation of NRF2. Additionally, we showed that both MTs upregulate the transcriptional activity of NRF2 on the MMP9 promoter in Hepa1-6 and Huh7 cells, suggesting that MT derived gain-of-function of NRF2 may be important for liver tumor progression. We also found that ectopic overexpression of oncogenic BRAF WT and V600E increases the transcriptional activity of NRF2 WT on both the 3xARE reporter and MMP9 promoter. Interestingly, NRF2 D29A and L30F MTs with oncogenic BRAF V600E MT synergistically upregulate the transcription activity of NRF2 on the 3xARE reporter and MMP9 promoter in Hepa1-6 and Huh7 cells. In summary, our findings suggest that MTs in NRF2 have pathogenic effects, and that NRF2 MTs together with oncogenic BRAF V600E MT synergistically cause more aberrant transcriptional activity. The high activity of NRF2 MTs in HCC with BRAF MT warrants further exploration of the potential diagnostic, prognostic, and therapeutic utility of this pathway in HCC.

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“…Interestingly, genetic analyses revealed that the NFE2L2 mutational profile found in LUAD is significantly different from LUSC [96]. In fact, while KEAP1 is mostly mutated in LUAD, NFE2L2 is mainly affected in LUSC [97,98]; in the latter, CUL3 is also significantly mutated [12,26]. Other genetic alterations in this signaling cascade also found in LUSC patients include single nucleotide polymorphisms (SNPs) in KEAP1 and CUL3 [99], an increased number of NFE2L2 copies [100], KEAP1 loss of heterozygosity (LOH) and KEAP1 promoter methylations [101].…”

Section: Bad Side Of Nrf2 In Nsclc Progressionmentioning

confidence: 99%

Role of NRF2 in Lung Cancer

Sánchez-Ortega

Carrera

Garrido

2021

Cells

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The gene expression program induced by NRF2 transcription factor plays a critical role in cell defense responses against a broad variety of cellular stresses, most importantly oxidative stress. NRF2 stability is fine-tuned regulated by KEAP1, which drives its degradation in the absence of oxidative stress. In the context of cancer, NRF2 cytoprotective functions were initially linked to anti-oncogenic properties. However, in the last few decades, growing evidence indicates that NRF2 acts as a tumor driver, inducing metastasis and resistance to chemotherapy. Constitutive activation of NRF2 has been found to be frequent in several tumors, including some lung cancer sub-types and it has been associated to the maintenance of a malignant cell phenotype. This apparently contradictory effect of the NRF2/KEAP1 signaling pathway in cancer (cell protection against cancer versus pro-tumoral properties) has generated a great controversy about its functions in this disease. In this review, we will describe the molecular mechanism regulating this signaling pathway in physiological conditions and summarize the most important findings related to the role of NRF2/KEAP1 in lung cancer. The focus will be placed on NRF2 activation mechanisms, the implication of those in lung cancer progression and current therapeutic strategies directed at blocking NRF2 action.

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Exome sequencing identifies somatic mutations in novel driver genes in non-small cell lung cancer

Cited by 11 publications

References 45 publications

Integrating HECW1 expression into the clinical indicators exhibits high accuracy in assessing the prognosis of patients with clear cell renal cell carcinoma

Integrating HECW1 expression into the clinical indicators exhibits high accuracy in assessing the prognosis of patients with clear cell renal cell carcinoma

NRF2 DLG Domain Mutations Identified in Japanese Liver Cancer Patients Affect the Transcriptional Activity in HCC Cell Lines

Role of NRF2 in Lung Cancer

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