Gene aberrations for precision medicine against lung adenocarcinoma

Saito, Motonobu; Shiraishi, Kouya; Kunitoh, Hideo; Takenoshita, Seiichi; Yokota, Jun; Kohno, Takashi

doi:10.1111/cas.12941

Cited by 191 publications

(142 citation statements)

References 72 publications

(121 reference statements)

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“…Lung cancer is the most common malignancy and the leading cause of cancer-related deaths worldwide (1) whereas lung adenocarcinoma is the most frequent histological subtype of lung cancer (2). Oncogene aberrations have been extensively studied in the adenocarcinoma subtype (3), and show great molecular heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

Aberrant status and clinicopathologic characteristic associations of 11 target genes in 1,321 Chinese patients with lung adenocarcinoma

Zhao¹,

Zhan²,

Li³

et al. 2018

J. Thorac. Dis.

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epidermal growth factor receptor (EGFR) (729, 58.5%), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) (83, 6.7%), human epidermal growth factor receptor 2 (HER2) (82, 6.6%), anaplastic lymphoma kinase (ALK) (23, 1.8%), phosphoinositide-3-kinase catalytic alpha polypeptide (PIK3CA) (20, 1.6%), Ret proto-oncogene RET (15, 1.2%), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) (12, 1.0%), B-raf proto-oncogene (BRAF) (9, 0.7%), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) (3, 0.2%). Fourteen (1.9%) of 731 patients were PD-1 positive and 95 (13.0%) were PD-L1 positive in tumor cells. In men and smokers, there were more frequent KRAS mutations (both P<0.001) and PD-L1 positive tumors (P<0.001, P=0.005, respectively), and less frequent EGFR mutations (P=0.049, <0.001, respectively). In ground-glass opacity (GGO) or ground-glass nodules (GGN), there were more HER2 (P=0.033) but less EGFR (P=0.025) and PIK3CA mutations (P=0.012), and ALK translocations (P=0.014). EGFR (P<0.001), KRAS mutations (P=0.004) and PD-L1 positive tumors (P=0.046) were more frequent in older patients, while HER2 (P<0.001), ALK (P=0.005) and ROS1 aberrations (P=0.044) were less frequent.Invasive mucinous adenocarcinoma was significantly associated with KRAS and ALK aberrations (both P<0.001), while solid predominant adenocarcinoma was associated with ROS1 translocations (P=0.036) and PD-L1 expression (P<0.001). KRAS, HER2, and ALK aberrations were scarce in patients with EGFR mutations (all P<0.001), while PD-L1 positive tumors positively correlated with ALK translocations (P=0.031) and negatively correlated with HER2 mutations (P=0.019). Conclusions: Most patients with primary lung adenocarcinoma harbored target gene aberrations. The frequency of each alteration differed in patients depending on clinicopathologic characteristics.

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Section: Introductionmentioning

confidence: 99%

Aberrant status and clinicopathologic characteristic associations of 11 target genes in 1,321 Chinese patients with lung adenocarcinoma

Zhao¹,

Zhan²,

Li³

et al. 2018

J. Thorac. Dis.

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“…In recent years, there have been dramatic advances in the treatment of lung adenocarcinoma because of the development of therapies targeting driver oncogene alterations, for example, drugs targeting the epidermal growth factor receptor (EGFR) mutation or the anaplastic lymphoma kinase (ALK) fusion [1, 2]. However, most patients will inevitably develop acquired resistance to the targeted therapy [3–5].…”

Section: Introductionmentioning

confidence: 99%

The significance of programmed cell death ligand 1 expression in resected lung adenocarcinoma

