The status of homologous recombination deficiency and BRCA1/2 gene mutation in ovarian cancer patients in the Yunnan region and their clinical significance / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：采用基于中国人群单核苷酸多态性位点开发的同源重组缺陷（HRD）检测工具评估云南地区卵巢癌患者的HRD状态和BRCA1/2基因突变频率并探讨其临床意义。方法：共纳入2021年1月至2023年5月间在云南省肿瘤医院收治的卵巢癌患者248例，HRD状态采用基因组瘢痕评分法（GSS）（主要依据拷贝数的长度、类型、位置及基因组断片）或HRD评分法（杂合性缺失、端粒等位基因失衡及大片段移位等基因组不稳定事件的总和）进行评估，当组织样本的GSS≥50分或HRD评分≥42分者或检测到有害的BRCA1/2基因突变时HRD被定义为阳性。分析患者HRD状态与临床病理特征的关系。结果：248名卵巢癌患者中70.97%的患者HRD呈阳性，其中BRCA1/2基因突变率为30.65%。Ⅲ~Ⅵ期、高级别浆液腺癌的卵巢癌患者具有更高的HRD阳性率（均P<0.01），HRD评分更高的患者其合并其他基因突变的频率也越高（P<0.05）。HRD状态与卵巢癌的病理类型、临床分期和其他基因突变均有关联（均P<0.01）。结论：云南地区卵巢癌患者HRD阳性率较高，HRD阳性的卵巢癌患者可以从聚ADP核糖聚合酶（PARP）抑制剂治疗中获得更大的收益。

Mutational characteristics of Chinese Han and ethnic minorities in southwestern China: a propensity score matched analysis.

Background: In China, there has never been a comprehensive analysis of lung cancer-associated genetic mutations focused on ethnic minorities in the southwestern region. Our study aimed to provide valuable information on lung cancer-associated genetic alterations for cancer diagnosis and treatment, especially in ethnic minorities. Methods: Retrospective data acquisition was conducted spanning 3 years (2016.01-2019.06) among all patients who were diagnosed with lung cancer at the Third Affiliated Hospital of Kunming Medical University Hospital. A total of 5,167 patients including 373 ethnic minorities were included in this study. Propensity score matching (PSM) was used to eliminate the bias between Han and other ethnic minorities, including gender, age, smoking history, metastasis status, clinical stage, histological type, sample type, region, and Xuanwei origin. All tests were two-tailed, and significance was defined as P less than 0.05. Results: In terms of the prevalence of EGFR, EGFR L858R, EGFR T790M, ROS1, RET, MET, BRAF, and ERBB2 mutations, there was no significant difference among ethnic groups in Yunnan Province (P>0.05). A higher proportion of EGFR 19 deletion was observed in Hui patients with lung cancer compared with patients of other ethnicities in Yunnan (P=0.048). The prevalence of KRAS mutations was higher in Hani (17.65%, 3/17) and Han patients (11.44%, 80/699) than that in other Yunnan ethnicities (6.04%, 9/149; P=0.07). In Hui patients, ALK fusion was correlated with a history of non-smoking and male gender. In Bai patients, BRAF mutation was also correlated with a history of non-smoking. In all ethnic groups, EGFR mutation was more frequent in women. Conclusions: This study is the first in-depth large case-control study on genetic mutation profiles among multi-ethnic patients in southwestern China, especially focused on ethnic minorities in this area. Our study may facilitate the understanding of the etiology of this malignant disease and consequently help to reduce the incidence of lung cancer in Yunnan ethnic minority areas.

Unique Profile of Driver Gene Mutations in Patients With Non-Small-Cell Lung Cancer in Qujing City, Yunnan Province, Southwest China.

