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.

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 < 0.001). Moreover, MUC5AC was more significant in invasive mucinous adenocarcinoma (P < 0.001), as well as in tumors with KRAS mutations (P = 0.005) and a lack of thyroid transcription factor 1 expression (P < 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 < 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.

Does EGFR mutation define the histological predominant subtype of lung adenocarcinoma?

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7557-7557
Author(s):  
Eri Sugiyama ◽  
Koichi Goto ◽  
Genichiro Ishii ◽  
Tomohiro Haruki ◽  
Shingo Matsumoto ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Egfr Mutations ◽  
Heavy Smoker ◽  
Cancer Center ◽  
Histological Subtypes ◽  
Invasive Adenocarcinoma ◽  
Predominant Subtype ◽  
Egfr Tyrosine Kinase Inhibitors

7557 Background: In 2011, invasive adenocarcinomas were newly classified into the five predominant subtypes by IASLC/ATS/ERS: lepidic, papillary, acinar, micropapillary, and solid. The purpose of this study is to investigate the correlation between EGFRmutation and the histological predominant subtype of lung adenocarcinoma. Methods: Among a total of 1,736 patients with lung adenocarcinoma who underwent surgical resection from 2002 to 2011 in National Cancer Center Hospital East, 1,507 were classified into invasive adenocarcinoma. 526 of whom were examined EGFR mutation status. Histological predominant subtypes were evaluated at the maximum cut surface of tumors. The EGFR mutation analysis was performed by PCR-invader method. Treatment efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in 73 relapsed patients with EGFRmajor mutations were also examined. Results: 526 adenocarcinomas were consisted of 95 lepidic (18%), 221 papillary (42%), 80 acinar (15%), 9 micropapillary (2%), and 121 solid predominant subtype (23%). EGFR mutations were detected in 227 adenocarcinomas (43%), and its frequency in the solid subtype (22%) was significantly less than that of other histological subtypes (lepidic 47%, papillary 53%, and acinar 44%; P < 0.01). The proportion of minor mutations, other than exon 21 L858R and exon 19 deletions, were significantly higher in the solid subtype (22%) than that of the others (lepidic 4%, and papillary 12%; P < 0.01). In 73 patients with EGFR major mutations treated by EGFR-TKIs, the response rate was not different between histological subtypes (lepidic 86%, papillary 76%, acinar 89%, and solid 60%). Conclusions: The correlation between histological predominant subtypes of lung adenocarcinoma and the presence of EGFR mutations or the efficacy of EGFR-TKI were not identified in this study. Little is known about the reason why EGFR minor mutations were highly detected in the solid subtype of adenocarcinoma, however it is possibly due to the high frequency of heavy smokers in solid subtype (heavy smoker: solid 67% vs. others 27-44%).

MET exon 14 mutations in advanced lung adenocarcinoma: Frequency and coexisting alterations.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20656-e20656
Author(s):  
Rossella Bruno ◽  
Cristiana Lupi ◽  
Lorenza Landi ◽  
Greta Alì ◽  
Elisa Sensi ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Lung Adenocarcinoma ◽  
Splice Site ◽  
Target Therapy ◽  
High Rate ◽  
Driver Mutations ◽  
Tyrosine Kinase Receptor ◽  
Missense Mutations ◽  
Kras Mutations ◽  
Met Amplification

