scholarly journals A comprehensive study on the oncogenic mutation and molecular pathology in Chinese lung adenocarcinoma patients

2020 ◽  
Author(s):  
Xilin Zhang ◽  
Yan Jiang ◽  
Huanming Yu ◽  
Hui Xia ◽  
Xiang Wang
Keyword(s):  
Lung Adenocarcinoma ◽  
Critical Role ◽  
Evaluation Criteria ◽  
Gene Mutations ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Amplification Refractory Mutation System ◽  
Clinicopathologic Characteristics ◽  
Oncogenic Mutation ◽  
Formalin Fixed Paraffin Embedded

Abstract Background: Several genetic driver alterations have been identified in micropapillary lung adenocarcinoma (MPA). However, the frequency of co-alteration of ROS1, EGFR and EML4-ALK is yet unclear. Herein, we investigated the relationship between clinicopathologic characteristics and well-identified driver mutations of MPA compared with non-micropapillary lung adenocarcinoma (LA). Methods: Formalin fixed paraffin-embedded (FFPE) sections derived from lung adenocarcinoma patients who never received adjuvant chemotherapy or radiation therapy prior to surgical resection were collected from October 2016 to June 2019. EGFR mutations, ROS1 rearrangements and EML4-ALK fusion were identified in a set of 131 MPA and LA cases by using the Amplification Refractory Mutation System (ARMS). The response rate and duration of response were assessed using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Results: EGFR mutations had occurred in 42 (76.4%) MPA patients and 42 (55.3%) LA patients. Interestingly, ROS1 rearrangements were highly enriched only in the MPA cases (6/55, 10.9%) but rarely in the LA cases (1/76, 1.3%). Furthermore, 7.3% (4/55) MPA samples had double gene mutations, while only 1.3% (1/76) LA cases had double gene alterations. Of 5 patients with harboring two driver oncogenes mutations, four patients (80%) obtained partial response and one patient (20%) suffered recurrence. Conclusions: A higher prevalence of ROS1 rearrangement or combined mutations of ROS1, EGFR and EML4-ALK may play a critical role in the tumorigenesis of MPA. These findings provide a novel therapeutic strategy for patients with malignant MPA through combining TKIs than one TKI.

scholarly journals A comprehensive study on the oncogenic mutation and molecular pathology in Chinese lung adenocarcinoma patients

2020 ◽  
Author(s):  
Xilin Zhang ◽  
Yan Jiang ◽  
Huanming Yu ◽  
Hui Xia ◽  
Xiang Wang
Keyword(s):  
Lung Adenocarcinoma ◽  
Critical Role ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Molecular Characteristics ◽  
Amplification Refractory Mutation System ◽  
Oncogenic Mutation ◽  
Formalin Fixed Paraffin Embedded ◽  
Ros1 Rearrangement

Abstract Background: Several driver genetic alterations have been identified in micropapillary lung adenocarcinoma (MPA). However, the frequency of ROS1 rearrangements is yet unclear. Herein, we investigated the associations between clinicopathological and molecular characteristics of MPA compared with non-micropapillary lung adenocarcinoma (LA). Methods: Formalin fixed paraffin-embedded (FFPE) sections derived from lung adenocarcinoma patients who never received adjuvant chemotherapy or radiation therapy prior to surgical resection were collected from October 2016 to June 2019. EGFR mutations, ROS1 rearrangement and EML4-ALK fusion were identified in a set of 131 MPA and LA cases by using the Amplification Refractory Mutation System (ARMS). Results: EGFR mutations had occurred in 42 (76.4%) MPA patients and 42 (55.3%) LA patients. But interestingly, ROS1 rearrangement was present in 10.9% (6/55) MPA cases and 1.3% (1/76) LA cases. Moreover, 7.3% (4/55) MPA samples had multiple gene mutations, while only 1.3% (1/76) LA cases had double gene alterations. Of 5 patients with harbouring two driver oncogenes mutations, four patients (80%) obtained partially response and one patient (20%) suffered recurrence. Conclusions: A higher prevalence of ROS1 rearrangements or combined mutations of ROS1 and EGFR or EML4-ALK may play a critical role in the tumorigenesis of MPA. These findings provide a novel therapeutic strategy for the patients with malignant MPA through combining TKIs than one TKI.