OBJECTIVE: Qujing City, Yunnan Province, China, has a high incidence of lung cancer and related mortality. The etiology of NSCLC in Qujing area and distribution of associated molecular aberrations has not been fully elucidated. This study aimed to reveal the profile of driver gene mutations in patients with non-small-cell lung cancer (NSCLC) in Qujing and explore their relationships with clinicopathological characteristics. METHODS: In this study, the mutation profiles of NSCLC driver genes, including EGFR, ALK, ROS1, KRAS, BRAF, RET, MET, HER2, NRAS, and PIK3CA, were investigated in patients with NSCLC from Qujing and compared with those from other regions in Yunnan Province. The associations between molecular mutations and clinicopathological characteristics were further analyzed. RESULTS: A distinct profile of driver gene mutations was discovered in patients with NSCLC from Qujing. Interestingly, a higher proportion of EGFR compound mutations, including G719X + S768I (19.65% vs 3.38%, P < 0.0001) and G719X + L861Q (21.10% vs 2.82%, P < 0.0001), was observed in patients with NSCLC in Qujing compared with patients in non-Qujing area, besides significantly different distributions of EGFR (46.01% vs. 51.07%, P = 0.0125), ALK (3.17% vs. 6.97%, P = 0.0012), ROS1 (0.5% vs. 2.02%, P = 0.0113), and KRAS (23.02% vs. 7.85%, P < 0.0001). Further, EGFR compound mutations were more likely associated with the occupation of patients (living/working in rural areas, e.g., farmers). Moreover, KRAS G12C was the dominant subtype (51.11% vs 25.00%, P = 0.0275) among patients with NSCLC having KRAS mutations in Qujing. CONCLUSIONS: Patients with NSCLC in Qujing displayed a unique profile of driver gene mutations, especially a higher prevalence of EGFR compound mutations and dominant KRAS G12C subtype, in this study, indicating a peculiar etiology of NSCLC in Qujing. Therefore, a different paradigm of therapeutic strategy might need to be considered for patients with NSCLC in Qujing.

lncRNA DLEU2 modulates cell proliferation and invasion of non-small cell lung cancer by regulating miR-30c-5p/SOX9 axis.

Increasing evidence indicated that long noncoding RNAs (lncRNA) play critical roles in the progression of multiple cancers and that dysregulation of lncRNA promotes tumor progression. However, the function and underlying mechanism of lncRNA DLEU2 in biological behaviors of NSCLC cells are still largely unknown. Our studies confirmed that lncRNA DLEU2 was highly expressed in NSCLC tissues and cell lines, which was correlated with shorter overall survival in NSCLC patients. In vitro, knockdown of lncRNA DLEU2 inhibited proliferation, invasion, migration and induced apoptosis of both A549 and LLC cells; In vivo, it suppressed tumor growth and metastasis. lncRNA DLEU2 directly interacted with miR-30c-5p, which further targeted SOX9 and exerted oncogenic functions in NSCLC. Mechanistically, overexpression of lncRNA DLEU2 exhibits tumorigenic effects through downregulating the inhibitory effect of miR-30c-5p on SOX9 expression. In conclusion, Our finding confirmed that lncRNA DLEU2 as a novel oncogenic in NSCLC, which provide a potential novel diagnostic and therapeutic target for NSCLC.

MicroRNA-195 suppresses the progression of lung adenocarcinoma by directly targeting apelin.

BACKGROUND: Apelin plays an important role in many types of tumors. We aimed to identify the effects of miR-195 on inhibiting apelin and clarify the regulating mechanism of miR-195-apelin in lung adenocarcinoma cells. METHODS: We detected the expression levels of apelin and miR-195 in lung adenocarcinoma tissues and lung cancer cell lines using Western blotting and quantitative reverse transcription PCR assay, respectively. Luciferase reporter assay was used to confirm the target gene of miR-195. The effects of miR-195 and apelin on the proliferation and cell cycle of lung adenocarcinoma cells were assessed by methyl thiazolyl tetrazolium and colony formation assays, and flow cytometry. Wound-healing and transwell invasion experiments were employed to examine cellular migration and invasion. A tumor xenograft model was then used to investigate the role of miR-195 on tumor growth in vivo. RESULTS: The expression level of apelin and miR-195 showed an inverse correlation in lung adenocarcinoma tissues and cell lines. Luciferase reporter assay suggested that miR-195 directly targets apelin messenger RNA. Overexpression of miR-195 significantly inhibited the proliferation, migration, and invasion of lung adenocarcinoma cells in vitro and suppressed tumor growth in vivo. Further analysis revealed that apelin is one of the functional target genes of miR-195, and the overexpression of apelin efficiently inhibits the promotion of cell proliferation and invasion mediated by miR-195 mimics in lung adenocarcinoma cells. CONCLUSIONS: Our data constitute evidence that miR-195 inhibits lung adenocarcinoma cell proliferation and invasion though targeting apelin and provides novel insight into the mechanism underlying the development of lung adenocarcinoma.