e20656 Background: In lung cancer the evaluation of MET, a tyrosine kinase receptor involved in tumor growth and invasiveness, for copy number amplification and point mutations is relevant for prognosis and therapy. In lung adenocarcinoma (ADC) MET amplification is observed in 1-2% and MET mutations in 3-4% of cases. Mutations mainly occur in exon 14 (ex14), which encodes for the juxtamembrane negative regulatory domain, including splice site alterations and missense mutations within the exon.Commonly, MET ex14 alterations, in particular splice site ones, are mutually exclusive with other driver mutations, but co-occurrence with MET and MDM2 amplification and KRAS mutations was described. We evaluated METex14 mutation frequency and coexistence with additional driver alterations in a prospective cohort of Italian ADC patients. Methods: 315 ADC patients were tested (January-December 2016) for MET ex14 alterations by Sanger Sequencing on formalin-fixed paraffin-embedded tissues and cytological smears (tumor cells > 40%). MET positive cases were screened also for other oncogenes, among which KRAS, BRAF and PIK3CA, using a MALDI-TOF platform, and for ROS1 translocations and MET amplification by FISH. Results: 16 patients (5%) were MET positive: 7 splice site mutations (43%) and 9 (57%) other alterations within ex14. Among splice site mutations 1 co-occurred with ROS1 translocation and 1 with MET amplification. Among other mutations we found 5 T1010I missense mutations: 3 co-occurring with G12D/G13C/Q61H KRAS, 1 with G469A BRAF and 1 with a MET intron 13 point mutation; 2 R988C mutations: 1 with G13C KRAS and 1 with G13C KRAS plus ROS1 translocation; 1 P1026S mutation and 1 frameshift deletion (p.A991del;R992fs*999), both with G12C KRAS. Conclusions: Splice site mutations cause MET activation by exon skipping and increase sensitivity to tyrosine-kinase inhibitors, whereas how other ex14 mutations affect MET function is not fully understood. In our cohort we found a high rate of METex14 mutations together with alterations in other oncogenes, mostly KRAS. The interaction of MET with cancer signaling pathways deserve further investigation in order to better define the role of ex14 mutations in the context of target therapy.

Molecular profiling as predictor of outcomes in a Brazilian cohort of stage IV lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20668-e20668
Author(s):  
Nicolas Peruzzo ◽  
Juliano Ce Coelho ◽  
Gabriel de Souza Macedo ◽  
Tiago Finger Andreis ◽  
Gustavo Gössling ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cox Regression ◽  
De Novo ◽  
Stage Iv ◽  
Molecular Profiling ◽  
Driver Mutation ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Kras Mutations ◽  
Egfr Mutated

e20668 Background: Lung cancer is the leading cause of cancer deaths globally. In stage IV non-small cell lung cancer (NSCLC), identification of a tumor driver mutation is critical, since it tailors treatment. We aimed to analyze clinical outcomes according to molecular profiling in patients (pts) with stage IV NSCLC. Methods: In this retrospective cohort study, we enrolled 57 pts with stage IV NSCLC treated at a public hospital in Southern Brazil between 2016 and 2018. Results: Median follow-up was 20.3 months, 53% were men, mean age was 65 years, 86% had smoked, 84% had de novo metastatic NSCLC and 96% had non-squamous carcinoma. Regarding molecular profiling, somatic mutations in KRAS, EGFR and BRAF were identified in 33%, 16% and 4% of pts, respectively. None of the pts had ALK mutations, and in 47% no identifiable driver mutation was found. In the EGFR-mutated subgroup, 67% had a deletion of exon 19, 22% had the exon 21 L858R mutation and 11% had exon 20 mutations. Palliative systemic therapy (PST) was delivered to 60% of the pts. Two or more lines of PST were delivered to 23%. The main reason for upfront best supportive care was ECOG PS 3-4 (poor). In the subgroup of pts with sensitizing EGFR mutations (8 pts), 75% received Gefitinib, the only anti-EGFR drug available in our public health system; the other pts died before recognition of the mutation. Median Progression Free-Survival was 6.3 months overall, 10.3 months for EGFR-mutated pts, 7.6 months for KRAS-mutated, 7.5 months for BRAF-mutated, and 5.2 months for pts with no mutation identified. Median Overall Survival (OS) was 7.7 months overall, 13.2 months for EGFR-mutated pts, 7.4 months for KRAS-mutated, 12.9 months for BRAF-mutated, and 5.3 months for pts with no mutation identified. In the Cox regression multivariate analysis, poor PS (HR 3.80, P < 0.0001) and second-line PST (HR 0.23, P = 0.002) were independent predictors of OS. No driver mutations were predictors of OS, although we did find a tendency towards better OS in pts with EGFR mutations and worse OS in pts with KRAS mutations or no identifiable mutation. Conclusions: In this cohort, genotyping results did not predict survival outcomes. This is probably due to the small number of pts studied, and data should be reanalyzed in larger cohorts.