scholarly journals A comprehensive study on the oncogenic mutation and molecular pathology in Chinese lung adenocarcinoma patients

2020 ◽  
Author(s):  
Xilin Zhang ◽  
Yan Jiang ◽  
Huanming Yu ◽  
Hui Xia ◽  
Xiang Wang
Keyword(s):  
Lung Adenocarcinoma ◽  
Critical Role ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Molecular Characteristics ◽  
Novel Therapy ◽  
Multiple Gene ◽  
Oncogenic Mutation ◽  
Therapy Strategy

Abstract Background: Several driver genetic alterations have been identified in micropapillary lung adenocarcinoma (MPA). However, the frequency of ROS1 rearrangements is yet unclear. Herein, we investigated the associations between clinicopathological and molecular characteristics of MPA compared with non-micropapillary lung adenocarcinoma (LA).Methods: FFPE sections derived from lung adenocarcinoma patients who never received adjuvant chemotherapy or radiation therapy prior to surgical resection were collected from October 2016 to June 2019. EGFR mutations, ROS1 rearrangements and EML4-ALK fusions were identified in a set of 131 MPA and LA cases by using the Amplification Refractory Mutation System.Results: EGFR mutations had occurred in 42 (76.4%) MPA patients and 42 (55.3%) LA patients. But interestingly, ROS1 rearrangement was present in 10.9% (6/55) MPA cases and 1.3% (1/76) LA cases. Moreover, 7.3% (4/55) MPA samples had multiple gene mutations, while only 1.3% (1/76) LA cases had double gene alterations.Conclusions: A higher prevalence of ROS1 rearrangements or combined mutations of ROS1 and EGFR or EML4-ALK may play a critical role in the tumorigenesis of MPA. These finding provides a novel therapy strategy for the patients with malignant MPA through combining TKIs than one TKI.

Multigene Combined Detection by RT-qPCR Using Cytological Specimens

2021 ◽  
pp. 1-10
Author(s):  
Yang Ma ◽  
Jingxia Zhao ◽  
Yun Du ◽  
Rui Wang ◽  
Xiaokun Ji ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Smoking Status ◽  
Single Gene ◽  
Rna Extraction ◽  
Pcr Amplification ◽  
Driver Mutations ◽  
Amplification Refractory Mutation System ◽  
Driver Genes ◽  
Mutation Status ◽  
Pik3ca Mutations

