Objective To investigate the prognostic value of ERBB2 Exon20ins (Exon20ins) in advanced non-small cell lung cancer (NSCLC) patients receiving first-line chemotherapy combined with immunotherapy. Methods A retrospective analysis was conducted on clinical data from ERBB2-mutant stage IV NSCLC patients who received first-line chemotherapy combined with immunotherapy at West China Hospital of Sichuan University between 2020 and 2024. ERBB2 wild-type patients were matched using propensity score matching. Clinical pathological characteristics, distant metastatic sites, and treatment outcomes were compared among patients with different mutation statuses. The primary endpoint was progression-free survival (PFS), and Kaplan-Meier method was used to plot survival curves. Cox regression analysis was performed to adjust for confounding factors. Results This study included 41 ERBB2-mutant stage IV NSCLC patients, of whom 22 had Exon20ins mutations, and 19 had other ERBB2 mutations. Forty-one ERBB2 wild-type patients were matched for comparison. The mean age of all patients was 60.0±9.3 years, with 61 males (74.4%). A total of 67 patients (81.7%) received chemotherapy combined with immunotherapy, and 15 patients (18.3%) received chemotherapy combined with immunotherapy and anti-angiogenesis therapy. The Exon20ins group showed a higher incidence of lymph node metastasis compared with the ERBB2 other mutation group and the wild-type group (36.4% vs. 15.8% vs. 9.8%, P=0.045). The median PFS in the Exon20ins group was significantly shorter than in the other mutation group (5.8 months vs. 10.3 months, P=0.025) and the wild-type group (5.8 months vs. 8.3 months, P=0.023). Univariate Cox regression analysis indicated that the ERBB2 Exon20ins mutation was an adverse prognostic factor (Exon20ins vs. other ERBB2 mutations, HR=2.9, 95%CI 1.18 - 7.1, P=0.014; Exon20ins vs. wild-type, HR=2.6, 95%CI 1.25 - 5.6, P=0.014). The combination with anti-angiogenesis therapy did not significantly affect the prognosis of PFS (HR=0.66, 95%CI 0.28 - 1.6, P=0.363). Multivariate Cox regression analysis revealed that the ERBB2 Exon20ins mutation was an independent adverse prognostic factor for PFS (Exon20ins vs. other ERBB2 mutations, HR=3.3, 95%CI 1.27 - 8.3, P=0.015; Exon20ins vs. wild-type, HR=2.7, 95%CI 1.2 - 5.88, P=0.014). For the 67 patients receiving chemotherapy combined with immunotherapy, Cox regression analysis showed that the ERBB2 Exon20ins mutation was still associated with poor prognosis in advanced NSCLC (Exon20ins vs. other ERBB2 mutations, HR=3.2, 95%CI 1.12 - 9.1, P=0.030; Exon20ins vs. wild-type, HR=2.5, 95%CI 1 - 5.88, P=0.040). Conclusions Advanced NSCLC patients with ERBB2 Exon20ins mutation have a worse prognosis compared with those with other ERBB2 mutation subtypes or ERBB2 wild-type when treated with first-line chemotherapy combined with immunotherapy. This suggests that ERBB2 Exon20ins mutation, as a particularly refractory mutation, requires the exploration of new combination strategies based on molecular subtyping to improve survival outcomes.