Detection of EGFR gene mutation in periphral blood of NSCLC patients in Yunnan by Super-ARMS and its clinical significance / 中国肿瘤生物治疗杂志

@#Objective: To detect the mutation of epidermal growth factor receptor (EGFR) gene in peripheral blood of non-small cell lung cancer (NSCLC) patients in Yunnan area with Super-ARMS, and to explore its correlation with clinicopathological characteristics. Methods: A total of 222 blood samples from patients with NSCLC were collected between January 2017 to December 2018 in the Molecular Diagnostic Center of Yunnan Cancer Hospital. The EGFR gene mutation in peripheral blood samples was detected by SuperARMS, and the relationship between EGFR gene mutation and clinicopathological features was analyzed. Meanwhile, the independent risk factors influencing EFGR mutation were also analyzed. Results: In the peripheral blood of 222 NSCLC patients, there were 81 cases (36.5%) with EGFR gene mutation. Among them, exon 19 deletion and L858R gene point mutation were the most common (75.3% of total mutation); female patients had a higher mutation rate than male patients (45.9% vs 27.0%); patients <60 years old had a higher incidence of mutation than patients≥60 years old (43.2% vs 28.8%) (P<0.05 or P<0.01); moreover, patients with no history of smoking, no history of radical surgery, adenocarcinoma, advanced stage and no history of chemotherapy had higher incidence of EGFR mutation (43.9% vs 21.6%, 39.2% vs 21.2%, 43.9% vs 4.8%, 39.7% vs 23.3% and 44.0% vs 23.5%) (P<0.05 or P<0.01). Multivariate logistic analysis showed that young, no smoking history, adenocarcinoma and no surgical history were independent risk factors for EGFR gene mutation (all P<0.01). Conclusion: In the peripheral blood of patients with NSCLC in Yunnan, the mutation rate of EGFR gene is higher in patients with age<60 years old, adenocarcinoma and non-smoking. Super-ARMS method is more sensitive in the detection of EGFR mutation in peripheral blood of lung cancer patients.

Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) of Yunnan in southwestern China.

To investigate the Epidermal Growth Factor Receptor (EGFR) mutation status in non-small cell lung cancer (NSCLC) in Yunnan province in southwestern China, we detected EGFR mutation by Amplification Refractory Mutation System (ARMS) polymerase chain reaction (PCR) using DNA samples from 447 pathologically confirmed NSCLC specimens (175 tissue, 256 plasma and 16 cytologic samples). The relationship between EGFR mutations and demographic and clinical factors were further explored. Subgroup analyses according to sample type (tissue and plasma) and histological type (adenocarcinoma) were done. We found the mutation rate was 34.9% in overall patients (42.3%, 29.7%, and 37.5% for tissue, plasma, and cytologic samples respectively). We found female (p < 0.0001), no smoking (p = 0.001), adenocarcinoma (p < 0.0001), and tissue specimen (p = 0.026) were associated with higher EGFR mutation rate. The most common mutations were exon 19 deletions (40%) and L858R point (30%) mutation. Interestingly, NSCLC patients from Xuanwei harbored a strikingly divergent mutational pattern for EGFR when compared with non-Xuanwei patients (higher G719X, G719X+S768I mutations, but lower 19 deletion and L858R mutations). Generally, EGFR mutation rate and pattern in Yunnan province was in accord with other Asian populations. However, Xuanwei subgroup showed strikingly divergent EGFR mutation spectrum from other general population. Our analysis also indicated that cftDNA analysis for EGFR mutations detection was feasibility for the patients lacking sufficient tissue for molecular analyses.