<b><i>Objective:</i></b> The aim of the study was to investigate the mutation status of multiple driver genes by RT-qPCR and their significance in advanced lung adenocarcinoma using cytological specimens. <b><i>Materials and Methods:</i></b> 155 cytological specimens that had been diagnosed with lung adenocarcinoma in the Fourth Hospital of Hebei Medical University were selected from April to November 2019. The cytological specimens included serous cavity effusion and fine-needle aspiration biopsies. Among cytological specimens, 108 cases were processed by using the cell block method (CBM), and 47 cases were processed by the disposable membrane cell collector method (MCM) before DNA/RNA extraction. Ten drive genes of EGFR, ALK, ROS1, BRAF, KRAS, NRAS, HER2, RET, PIK3CA, and MET were combined detected at one step by the amplification refractory mutation system and ABI 7500 RT-qPCR. <b><i>Results:</i></b> The purity of RNA (<i>p</i> = 0.005) and DNA (<i>p</i> = 0.001) extracted by using the MCM was both significantly higher than that extracted by using the CBM. Forty-seven cases of fresh cell specimens processed by the MCM all succeeded in multigene detections, while of 108 specimens processed by the CBM, 6 cases failed in multigene detections. Among 149 specimens, single-gene mutation rates of EGFR, ALK, ROS1, RET, HER2, MET, KRAS, NRAS, BRAF, and PIK3CA mutations were 57.71%, 6.04%, 3.36%, 2.68%, 2.01%, 2.01%, 1.34%, 0.67%, 0% and 0% respectively, and 6 cases including 2 coexistence mutations. We found that mutation status was correlated with gender (<i>p</i> = 0.047), but not correlated with age (<i>p</i> = 0.141) and smoking status (<i>p</i> = 0.083). We found that the EGFR mutation status was correlated with gender (<i>p</i> = 0.003), age (<i>p</i> = 0.015) and smoking habits (<i>p</i> = 0.007), and ALK mutation status was correlated with age (<i>p</i> = 0.002). <b><i>Conclusion:</i></b> Compared with the CBM, the MCM can improve the efficiency of DNA/RNA extraction and PCR amplification by removing impurities and enriching tumor cells. And we speculate that the successful detection rate of fresh cytological specimens was higher than that of paraffin-embedded specimens. EGFR, ALK, and ROS1 mutations were the main driver mutations in patients with advanced lung adenocarcinoma. We speculate that EGFR and ALK are more prone to concomitant mutations, respectively. Targeted therapies for patients with coexisting mutations need further study.

scholarly journals MUC5AC enhances tumor heterogeneity in lung adenocarcinoma with mucin production and is associated with poor prognosis

2020 ◽  
Vol 50 (6) ◽  
pp. 701-711
Author(s):  
Yujie Dong ◽  
Lijuan Zhou ◽  
Dan Zhao ◽  
Kun Li ◽  
Zichen Liu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Lung Adenocarcinoma ◽  
Poor Prognosis ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Kras Mutations ◽  
Mucin Production ◽  
Thyroid Transcription Factor 1 ◽  
Thyroid Transcription Factor ◽  
Transcription Factor 1

Abstract Objective The clinicopathological significance of Mucin5AC (MUC5AC) in lung adenocarcinoma with mucin production is still unclear. This study aimed to explore MUC5AC expression in lung adenocarcinoma with mucin production and its correlation with histological subtypes, common driver mutations and its impact on prognosis. Methods MUC5AC and thyroid transcription factor 1 immunohistochemistry was performed on surgical samples from 90 patients with lung adenocarcinoma with mucin production. Common driver mutations including EGFR and KRAS mutations and ALK rearrangement were detected by established methods. Results MUC5AC was significantly associated with lymphovascular invasion (P = 0.023) and tumors with intra-cytoplasmic mucin (P &lt; 0.001). Moreover, MUC5AC was more significant in invasive mucinous adenocarcinoma (P &lt; 0.001), as well as in tumors with KRAS mutations (P = 0.005) and a lack of thyroid transcription factor 1 expression (P &lt; 0.001). Conversely, MUC5AC was less significantly detected in acinar predominant adenocarcinoma (P = 0.036) and tumors with EGFR mutations (P = 0.001). Notably, MUC5AC in non-pure mucinous subtype of lung adenocarcinoma with mucin production showed more aggressive behavior, distinct expression pattern and a lack of significant correlation with thyroid transcription factor 1 (P = 0.113) when compared with pure mucinous subtype. MUC5AC-positive tumors were significantly associated with a worse prognosis compared to MUC5AC-negative tumors (P &lt; 0.001). A multivariate survival analysis showed that MUC5AC was an independent prognosis factor for poor prognosis (P = 0.006). Conclusions The clinicopathological features of non-pure mucinous subtype of lung adenocarcinoma with mucin production were distinct and should be distinguished from pure mucinous subtype. MUC5AC was associated with poor prognosis and could be a potential therapeutic target for this distinct type of lung adenocarcinoma that has few effective treatments.

scholarly journals Detected EGFR mutation in cerebrospinal fluid of lung adenocarcinoma patients with meningeal metastasis