Genetic Alterations in Chinese Resected Lung Cancer with Invasive Mucinous Adenocarcinoma: Genomic Profiling and Prognostic Value Analysis

2021 ◽  
Author(s):  
James D. Klingensmith
Keyword(s):  
Mucinous Adenocarcinoma ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Genetic Profile ◽  
Kras Mutations ◽  
Genetic Characteristics ◽  
Value Analysis ◽  
Invasive Mucinous Adenocarcinoma

Lung invasive mucinous adenocarcinoma (IMA) is a unique histological subtype with different clinical and pathological characteristics. Despite prior genomic investigations on lung IMA, little is known about the genetic features and prognosis-related biomarkers in Chinese surgically resected lung IMA. IMA showed a distinct genetic profile, with more diversified driver mutations and co-occurrence of tumor drivers/suppressors than non-IMA. From non-IMA to mixed-IMA to pure-IMA, the frequency of EGFR (72.0 percent vs. 40.0 percent vs. 23.1 percent, p=0.002) and ALK (undetected vs. 20.0 percent vs. 26.9%, p=0.015) changes exhibited a trend of steady decline and rise, respectively. KRAS mutations were more common in pure-IMA than in mixed-IMA, however the difference was statistically insignificant (23.1 percent vs. 4.0 percent, p=0.10). Pure-IMA had a lower rate of TP53 mutation than mixed-IMA and non-IMA (23.1 percent vs. 52.0 percent vs. 56.0 percent, p=0.03). Furthermore, IMA had fewer arm-level amplifications (p=0.04) and more arm-level deletions (p=0.004) than non-IMA, with a steady drop in amplification and rise in deletion frequency from non-IMA to mixed-IMA to pure-IMA, respectively. Patients with EGFR mutations (mDFS=30.3 vs. 16.0 months, HR=0.19, P=0.027) and PI3K pathway mutations (mDFS=36.0 vs. 16.0 months, HR=0.12, P=0.023) had longer DFS than patients with poorly differentiated tumors (mDFS=14.1 vs. 28.0 months, HR=3.75, p=0.037) or KRAS mutations (mDFS=13 KRAS mutations, PI3K pathway changes, and tumor differentiation status were all shown to be independent predictors with statistically significant effects on IMA patients' clinical outcomes in multivariate analysis. Our research shed light on the genomics of Chinese lung IMA that had been surgically removed. In IMA patients with stage III illness, we also discovered many genetic characteristics that might be used as indicators for postoperative recurrence.

Driver mutations to predict for poorer outcomes in non-small cell lung cancer patients treated with concurrent chemoradiation and consolidation durvalumab.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8528-8528
Author(s):  
Yufei Liu ◽  
Zhe Zhang ◽  
Waree Rinsurongkawong ◽  
Xiuning Le ◽  
Carl Michael Gay ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Small Cell ◽  
Driver Mutation ◽  
Driver Mutations ◽  
Small Cell Lung ◽  
Kras Mutations ◽  
Mutation Status

8528 Background: The use of durvalumab after chemoradiation in locally advanced non-small cell lung cancer (NSCLC) patients significantly improves overall survival. However, it is unclear whether this benefit applies to all genetic subtypes of lung cancer. We hypothesize that patients with driver mutation NSCLC may derive less benefit from consolidation durvalumab. Methods: Using the Genomic Marker-Guided Therapy Initiative (GEMINI) database at MD Anderson, we identified 134 patients who were treated with chemoradiation followed by durvalumab for NSCLC. We segregated patients with driver mutations to targetable (EGFR, ALK translocation, ROS1 fusion, MET exon 14 skipping, RET fusion, and/or BRAF) (N = 24) and those driven by canonical KRAS mutations (N = 26). The rest (N = 84) had none of these mutations. We gathered demographic, treatment, and outcome data and compared progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. We used multivariate regression analysis to account for demographic and treatment variables. Results: For our cohort, median age at diagnosis was 64.8, 52% were female (n = 70), and median follow up was 1.5 years. 86% of patients have a history of smoking (n = 115). 21% had squamous cell histology (n = 28). 2 patients had stage IIA disease, 6 had stage IIB, 48 had stage IIIA, 56 had stage IIIB, 13 had stage IIIC, and 9 had stage IV. 73 patients had progression after durvalumab and 37 patients died. Patients with driver mutations had significantly worse median PFS compared to those without driver mutations (8.9 mo vs 26.6 mo; HR 2.62 p < 0.001). Patients with KRAS mutations had particularly poor PFS (Median 7.9 mo, HR 3.34, p < 0.001), while patients with targetable driver mutations trended to worse PFS (Median 14.5 mo, HR 1.96, p = 0.056). The median OS for the cohort was 4.8 yrs with no significant differences based on driver mutation status. On multivariate analysis, only driver mutation status was associated with PFS, but not OS. For patients with first progression, we found the targetable driver group to have significantly improved time to second objective progression (PFS2) compared to the KRAS (HR 0.28, p = 0.011) or non-mutated group (HR 0.38, p = 0.025). All patients in the targetable driver group received targeted therapy after first progression. Conclusions: Our results suggest that patients with driver mutations have worse PFS compared to patients without these mutations after chemoradiation. However, patients with targetable oncogene driver mutations have significantly improved prognosis after initial progression compared to the other groups, likely due to targeted therapy, suggesting that these therapies, including novel approaches towards KRAS mutants, should be further explored in this setting.

