scholarly journals Identification of the Unique Clinical and Genetic Features of Chinese Lung Cancer Patients With EGFR Germline Mutations in a Large-Scale Retrospective Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Xinqing Lin ◽  
Muyun Peng ◽  
Quanfang Chen ◽  
Mingming Yuan ◽  
Rongrong Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Large Scale ◽  
Kinase Inhibitors ◽  
Familial Aggregation ◽  
Young Patients ◽  
Germline Mutations ◽  
Chinese Patients ◽  
Genetic Characteristics ◽  
Inherited Susceptibility ◽  
Epidemiological Surveys

BackgroundEpidemiological surveys have suggested that lung cancer has inherited susceptibility and shows familial aggregation. However, the distribution and prevalence of epidermal growth factor receptor (EGFR) germline variants and their roles in lung cancer genetic predisposition in Chinese population remain to be elucidated.MethodsIn this study, EGFR germline and somatic variants were retrospectively reviewed from the next-generation sequencing results of 31,906 patients with lung cancer. Clinical information was also collected for patients with confirmed EGFR germline mutations.ResultsA total of 22 germline EGFR variants were identified in 64 patients with lung cancer, accounting for 0.2% of the total cases studied. Five patients were diagnosed as multiple primary carcinomas. Family history was documented in 31.3% (20/64) of patients, 55% of which were diagnosed as lung cancer. G863D was the most frequent EGFR germline mutation, followed by P848L, D1014N, and K757R. Somatic EGFR-sensitive mutations were identified in 51.6% of patients with germline EGFR mutations. The proportion of L858R mutation, exon 19 deletion, and rare sensitive mutation was 50%, 17.6%, and 32.4%, respectively. D1014N and T790M mutations were common in young patients. The family members of patients with P848L, R776H, V769M, and V774M mutations were more commonly diagnosed with cancers. A total of 19 patients were confirmed to have received EGFR tyrosine kinase inhibitors (TKIs), but the response to EGFR-TKIs differed among patients with different EGFR mutations.ConclusionChinese patients with lung cancer harbored unique and dispersive EGFR germline mutations and showed unique clinical and genetic characteristics, with varied response patterns to EGFR-TKI treatment.

Genomic landscape and clinicopathological characteristics of lung cancer in young Chinese patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13520-e13520
Author(s):  
Jiexia Zhang ◽  
Xiaoling Tong ◽  
Hua Bao ◽  
Xue Wu ◽  
Xiaonan Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Large Scale ◽  
Young Patients ◽  
Clinical Information ◽  
Copy Number Gain ◽  
Genetic Alterations ◽  
Young Female ◽  
Chinese Patients ◽  
Egfr Mutations ◽  
Life Styles

e13520 Background: Approximately 2-3% of lung cancer (LC) was found in very young patients (≤ 45 years old) and they were reported to have different clinical characteristics and genetic profiles when compared to older patients. However, it is still lack of large-scale genomic studies that could provide deep insights into the tumorigenesis, precision treatment and prognosis for this particular population. Methods: Clinically annotated data of targeted next generation sequencing (NGS) on 7858 tumor tissue specimens from LC patients were analyzed. For all specimens, a total of 422 or 425 cancer-related genes were interrogated with a mean coverage depth greater than 500x. Results: Of 7858 LC cases, 814 of them were younger than 45 (age at diagnosis), which were compared to 7044 old LC cases ( > 45 years old). Clinical information showed that young LC are more prevalent in female, to be more advanced disease and to have more adenocarcinoma in histology. Somatic genomic data analysis revealed that compared to old LC, young LC has significantly higher ALK/ROS1/RET fusions, ERBB2 mutations and 5q amplification(FDR < 0.1), but lower mutational frequencies in KRAS, CDKN2A, ERBB4, FAT1, NF1, lower copy number gain (CNG) of PIK3CA, MDM2, FGFR1, and less 5q deletion(FDR < 0.1). Interestingly, in young LC, genetic differences between female and male are not significant, with TP53 and EGFR being most frequently mutated in both sexes. Similarly, the differences between young and old female LC are also limit, with young female LC having more ALK fusions (13.43% vs. 5.1%, FDR < 0.01), less EGFR mutations and MDM2 CNG than old female. On the contrary, male patients demonstrated much wide disparity between young and old LC: young LC was enriched with ALK/ROS1/RET/ERBB2 fusions and mutations in EGFR, ERBB2 and SMAD2, while old LC have more mutations in KRAS, TP53, CDKN2A, and CNG of PIK3CA (all FDR < 0.1). We also found that EGFR exon19 deletion (19del) was significantly enriched in young LC, especially in male, while p.L858R showed preference in old LC. Conclusions: The data suggest that the prevalence of different genetic alterations is both age and sex related. The high level of ALK/ROS1/RET fusions and less CNV in young LC could potentially lead to more effective treatment and better prognosis. We also noted that genomic alterations in young LC were not significantly different across sexes, but the disparity by sex was enormously enlarged in old LC, which might be correlated to their life-long exposures, such as smoking, life styles and sex-affected factors.