ObjectiveTo investigate the relation between disulfidptosis-related genes (DRGs) and prognosis or immunotherapy response of patients with pancreatic cancer (PC). MethodsThe transcriptome data, somatic mutation data, and corresponding clinical information of the patients with PC in The Cancer Genome Atlas (TCGA) were downloaded. The DRGs mutated in the PC were screened out from the 15 known DRGs. The DRGs subtypes were identified by consensus clustering algorithm, and then the relation between the identified DRGs subtypes and the prognosis of patients with PC, immune cell infiltration or functional enrichment pathway was analyzed. Further, a risk score was calculated according to the DRGs gene expression level, and the patients were categorized into high-risk and low-risk groups based on the mean value of the risk score. The risk score and overall survival of the patients with high-risk and low-risk were compared. Finally, the relation between the risk score and (or) tumor mutation burden (TMB) and the prognosis of patients with PC was assessed. ResultsThe transcriptome data and corresponding clinical information of the 177 patients with PC were downloaded from TCGA, including 161 patients with somatic mutation data. A total of 10 mutated DRGs were screened out. Two DRGs subtypes were identified, namely subtype A and subtype B. The overall survival of PC patients with subtype A was better than that of patients with subtype B (χ2=8.316, P=0.003). The abundance of immune cell infiltration in the PC patients with subtype A was higher and mainly enriched in the metabolic and conduction related pathways as compaired with the patients with subtype B. The mean risk score of 177 patients with PC was 1.921, including 157 cases in the high-risk group and 20 cases in the low-risk group. The risk score of patients with subtype B was higher than that of patients with subtype A (t=14.031, P<0.001). The overall survival of the low-risk group was better than that of the high-risk group (χ2=17.058, P<0.001), and the TMB value of the PC patients with high-risk was higher than that of the PC patients with low-risk (t=5.642, P=0.014). The mean TMB of 161 patients with somatic mutation data was 2.767, including 128 cases in the high-TMB group and 33 cases in the low-TMB group. The overall survival of patients in the high-TMB group was worse than that of patients in the low-TMB group (χ2=7.425, P=0.006). ConclusionDRGs are closely related to the prognosis and immunotherapy response of patients with PC, and targeted treatment of DRGs might potentially provide a new idea for the diagnosis and treatment of PC.
Leber’s hereditary optic neuropathy (LHON) is a paradigm maternal hereditary eye disease, mainly involving the retinal and macular fibers of the optic disc in the anterior ethmoid plate of the sclera. LHON has the characteristics of sex bias among males and incomplete penetrance. Primary mitochondrial DNA mutations m.11778G>A, m. 14484T>C, m.3460G>A are the molecular basis of LHON. However, other risk factors, such as secondary mitochondrial DNA mutations, mitochondrial haplotypes, nuclear modification genes, estrogen, vitamin B12 and environmental factors, work together to affect its phenotypic expression. The clinical diagnosis of LHON mainly limited to the detection of the primary mutation site of mitochondrial DNA. Therefore, comprehensive analysis of multiple risk factors of LHON will facilitate to construct multi-dimensional model of prevention, diagnosis and treatment system, which provide accurate and individualized medical services for patients. These may alleviate the incidence in LHON families. It also provides new ideas and different angles for the in-depth study of the pathogenesis of LHON.
Objective To explore the effect of dendritic cells (DCs) allergized by K-ras mutant peptide on expressions of chemokines CCL19, CCL22, and cytoskeletal protein fascin-1. Methods DCs were derived from peripheral blood in the presence of granuloceyte/macrophage-colony stimulating factor, interleukin (IL) -4 in vitro. The DCs were collected on day 7 after culture, and were divided into non-K-ras mutant peptide group (addition of RPMI 1604 culture solution 50 μg/ml) and K-ras mutant peptide group (addition of K-ras mutant peptide 50 μg/ml). Phenotype was identified by flow cytometry. The morphological structure was observed by scanning and transmission electron microscopies, respectively. The expressions of IL-12, CCL19, and CCL22 were tested continuously by enzyme-linked immunosorbent assay (ELISA). The expression of cytoskeletal protein fascin-1 was determined by Western blot. Results ①The expressions of CD1a, CD80, and CD86 after loading K-ras mutant peptide were higher than that before loading K-ras mutant peptide (Plt;0.01). ②The DCs with petal-like and branch-like profections after loading were observed under scanning electron microscopy; The DCs with irregular shapes, branch-like or burr-like were showed under transmission electron microscopy. ③The expressions of IL-12, CCL19, and CCL22 in the Kras mutant peptide group were higher than those in the non-K-ras mutant peptide group at different times (6, 12, 24, and 48 h) after loading Kras mutant peptide (Plt;0.01). ④The expression of fascin-1 in the K-ras mutant peptide group was also higher than that in the non-K-ras mutant peptide group (Plt;0.01). Conclusion K-ras mutant peptide can promote DC to mature and improve the expression of chemokines and cytoskeletal protein which will strengthen DC migration.