Open Medicine ◽  
2016 ◽  
Vol 11 (1) ◽  
pp. 93-96 ◽  
Author(s):  
Jiang Rong ◽  
Ma Chunhua ◽  
Lv Yuan ◽  
Mu Ning ◽  
Li Jinduo ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Lung Adenocarcinoma ◽  
Gene Mutation ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Egfr Mutations ◽  
Egfr Gene ◽  
Sequencing Method ◽  
Direct Sequencing Method ◽  
Egfr Gene Mutation

AbstractObjectiveTo discuss the application of ARMS method to detect EGFR gene mutation in cerebrospinal fluid of lung adenocarcinoma patients with meningeal metastasis.Methods5 cases of lung adenocarcinoma were identified with meningeal metastasis that were cleared EGFR gene mutation by gene sequencing method. From each patient 5ml cerebrospinal fluid was obtained by lumbar puncture. ARMS method was used to detect EGFR mutations in cerebrospinal fluid.Results5 samples of cerebrospinal fluid were successfully detected by ARMS method, 3 samples found that EGFR gene mutations, the mutations in line with direct sequencing method.ConclusionARMS method can be used to detect EGFR gene mutations of cerebrospinal fluid samples in lung adenocarcinoma with meningeal metastasis. But cerebrospinal fluid specimens from histological specimens, blood samples need to be confirmed by further comparative study whether there is advantage.

Prognostic implication of the EGFR gene mutations in a large cohort of Japanese patients with early stage lung adenocarcinoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7574-7574 ◽  
Author(s):  
T. Kosaka ◽  
Y. Yatabe ◽  
R. Onozato ◽  
T. Mitsudomi
Keyword(s):  
Lung Adenocarcinoma ◽  
Early Stage ◽  
Gene Mutations ◽  
Egfr Mutations ◽  
Prognostic Impact ◽  
Egfr Gene ◽  
Deletion Mutations ◽  
Exon 19 Deletion ◽  
Never Smokers ◽  
Exon 19

7574 Background: Prognostic impact of epidermal growth factor receptor (EGFR) gene mutations in lung adenocarcinoma remains controversial. We examined a large cohort of lung adenocarcinoma resected in a single institution for EGFR mutations and evaluated its prognostic implication. Methods: We analyzed 402 patients with lung adenocarcinoma who underwent potentially curative pulmonary resection at our department, from May 2000 through December 2005. Total RNA was extracted and direct sequencing of exons 18–21 of EGFR gene was performed after reverse transcription - polymerase chain reaction. KRAS and TP53 gene mutations were also analyzed in 209 adenocarcinoma patients from this cohort. Results: We found that 196 patients (49%) had EGFR mutations. Of them, exon 19 deletion mutations were 83 (42%) and L858R mutations were 92 (47%). EGFR mutations were significantly frequent in female (P<0.0001), never smokers (P<0.0001), and well to moderately differentiated adenocarcinoma (P<0.0001). In 347 patients who were not treated with gefitinib, prognostic effect of EGFR mutations was evaluated. Patients with EGFR mutations survived for a longer period than those without the mutations after surgery in univariate analysis (P=0.0046, log rank test). We did not detect any difference in overall survival between the patients with exon 19 deletion mutations and those with L858R mutations (P=0.3962). There were tendencies that patients with KRAS mutations or TP53 mutations survived for a shorter period than those without mutations, although there was no statistical significance (P=0.2534 and 0.0859). Multivariate analysis using the Cox proportional hazards model revealed that never smokers (P=0.0253) and disease stage (P<0.0001) were independent prognostic factors. However, all gene mutations were not independent prognostic factors (EGFR; P=0.4763, KRAS; P=0.7998, TP53; P=0.3464). Conclusion: EGFR mutations were not independently associated with prognosis of patients with early stage adenocarcinoma of the lung. Furthermore, there was no difference between exon 19 deletion mutations and L858R mutations in their prognostic impact. No significant financial relationships to disclose.