The landscape of germline mutations and the relationship with tumor mutation burden in Chinese patients with lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10522-10522
Author(s):  
Jian Shi ◽  
Rongfeng Liu ◽  
Guanglei Huang ◽  
Lixing Wang ◽  
Baoen Shan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Germline Mutation ◽  
Germline Mutations ◽  
Gene Panel ◽  
Chinese Patients ◽  
Literature Report ◽  
Pathogenic Mutations ◽  
Incidence And Mortality ◽  
The Media ◽  
The Relationship

10522 Background: Lung cancer is one of the most common types of cancer, ranking the first in the incidence and mortality of malignant tumors in the world and China. Although studies have been reported that genetic susceptibility to lung cancer is associated with certain germline mutations, the relationship between lung cancer risk and inherited genetic factors remains relatively elusive. However, the effect of germline mutation on TMB in lung cancer has not been explored. Herein, DNA genomic profiling was performed through NGS with a 539-gene panel to explore the germline mutations and the relationship with TMB in Chinese patients with lung cancer. Methods: We retrospectively analyzed the germline mutations through a comprehensive 539-gene profiling of 3541 Chinese patients with lung cancer. 539-gene panel contained germline mutations in 90 hereditary tumor-associated genes. We screened out the pathogenic and likely pathogenic germline mutations according to the standards and guidelines for the interpretation of sequence variants of The American College of Medical Genetics and Genomics (ACMG), and picked out there is no records in Clinvar database and no literature report. TMB of tissue or blood ctDNA in 3541 patients were further analyzed in with pathogenic mutations (P group), with likely pathogenic mutations (LP group), and no germline mutations group (Non-P group). The difference in TMB was analyzed via the Wilcoxon sign test. Results: In 3541 patients with lung cancer, 177 (4.999%) patients were identified harboring pathogenic or likely pathogenic germline mutations, in which 78 P group and 99 LP group, the rest 3364 were Non-P group. The highest prevalence of germline mutation was found in BRCA2 (0.565%), ATM (0.339%), MUTYH (0.282%), and BRCA1 (0.254%). In 177 patients with pathogenic or likely pathogenic germline mutations, 67 mutations were recorded as UNK (unknow) in Clinvar database and no literature report. The media TMB of tissue in P group, LP group and Non-P group were 5.149, 5.535 and 5.547 respectively. The media TMB of blood ctDNA in P group, LP group and Non-P group were 4.257, 3.945 and 4.483 respectively. There was no statistical difference in TMB between P and Non-P groups (tissue p = 0.98; ctDNA p = 0.5). Conclusions: In our study, we firstly identified 67 novel germline mutations and studied on the relationship between germline mutations and TMB in lung cancer, which expanded the understanding of germline mutations.

The targetable mutation landscape of Chinese patients with non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13018-e13018
Author(s):  
Jun Li ◽  
Cuiyun Zhang ◽  
Jiuzhou Zhao ◽  
Zhizhong Wang ◽  
Bing Wei ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Chinese Patients ◽  
Molecular Testing ◽  
Small Cell Lung ◽  
Essential Information ◽  
Nsclc Patients

e13018 Background: In recent years, the prognosis of non-small cell lung cancer (NSCLC) patients has been substantially improved by targeted therapies against specific molecular aberrations, i.e. tyrosine kinase inhibitors (TKIs) for Epidermal Growth Factor Receptor ( EGFR) etc. Several genes have been suggested by NCCN guideline (v7.2017) to test for NSCLC patients, including EGFR, ALK, ROS1, BRAF, MET, RET, HER2 and KRAS. The aim of this study is to profile the landscape of actionable mutations in Chinese NSCLC patients. Methods: From 2015 to 2017 621 treatment naïve NSCLC patients enrolled in the affiliated cancer hospital of Zhengzhou University were included in this analysis. DNA was extracted from the FFPE biopsies of these patients and processed for target capture sequencing covering the exons and flanking splicing regions of the 8 genes suggested by NCCN guideline, as well as introns of ROS, ALK and RET. Results: In total, 593 out of the 621 NSCLC patients harbor one or more mutations in these 8 genes, accounting for 95.5% of all the cases. EGFR, ALK and HER2 are the top 3 mutants, with a frequency of 52%, 32% and 26% respectively. Genetic aberrations in BRAF, MET, ROS1, KRAS and RET occur in 22%, 18%, 16% and 14% of the patients. The most common variation is missense; T > G, C > T and C > A changes are more often observed than T > C, T > A and C > G; the median number of variants per sample is 2, ranging from 1 to 13. There are 418 mutations detected on EGFR, of which 206 (49.28%) are clinically relevant. EGFR L858R, Exon19 deletion, Exon20 insertion, G719, A750P were observed in 123 (29.43%), 43 (10.29%), 8 (1.91%), 6 (1.44%) and 6 (1.44%) cases respectively. Gene fusions were identified in 78 cases, and the EML4- ALK is the most common one occurred in 54 patients, other fusion genes include KIF5B- ALK (11) ， CCDC6- RET (4), CD74- ROS1 (4), EZR- ROS1 (2), ERC1- RET (1), , SDC4- ROS1 (1) and TCOF1- ROS1 (1). Conclusions: Target sequencing of the 8 genes suggested by NCCN guideline for NSCLC patients reveals essential information for designing personalized therapeutic regimen. Chinese patients, maybe other Asian countries also, may benefit more from this molecular testing, because of the high occurrence of actionable mutations.