ObjectiveTo observe the clinical manifestation and gene mutation of a pedigree with Sorsby fundus dystrophy (SFD). Methods Ten members in 3 generations of a pedigree with SFD were included in this study. Four patients were observed in the pedigree, including 2 females and 2 males. All 10 members underwent comprehensive ophthalmic examinations, including best-corrected visual acuity, intraocular pressure, slit-lamp biomicroscopy, indirect ophthalmoscopy, fundus color photography and spectral domain optical coherence tomography. Genomic DNA was extracted from peripheral venous blood which was collected from all the members. Relevant exons of ocular diseases were detected by the next generation sequencing method from the proband. The other members underwent Sanger verification. Results Among the four patients, fading eyesight was appeared at their 44, 46, 47 and 40 year-old respectively. The two male patients had bilateral morbidity, and the two female patients had monocular symptoms. DNA sequencing results showed that the proband, other 3 patients and 2 members from the Ⅲ generation had heterozygous mutation of TIMP3 gene in exon 5. The amino acid encoded by TIMP3 gene No.204 codon changed from serine to cysteine (TIMP3:NM_000362:Exon5:c.A610T/p.S204C). CoclusionsThe invasion time of all the patients in this pedigree is after their 40 year-old. Heterozygous mutation at c.610A＞T (p.S204C) in TIMP3 gene is the causative gene of SFD in this pedigree.
Objective To investigate the molecular mechanisms by which the long non-coding RNA (lncRNA) MIR223HG affects the proliferation, migration and apoptosis of lung adenocarcinoma cells. MethodsDNA damaging agent Zeocin was used to treat human embryo lung cell (MRC-5) and lung cancer cell (A549 and H1299), and the expression of MIR223HG was tested by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Moreover, the ataxia-telangiectasia mutated (ATM) protein and ATM pathway downstream factor Cell cycle checkpoint kinase 2 (Chk2), p53 tumor suppressor protein (p53) in the lung cancer cell (A549 and H1299) with Zeocin were also tested by qRT-PCR. Cell transfection and Transwell migration assay, colony formation assays, apoptosis assays were performed to verify the role of ATM in the expression of MIR223HG in lung adenocarcinoma. ResultsThe expression of MIR223HG was reduced markedly in the lung cancer cells (A549 and H1299) compared with human embryo lung cell (MRC-5) after treated with Zeocin. ATM protein and its downstream factors Chk2, p53 involved in the process, and ATM regulated the expression of MIR223HG in the lung cancer cells with Zeocin. Futhermore, ATM joined in the processes that MIR223HG regulated the lung cancer cells proliferation, migration and apoptosis. Conclusions The expression of MIR223HG is related to the DNA damage response in the lung cancer, and MIR223HG regulates lung cancer cells proliferation, migration and apoptosis by ATM/Chk2/p53 pathway. MIR223HG may be a potential therapeutic target for lung adenocarcinoma treatment.