Differential responses to therapy in Hispanic NSCLC patients with EGFR, KRAS, or TP53 mutations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21027-e21027
Author(s):  
Fahmin Basher ◽  
Diana Saravia ◽  
Gilberto Lopes
Keyword(s):  
Checkpoint Inhibitors ◽  
Egfr Mutations ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Kras Mutations ◽  
Tp53 Mutations ◽  
Hispanic Patients ◽  
Tumor Mutational Burden ◽  
Receive Treatment ◽  
Nsclc Patients

e21027 Background: Hispanic (H) patients with non-small cell lung cancer (NSCLC) tend to have more advanced disease at time of diagnosis and less likely to receive treatment compared to non-Hispanic white (NHW) Americans. While survival outcomes do not differ greatly, Hispanic patients tend to have lower response rates to immunotherapy and to targeted therapy with known EGFR mutations. We sought to determine if Hispanic patients with other common mutations present in NSCLC also demonstrate suboptimal responses to therapy compared to NHW patients. Methods: We performed a retrospective review of 468 patients with advanced stage NSCLC at the University of Miami / Sylvester Comprehensive Cancer Center who underwent next-generation sequencing (NGS) for whom treatment outcomes could be identified. Genomic results were obtained from Guardant360 and Foundation One testing in blood or tissue, respectively. Results: In our cohort, 154 patients (33%) were of Hispanic ethnicity, while 279 patients (60%) were NHW. Median age at time of diagnosis was 59, and 50% were male. PD-L1 status was known for 217 patients, with 110 expressing some level of PD-L1. EGFR mutations were present in 25% of all patients, KRAS mutations in 25%, and TP53 mutations in 61%. Average tumor mutational burden was 4.0 in Hispanic patients and 3.6 in NHW patients. We compared outcomes in patients receiving any therapy as well as those specifically receiving immune checkpoint inhibitors (ICI). No differences in OS were observed in our overall patient cohort between H and NHW patients. However, when stratifying patients with EGFR or KRAS mutations, Hispanic patients exhibit significantly shorter OS than their NHW counterparts. In patients with TP53 mutations, we observed no differences between H and NHW outcomes considering all therapy, but Hispanic patients exhibited improved OS with the use of ICI. Conclusions: Our data suggest that the presence of certain mutations in Hispanic patients with advanced NSCLC may serve some prognostic value in predicting responses to therapy, specifically the use of ICI. Further investigation is indicated to determine mechanisms leading to inferior responses after ICI therapy in Hispanic patients.[Table: see text]

scholarly journals Analysis of Predictive Biomarkers in Patients With Lung Adenocarcinoma From Southern Brazil Reveals a Distinct Profile From Other Regions of the Country

2019 ◽  
pp. 1-9 ◽  
Author(s):  
Tiago F. Andreis ◽  
Bruno S. Correa ◽  
Fernanda S. Vianna ◽  
Fernanda De-Paris ◽  
Marina Siebert ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Predictive Biomarkers ◽  
Egfr Mutations ◽  
Southern Brazil ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Histologic Subtype ◽  
Molecular Alterations ◽  
Common Histologic Subtype ◽  
L1 Protein