Shi

Sun

et al. 2017

Oncotarget

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BackgroundLung adenocarcinoma (AD) is a common variant of non-small cell lung cancer (NSCLC). Programmed cell death protein 1/programmed cell death ligand 1 (PD1/PD-L1) are promising immunotherapy targets and its expression may be an important biomarker of predicting clinical response. In this study, we evaluated PD-L1 expression in conjunction with clinicopathological characteristics and outcomes in resected lung adenocarcinoma.ResultsThis study included 133 cases of lung adenocarcinoma. PD-L1 expression rate in lung adenocarcinoma was 16.5% at the mRNA level and 13.5% at the protein level, and the kappa coefficient of the two examination methods was 0.824 (P = 0.219, highly correlated). PD-L1 was highly expressed in male patients and smokers with lung adenocarcinoma (P = 0.019 and 0.002, respectively), while no associations were identified between PD-L1 expression and age, tumor size, clinical stage, positive pleural invasion, lymph node metastasis, or therapy methods. Overexpression of PD-L1 was a significant indicator of shorter recurrence free survival time and overall survival (P = 0.000 and 0.000, respectively). Multivariate analysis revealed that PD-L1 expression was an independent risk factor for poor recurrence free survival and overall survival (P = 0.009 and 0.016, respectively).Materials and MethodsExpression of PD-L1 was examined with immunohistochemistry, using the VENTANA PD-L1 (SP263) rabbit monoclonal antibody. mRNA levels of PD-L1 were evaluated using in situ hybridization.ConclusionsPD-L1 overexpression is more frequently observed in male patients and smokers in lung adenocarcinoma. PD-L1 expression is an indicator of worse prognosis in surgically resected lung adenocarcinoma patients.

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“…A multistage GWAS (genome‐wide association studies) on lung cancer suggested that lung tumors attributed to differing carcinogens may have developed from individual genetic risk markers . And most notably, lung adenocarcinoma (LADC), the most frequent histological type of lung cancer, has exploited and elevated the clinical application of effective molecular targeted therapies . The effectiveness of precision medicine against LADCs urgently requires peculiar molecular markers and novel therapeutic strategies from vast changes in gene regulation.…”

Section: Introductionmentioning

confidence: 99%

SH2B1 promotes epithelial‐mesenchymal transition through the IRS1/β‐catenin signaling axis in lung adenocarcinoma

Wang

Cheng

Gao

et al. 2018

Molecular Carcinogenesis

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Lung adenocarcinoma (LADC), the most prevalent type of human lung cancer, is characterized by many molecular abnormalities. SH2B1, a member of the SH2‐domain containing family, have recently been shown to act as tumor activators in multiple cancers, including LADC. However, the mechanisms underlying SH2B1 overexpression are not completely understood. Here, we reported that SH2B1 expression levels were significantly upregulated and positively associated with EMT markers and poor patient survival in LADC specimens. Modulation of SH2B1 levels had distinct effects on cell proliferation, cell cycle, migration, invasion, and morphology in A549 and H1299 cells in vitro and in vivo. At the molecular level, overexpression of SH2B1 resulted in the upregulation of the EMT markers, especially induced β‐catenin accumulation and activated β‐catenin signaling to promote LADC cell proliferation and metastasis, while silencing SH2B1 had the opposite effect. Furthermore, ectopic expression of SH2B1 in H1299 cells increased IRS1 expression level. Reduced expression of IRS1 considerably inhibited H1299 cell proliferation, migration, and invasion which were driven by SH2B1 overexpression. Collectively, these results provide unequivocal evidence to establish that SH2B1‐IRS1‐β‐catenin axis is required for promoting EMT, and might prove to be a promising strategy for restraining tumor progression in LADC patients.

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Gene aberrations for precision medicine against lung adenocarcinoma

Cited by 191 publications

References 72 publications

Aberrant status and clinicopathologic characteristic associations of 11 target genes in 1,321 Chinese patients with lung adenocarcinoma

Aberrant status and clinicopathologic characteristic associations of 11 target genes in 1,321 Chinese patients with lung adenocarcinoma

The significance of programmed cell death ligand 1 expression in resected lung adenocarcinoma

SH2B1 promotes epithelial‐mesenchymal transition through the IRS1/β‐catenin signaling axis in lung adenocarcinoma

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