Objective To review retinitis pigmentosa (RP)-related gene researches in China. Methods RP genes and RP gene therapy as key words were searched from those online databases including China Knowledge Resource Integrated Database of China National Knowledge Infrastructure (CNKI), National Center for Biotechnology Information (NCBI), Human Gene Mutation Database (HGMD), and Human Genome Variation Society (HGVS). Related papers written by authors from China or other countries, published from 1991 to 2011 were collected for analysis. Results Overall 60 RP related genes have been identified now. Chinese researchers from 29 hospitals and research institutes confirmed 17 RP-related gene changes (239 mutations, 131 of them are pathogenic) in 300 RP families and 1572 sporadic RP patients from 1991 to 2011, as reported in 66 papers. Mutations in rhodopsin (RHO) gene, NR2E3 gene and RP1 gene were found in 2.0%, 2.9% and 1.0% of Chinese RP patients respectively. The relationship between genotypes and clinical phenotypes were investigated in 15 papers, including RHO gene, RDS gene, RP1 and RPGR or RP3 gene in ADRP families. Gene therapy for RP has been investigated in 4 papers. Seven hundred and eighteen papers about RP genemutation screening have been published from other countries, and more than 2000 variants were identified which including 352 disease-causing mutations. Mutations of RHO gene, RDS and RP1 were found in 25%-50%, 8% and 5% -10% of ADRP patients in Caucasian populations. RPGR mutations were found in 70%-80% of XLRP patients in Caucasian populations, and 50% -60% of mutations are identified in open reading frame (ORF) 15. Totally 391 papers about gene therapy for RP have been published. Conclusions Seventeen RP-related genes have been studied and 131 pathogenic mutations were found in China. Considering Chinese population, our RP research is still behind other countries.
ObjectiveTo analyze and identify the pathogenic mutation that caused a case of child’s renal coloboma syndrome (RCS).MethodsA child with congenital cataract in the right eye and optic disc defect in the left eye and his parents with normal phenotype were included in the study. The blood of the child and his parents were captured to extract DNA and make molecular test. The possible variants were screened through NGS sequencing using the ophthalmology gene panel on illumina NextSeq 500 platform, and proved the selected PAX2 mutation by Sanger sequencing. Pathogenicity report was retrieved through PubMed and related database. Pathogenicity analysis of the candidate mutated site has careful consideration of the patient’s clinical presentations and sequencing result base on Standards and Guidelines for the Interpretation of Sequence Variants revised by ACMG. According to the results of gene diagnosis, the child was executed related clinical examinations on kidney.ResultsThe sequence result showed that a heterozygous mutation in PAX2, c.70dupG (p.V26Gfs*28), which lead to truncated protein product that terminated after 28 amino acids of the mutated site. Both of his normal parents were not carriers of the heterozygous mutation. Sanger sequencing results of the child and his parents were consistent with the NGS sequencing. The autosomal dominant disease phenotype was inferred to be caused by the heterozygous mutation of c.70dupG (p.V26Gfs*28) of PAX2 gene. Renal color Doppler ultrasound results showed the child with small renal cysts on the left and mildly separated collecting system. Renal function tests showed the child with α1 microglobulin index increased.ConclusionThe heterozygous mutation c.70dupG (p.V26Gfs*28) in PAX2 is the genetic pathogenic cause for the patient with RCS.
Purpose To investigate the relationship between mitochondrial DNA 11778 mutation and clinical characteristics of patients with Laber is hereditary optic neuropathy(LHON). Methods PCR RFLPs (MaeⅢ) and mutation specific primer PCR(MSP-PCR) were used simultaneously to detect mitochondrial DNA 11778 mutation. Results Among 10 subjects who habored 11778 mutation,one was a carrier and nine were patients with LHON.Of the nine patients,six were males and three were females.The age of onset ranged from 12 to 25 years old and the onset interval of the two eyed varied between 0 to 6 months. The visual acuity was CF/10cm-0.1 except one who lost her vision after delivery but recovered gradually.The results of visual field,VEP and color vision were abnormal but ERG and systemic status were all normal. Conclusion Molecular biological detection of the ten subjects showed that they all habored mtDNA 11778 mutation.The existence of carrier and visual recovery imlied that mtDNA mutation was a primary cause of LHON,but other factors such as endocrine disorder might influence the pathogenesis of LHON. (Chin J Ocul Fundus Dis,1998,14:156-158)