ABSTRACT
BACKGROUND@#Occurrence at a younger age has been demonstrated to be associated with a distinct biology in non-small cell lung cancer. However, genomics and clinical characteristics among younger patients with lung adenocarcinoma remain to be determined. Here we studied the potentially targetable genetic alterations by next-generation sequencing (NGS) assay in young Chinese patients with lung adenocarcinoma.@*METHODS@#Eighty-nine surgically resected lung adenocarcinoma tissue samples from patients aged less than 45 years were collected with informed consent from all patients. Targeted NGS assays were used to identify actionable genetic alterations in the cancer tissues. Additionally, the genomic and clinical pathologic characteristics of 95 patients with lung adenocarcinoma who received NGS testing over the same period were analyzed retrospectively.@*RESULTS@#The frequencies of targetable genetic alterations in 184 patients with lung adenocarcinoma were analyzed by defined age categories, which unveiled a distinctive molecular profile in the younger group, aged less than 45 years. Notably, higher frequency of anaplastic lymphoma kinase (ALK) and human epidermal growth factor receptor 2 (HER2) genetic alterations were associated with young age. However, a reverse trend was observed for kirsten rat sarcoma viral oncogene (KRAS), serine/threonine kinase 11 (STK11) and epidermal growth factor receptor (EGFR) exon 20 mutations, which were more frequently identified in the older group, aged more than 45 years. Furthermore, concurrent EGFR/tumor protein p53 (TP53) mutations were much more prevalent in the younger patients (81.6% vs 44.9%), which might have a poor response to treatment with EGFR-tyrosine kinase inhibitor (EGFR-TKI).@*CONCLUSIONS@#NGS assay revealed a distinctive genetic profile in younger patients with adenocarcinoma. High frequency of concurrent EGFR/TP53 mutations was found in the younger patients, which especially warranted personalized treatment in this population.
ABSTRACT
Objective Next generation sequencing (NGS) was used for identifying the potential gene mutations in advanced gastric cancer(AGC) tissue in order to instruct the targeted drug use for AGC patients. Methods A total of 31 AGC patients from the Affiliated Hospital of Qingdao University between August 10, 2016 and April 23, 2017 were enrolled, and the tissues of gastric cancer were collected. 7 708 exons of 508 tumor related genes and 78 introns of 19 frequently rearranged genes were assessed for base substitutions, indels, copy number alterations, and gene fusions detection. The average median sequencing depth was 470×. Results Somatic mutations were detected in all the patients, of which 9.7 % (3/31) patients could select targeted drugs approved by National Comprehensive Cancer Network (NCCN) guideline according to the identified genetic alterations (human epidermal growth factor receptor 2 gene amplification / mutation). Other targetable genetic alterations were detected in 13 (41.9 %) AGC patients, including mTOR inhibitors, PARP inhibitors, FGFR inhibitors and other targeted drugs of mutations genes. Conclusion The detection of targeted genes based on NGS might help to identify available targeted drugs and to personalize targeted therapy for AGC patients.
ABSTRACT
Objective To explore antitumor effect of 131I-Trastuzumab on human epidermal growth factor receptor(HER) 2 overexpressing breast cancer cells and investigate its possible mechanism.Methods The expression levels of HER2 of three different breast cancer cell lines (BT474,MCF-7,HCC1937) were detected with immunofluorescence.Trastuzumab was labeled with 131I using the Iodogen method and 131I-Trastuzumab was isolated with ultrafiltration membrane,then the labeling efficiency,radiochemical purity and immunoreactivity were measured.The effects of 131I,Trastuzumab and 131I-Trastuzumab on viability of BT474 cells were evaluated with cell counting kit-8 (CCK-8) assay.The levels of total Akt and phosphorylated Akt (p-Akt) were detected with Western blot analysis.One-way analysis of variance (ANOVA),ANOVA for factorial design,Bonferroni correction and Pearson correlation analysis were used for data analysis.Results The expression level of HER2 in BT474 cells was much higher than those in HCC1937 and MCF-7 cells.The labeling efficiency,radiochemical purity and immunoreactivity of 131I-Trastuzumab were (89.71± 2.93)％,(91.80±1.43)％ and (58.84±3.35)％ respectively.131I (4.625 GBq/L),Trastuzumab(125.0 rmg/L) and 131I-Trastuzumab(4.625 GBq/L) exhibited a dose-dependent cytotoxicity against BT474 cells (r =-0.964,-0.912,-0.618;all P＜0.05).The cell viability of 131I-Trastuzumab treated gourp (34.73％ ±5.03％) was significantly lower than those of 131I and Trastuzumab treated groups (64.36％± 1.51％ and 58.09％±4.14％;t=10.373 and 8.180,both P＜0.05),and the cell viability of control group was (100.00±4.54)％.131I-Trastuzumab shown a positive multiplicative interaction between 131I and Trastuzumab (F=9.226,P＜0.05;CDI =0.929).Western blot results showed that there was no significant difference of total Akt expression among the control group,131I group,Trastuzumab group and 131I-Trastuzmab group (F=0.208,P＞0.05).P-Akt expression in both Trastuzumab group and 131I-Trastuzumab group were much lower than those of control group and 131I group (t=12.524,15.984,7.347,10.807;all P＜0.05),while there was no significant difference of p-Akt expression between Trastuzumab group and 131I-Trastuzumab group(t =3.460,P＞0.05).Conclusions 131I-Trastuzumab may kill HER2 overexpressing breast cancer cells more effectively than Trastuzumab alone.The underlying mechanism may be attributed to that 131I-Trastuzumab may enhance the radiosensitivity by the inhibitory effect on PI3K/Akt pathway and thus exert synergistic effects with 131I.