Ethnic difference of driver mutation frequencies and correlations between driver mutations and histologic subtypes in lung adenocarcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1552-1552
Author(s):  
Yuki Yamane ◽  
Koichi Goto ◽  
Akikazu Kawase ◽  
Katsuya Tsuchihara ◽  
Sachiyo Mimaki ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Ethnic Difference ◽  
The United States ◽  
Driver Mutation ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Cancer Center ◽  
Histological Subtypes ◽  
Kras Mutations ◽  
Met Amplification

1552 Background: The frequencies of known driver mutation in lung adenocarcinoma from patients in the United States have been reported by the NCI’s Lung Cancer Mutation Consortium (LCMC), indicating driver mutations were detected in 54% (280/516) of tumors. In this report, mutations found: EGFR 17%, KRAS 22%, HER2 0.6%, PIK3CA 1.2%, BRAF 2%, MET amplification 0.6%, MAP2K1 0.4%, NRAS 0.4%, AKT 0%, ALK rearrangements 7%. However little is known about ethnic difference of driver mutation frequencies and correlations between driver mutations and histological subtypes in lung adenocarcinoma. Methods: Known driver mutations in tumors from 97 Japanese patients with lung adenocarcinoma who underwent surgical resection between 1999 and 2003 in National Cancer Center Hospital East were analyzed by next-generation sequencing and confirmed by Sanger sequencing. Correlations between driver mutations and histological subtypes were also assessed. Results: Driver mutations were detected in 72% of tumors. Mutations found: EGFR 57%, KRAS9%, HER2 2%, PIK3CA 2%, BRAF 1%, MET amplification 1%, MAP2K1 0%, NRAS 0%, AKT 0%. Due to the limitation of rearrangement detection by exon-sequencing, ALK rearrangements were not analyzed. Compared with the report by LCMC, the frequency of EGFR mutations was high and that of KRAS mutations was low in the present study. All mutations were mutually exclusive. The number of predominant histological subtypes of tumors harbored EGFR mutations were papillary 28, acinar 3, solid 5, lepidic 19. That with KRAS mutations showed papillary 2, acinar 2, solid 2, lepidic 3, and HER2 mutations showed papillary 1 and acinar 1. Two tumors harbored PIK3CA mutations showed both histological acinar pattern. Each of BRAF mutation and MET amplification showed lepidic and papillary pattern, respectively. Conclusions: It was suggested that there should be ethnic difference of driver mutation frequencies in lung adenocarcinoma between Asian and non-Asian patients, although the details of ethnic distribution included in LCMC study has not been opened. In addition, each driver mutations did not correspond to specific histological subtypes of lung adenocarcinoma.

Somatic mutation spectrum of non-small cell lung cancers (NSCLCs) from African Americans (AAs).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6038-6038
Author(s):  
Philip Edward Lammers ◽  
Velmalia Matthews-Smith ◽  
Ya-Lin Yun ◽  
Yumei Pan ◽  
Snjezana Zaja-Milatovic ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
North American Population ◽  
Molecular Testing ◽  
Chi Square ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Anaplastic Lymphoma ◽  
Ffpe Tumor