scholarly journals Exploration of Lung Cancer-Related Genetic Factors via Mendelian Randomization Method Based on Genomic and Transcriptomic Summarized Data

2021 ◽  
Vol 9 ◽  
Author(s):  
Nitao Cheng ◽  
Xinran Cui ◽  
Chen Chen ◽  
Changsheng Li ◽  
Jingyu Huang
Keyword(s):  
Lung Cancer ◽  
Lung Carcinoma ◽  
Large Scale ◽  
Genetic Factors ◽  
Mendelian Randomization ◽  
Familial Aggregation ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
The Impact

Lung carcinoma is one of the most deadly malignant tumors in mankind. With the rising incidence of lung cancer, searching for the high effective cures become more and more imperative. There has been sufficient research evidence that living habits and situations such as smoking and air pollution are associated with an increased risk of lung cancer. Simultaneously, the influence of individual genetic susceptibility on lung carcinoma morbidity has been confirmed, and a growing body of evidence has been accumulated on the relationship between various risk factors and the risk of different pathological types of lung cancer. Additionally, the analyses from many large-scale cancer registries have shown a degree of familial aggregation of lung cancer. To explore lung cancer-related genetic factors, Genome-Wide Association Studies (GWAS) have been used to identify several lung cancer susceptibility sites and have been widely validated. However, the biological mechanism behind the impact of these site mutations on lung cancer remains unclear. Therefore, this study applied the Summary data-based Mendelian Randomization (SMR) model through the integration of two GWAS datasets and four expression Quantitative Trait Loci (eQTL) datasets to identify susceptibility genes. Using this strategy, we found ten of Single Nucleotide Polymorphisms (SNPs) sites that affect the occurrence and development of lung tumors by regulating the expression of seven genes. Further analysis of the signaling pathway about these genes not only provides important clues to explain the pathogenesis of lung cancer but also has critical significance for the diagnosis and treatment of lung cancer.

Somatic and germline mutation profiles of Chinese young colorectal cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15522-e15522
Author(s):  
Hongxia Li ◽  
Qianqian Duan ◽  
Yuan Tan
Keyword(s):  
Colorectal Cancer ◽  
Germline Mutation ◽  
Brca2 Mutation ◽  
Young Patients ◽  
Germline Mutations ◽  
Young Group ◽  
Chinese Patients ◽  
Screening And Surveillance ◽  
Chinese Cohort ◽  
Colorectal Cancer Patients

e15522 Background: In recently years, although CRC morbidity and mortality can be mitigated through appropriate screening and surveillance, the incidence rate of colorectal cancer (CRC) younger than 50 years old increased annually. Limited studies have investigated the underpinnings driving CRC development in Chinese younger population. In our study, we aim to explore the comprehensive mutational profile of Chinese CRC patients old (＞50) and young (≤50) diagnosed with CRC. Methods: Targeted sequencing with a 539 cancer-related genes panel was performed on 235 patients diagnosed with CRC. We investigate the landscape and difference of old and young CRC somatic and germline mutations in our Chinese cohort and compare with TCGA CRC cohort (N = 592). Results: Analysis revealed an overall 20.9% (49/235) mutation detection rate of young CRC in our Chinese cohort, which is higher than TCGA cohort (13.9%, 82/592). In our cohort, all Chinese young CRC patients can detect mutation and median mutation count is 10 mutations which is similar to old CRC patients (11 mutations). Comparing high frequency somatic mutations (young group with top 20), we found that BRCA2 mutation in young CRC group is significantly higher than old group (18.4% vs 7.0%, P = 0.025). In TCGA cohort, there is no difference between two groups with top 20 mutations and frequency of BRCA2 is 13.4% (11/82) in young CRC. For germline mutation, 12.29% (29/236) patients in our Chinese cohort harbored pathogenic and likely pathogenic (P/LP) germline mutations and 24.1% (7/29) CRC with P/LP germline mutations is young patients. In these seven P/LP mutation young patients, three patients have MMR gene mutation, two patients harbor ATM mutation, one patient has APC and another has SLX4 mutation. Moreover, young CRC have higher frequency MSI-H than old CRC patients (28.6% vs 18.2%). Conclusions: Our study has identified that young CRC patients account for a higher proportion in Chinese population and BRAC2 mutation may be an important factor in the early development of colorectal tumors in younger patients. In addition, our results also support the role of MSI statues in tumor oncogenesis in Chinese patients with early-onset CRC, indicating the need to include a more comprehensive germline mutation and genetic screening in our population.