PURPOSE Adenocarcinoma is the most common histologic subtype of non–small-cell lung cancer, representing 40% of all diagnoses. Several biomarkers are currently used to determine patient eligibility for targeted treatments, including analysis of molecular alterations in EGFR and ALK, as well as programmed death-ligand 1 (PD-L1) protein expression. Epidemiologic data reporting the frequency of these biomarkers in Brazilian patients with lung adenocarcinoma (LUAD) are limited, and existing studies predominantly included patients from the southeast region of the country. MATERIALS AND METHODS The goal of this study was to investigate the frequency of somatic mutations in the EGFR, KRAS, NRAS, and BRAF genes, ALK, and PD-L1 expression in a series of Brazilian patients diagnosed with LUAD predominantly recruited from centers in southern Brazil. Molecular analysis of the EGFR, KRAS, NRAS, and BRAF genes was performed by next-generation sequencing using DNA extracted from tumor tissue. Immunohistochemistry was used to detect ALK and PD-L1 expression. RESULTS Analysis of 619 tumors identified KRAS mutations in 189 (30.2%), EGFR mutations in 120 (19.16%), and BRAF mutations in 19 (3%). Immunohistochemistry demonstrated ALK and PD-L1 expression in 4% and 35.1% of patients, respectively. CONCLUSION To our knowledge, this is the first study investigating the molecular epidemiology of patients with LUAD from southern Brazil and the largest assessing the frequency of multiple predictive biomarkers for this tumor in the country. The study also reveals a distinct mutation profile compared with data originating from other regions of Brazil.

Genomic heterogeneity of multifocal NSCLC.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21595-e21595
Author(s):  
Mingjiu Chen ◽  
Haitao Ma ◽  
Haoda Yu ◽  
Chen Chen ◽  
Pingping Dai ◽  
...  
Keyword(s):  
Primary Lung Cancer ◽  
Germline Mutations ◽  
Driver Mutation ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Diagnostic Dilemma ◽  
Tissue Samples ◽  
Metachronous Tumor ◽  
Molecular Events ◽  
Group I

e21595 Background: Distinguishing multiple primary lung cancer (MPLC) and intrapulmonary metastasis (IPM) remains a common diagnostic dilemma but critical for developing a therapeutic strategy. Methods: In this study, we analyse genomic features of 584 tissue samples from 258 NSCLC patients with > 1 surgically-resected tumor. NGS was performed using panels of 1021/59 genes. Results: Among 80 patients with definite diagnosis, 23 patients (46 tumors) were diagnosed with IPM. And 57 patients (145 tumors) were MPLC, consisting of 53 synchronous and 3 metachronous tumor pairs. Among 23 IPM tumor pairs, we identified at least one shared somatic mutation. By contrast, 93%(53/57) MPLC tumor pairs exhibited entirely unique mutation profiles in each tumor. Of 57 MPLCs, 4(7%) had no driver alteration ( EGFR, KRAS, BRAF, ALK, ERBB2, MET Exon 14). 9(16%) had a driver in only one of the tumors. In the remaining 44 MPLCs, 40 had unique driver mutation in each tumor. 50%(20/40) had distinct EGFR mutations, the most common combination was L858R and delins in exon 19. Specifically, 8(20%) patients resided ≥3 unique driver mutations simultaneously. This observation indicated that multiple lesions in the same individual can be driven by distinct molecular events. In contrast, 21 available IPM tumor pairs shared the same driver mutation. Pathogenic germline mutations were also analysed. Two were found in 2 MPLCs, involving PLAB2 and BLM, which were both null variants. While there were no pathogenic germline mutations found in IPMs. Regarding the MSI status, all samples from either MPLCs and IPMs displayed MSS, unexpectedly. To further verify the findings above, the remaining 393 samples with uncertain diagnosis were classified into group M (no shared mutation, 218 samples /97 patients) and I (≥1 shared mutation, 175 samples/81 patients). We find the similarity results among all available patients, driver mutation profiles exhibited completely unique and multiple in group M and fully consistent in group I. Conclusions: Taken together, our analyses indicated that the genomic heterogeneity of multifocal NSCLC may be a potential strategy for differentiating IPM and MPLC. This may hold implications for prioritizing therapeutic strategies.

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