6038 Background: In the AA population, previous studies have presented conflicting data on the frequency of EGFR mutations (Reinersman JTO 2011;Leidner JCO 2009), while frequencies of other gene mutations and translocations, including anaplastic lymphoma kinase (ALK), have not been described. Methods: 161 archival FFPE tumor specimens from self reported AA patients with any stage NSCLC from 1997-2010 were collected from 3 sites in Tennessee (132 samples) and one site in Michigan (29 samples). Samples were evaluated for known recurrent driver mutations in EGFR, KRAS, BRAF, NRAS, AKT1, PI3KCA, PTEN, HER-2, MEK1 by standard SNaPshot/sizing assays, and translocations in ALK by FISH. Clinical data was collected on 119 patients. Chi-square was used to compare the frequency of mutations in subgroups and Kaplan-Meier and log rank were used to calculate and compare PFS between groups. Results: 5.0% of tumors had EGFR mutations, 14.9% had KRAS mutations, 0.6% had a BRAF, AKT1, PI3KCA, or HER2 mutation, and 0% had NRAS, PTEN, or MEK1 mutations. Of 35 ‘pan-negative’ non-squamous specimens, 0 had ALK translocations. PFS was the same in those with and without KRAS mutation (p=0.74) and showed a trend towards improvement in those with EGFR mutation (p=0.08). The frequency of EGFR mutations was higher in samples from Detroit versus those from Tennessee (17% vs 2.3%, p<0.01), as was the frequency of adenocarcinoma (62% vs 44%, p<0.05). The frequency of EGFR mutations in never smokers was higher in the samples from Detroit versus Tennessee (83% vs 7.1%, p<0.01). Conclusions: In the largest tumor mutational profiling study of NSCLC from AAs to date, EGFR mutations occurred less frequently than would be expected from a North American population. We noted a regional difference, with fewer EGFR mutations in Tennessee than in Michigan, a finding that may have been the result of more adenocarcinoma samples from Michigan. The rates of other mutations and translocations including ALK were low. While lung cancer tumors should continue to undergo routine molecular testing to prioritize therapy, future comprehensive genotyping efforts should focus on identifying novel driver mutations in this population. Funding: 5RC1CA162260 R01CA060691 R01CA87895.

Evaluation of the fully automated Idylla EGFR Mutation Assay in Chinese patients with lung adenocarcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21716-e21716
Author(s):  
Tian Qiu ◽  
Li Junling ◽  
Bo Zheng ◽  
Jianming Ying
Keyword(s):  
Lung Adenocarcinoma ◽  
Egfr Mutation ◽  
Growth Factor Receptor ◽  
Chinese Patients ◽  
Egfr Mutations ◽  
Arms Pcr ◽  
Formalin Fixed Paraffin ◽  
Ffpe Samples ◽  
Formalin Fixed Paraffin Embedded ◽  
User Friendly

e21716 Background: Epidermal growth factor receptor ( EGFR) mutation testing is nowadays an essential part of lung adenocarcinoma diagnosis. Its rapid detection is of utmost significance in order to ensure that patients receive timely and appropriate treatment. However, the current techniques for EGFR examination in China, ARMS-PCR and NGS, often take 3~7 days to deliver the final results. In contrast, the fully automated Idylla EGFR assay could detect 51 EGFR mutations directly from formalin-fixed, paraffin-embedded (FFPE) samples within 2.5 hours with < 2 minutes of hands-on time. The test has proven both accurate and robust among Caucasian lung adenocarcinoma patients but has never been clinically validated in Chinese patients. Methods: FFPE samples were retrospectively collected from 94 lung adenocarcinoma patients followed by EGFR testing using the Idylla system. Seventy-eight samples were also previously assessed with ARMS-PCR, 9 with NGS and 7 with both. In case of discordance, repeat testing was performed on the same tissue block with a third method. The sensitivity and specificity of the Idylla EGFR assay were evaluated against ARMS-PCR or NGS. Mutations beyond the scope of detection by the Idylla EGFR assay were not included in the analyses. Results: Of the 94 tumors enrolled, 77 were stage I-II. The Idylla system was consistent with ARMS-PCR or NGS for the EGFR mutational profiles of 92 tumors: 80 positive and 12 negative. Among the 2 cases of discrepancy, one was wild-type using Idylla but were found to harbor G719X/S768I using ARMS-PCR (and confirmed by NGS), while the other one carried L858R according to Idylla, as confirmed by ARMS-PCR, but was discovered to have an additional mutation L861Q using NGS. The Idylla EGFR test had a sensitivity of 97.6%, a specificity of 100% and an overall concordance of 97.9%. Conclusions: The Idylla system provides a rapid, accurate and user-friendly solution to EGFR characterization, especially in time-sensitive scenarios where special expertise and staff training could be a challenge.

Sign in / Sign up

Export Citation Format

Share Document