Role of Erlotinib in Influencing the Quality of Life of Cancer Patients

2020 ◽  
Vol 07 ◽  
Author(s):  
Deepika Purohit ◽  
Parijat Pandey
Keyword(s):  
Quality Of Life ◽  
Lung Cancer ◽  
Cancer Patients ◽  
Kinase Inhibitors ◽  
Treatment Modalities ◽  
Pancreatic Cancers ◽  
Review Reports ◽  
Causes Of Deaths

Background:: Cancer is one of the significant causes of morbidity and mortality in patients globally. Lung cancer, among other cancers, remains to be one of the principal causes of deaths in both men and women. The most common type of lung cancer is the non-small-cell lung cancer (NSCLC). Apart from lung cancer, pancreatic cancer is also one of the common cancers currently. Objective:: The assessment of QoL in erlotinib-treated patients can also prove to be very useful in the establishment of this drug as the main treatment option for the patients with pancreatic and lung cancer. Methods:: Therapies that target EGFR-mediated signalling are the latest keystones for treating these two types of cancers. They comprise of two main treatment modalities: firstly, against the extracellular fields, that include monoclonal antibodies and secondly, mechanisms that create interferences in the signalling pathways, primarily the small molecule tyrosine kinase inhibitors. Results:: Quality of life (QoL) is one of the key advantages in erlotinib therapy over chemotherapy. Conclusion:: The present review reports the role of erlotinib in improving the quality of life of cancer patients especially in NSCLC and pancreatic cancers. The studies or trials establishing the relations between erlotinib and QoL are discussed in detail in this review.

scholarly journals Circulating tumor cell copy-number heterogeneity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Marianne Oulhen ◽  
Patrycja Pawlikowska ◽  
Tala Tayoun ◽  
Marianna Garonzi ◽  
Genny Buson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Copy Number ◽  
Epithelial To Mesenchymal Transition ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mesenchymal Transition ◽  
Anaplastic Lymphoma

AbstractGatekeeper mutations are identified in only 50% of the cases at resistance to Anaplastic Lymphoma Kinase (ALK)-tyrosine kinase inhibitors (TKIs). Circulating tumor cells (CTCs) are relevant tools to identify additional resistance mechanisms and can be sequenced at the single-cell level. Here, we provide in-depth investigation of copy number alteration (CNA) heterogeneity in phenotypically characterized CTCs at resistance to ALK-TKIs in ALK-positive non-small cell lung cancer. Single CTC isolation and phenotyping were performed by DEPArray or fluorescence-activated cell sorting following enrichment and immunofluorescence staining (ALK/cytokeratins/CD45/Hoechst). CNA heterogeneity was evaluated in six ALK-rearranged patients harboring ≥ 10 CTCs/20 mL blood at resistance to 1st and 3rd ALK-TKIs and one presented gatekeeper mutations. Out of 82 CTCs isolated by FACS, 30 (37%) were ALK+/cytokeratins-, 46 (56%) ALK-/cytokeratins+ and 4 (5%) ALK+/cytokeratins+. Sequencing of 43 CTCs showed highly altered CNA profiles and high levels of chromosomal instability (CIN). Half of CTCs displayed a ploidy >2n and 32% experienced whole-genome doubling. Hierarchical clustering showed significant intra-patient and wide inter-patient CTC diversity. Classification of 121 oncogenic drivers revealed the predominant activation of cell cycle and DNA repair pathways and of RTK/RAS and PI3K to a lower frequency. CTCs showed wide CNA heterogeneity and elevated CIN at resistance to ALK-TKIs. The emergence of epithelial ALK-negative CTCs may drive resistance through activation of bypass signaling pathways, while ALK-rearranged CTCs showed epithelial-to-mesenchymal transition characteristics potentially contributing to ALK-TKI resistance. Comprehensive analysis of CTCs could be of great help to clinicians for precision medicine and resistance to ALK-targeted therapies.

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