Genomic Profiling of Driver Gene Mutations in Chinese Patients With Non-Small Cell Lung Cancer.
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ABSTRACT:
SUBMITTER: Meng H
PROVIDER: S-EPMC6842958 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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Genomic Profiling of Driver Gene Mutations in Chinese Patients With Non-Small Cell Lung Cancer.
Meng Hongxue H Guo Xuejie X Sun Dawei D Liang Yuebin Y Lang Jidong J Han Yingmin Y Lu Qingqing Q Zhang Yanxiang Y An Yanxin Y Tian Geng G Yuan Dawei D Xu Shidong S Geng Jingshu J
Frontiers in genetics 20191018
Worldwide, especially in China, lung cancer accounts to a major cause of mortality related to cancer. Treatment decisions mainly depend on oncogenic driver mutations, which offer novel therapeutic targets for anticancer therapy. However, studies of genomic profiling of driver gene mutations in mainland China are rare. Hence, this is an extensive study of these mutations in Non-small-cell lung cancer (NSCLC) Chinese patients. Comparison of driver gene mutations of lung adenocarcinoma with other r ...[more]
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Project description:To determine the frequency of driver mutations in Chinese non-small cell lung cancer (NSCLC) patients.Comprehensive mutational analysis was performed in 1356 lung adenocarcinoma, 503 squamous cell carcinoma, 57 adenosquamous lung carcinoma, 19 large cell carcinoma and 8 sarcomatoid carcinoma. The effect of EGFR tyrosine kinase inhibitors (TKIs) on EGFR-mutated lung adenocarcinoma patients after disease recurrence was investigated.Mutations in EGFR kinase domain, HER2 kinase domain, KRAS, BRAF, ALK, ROS1 and RET were mutually exclusive. In lung adenocarcinoma cases "pan-negative" for the seven above-mentioned driver mutations, we also detected two oncogenic EGFR extracellular domain mutations (A289D and R324L), two HER2 extracellular and transmembrane domain mutations (S310Y and V659E), one ARAF S214C mutation and two CD74-NRG1 fusions. Six (1.2%) FGFR3 activating mutations were identified in lung squamous cell carcinoma (five S249C and one R248C). There were three (15.8%) EGFR mutations and four (21.1%) KRAS mutations in large cell carcinoma. Three (37.5%) KRAS mutations were detected in sarcomatoid carcinoma. In EGFR-mutated lung adenocarcinoma patients who experienced disease recurrence, treatment with EGFR TKIs was an independent predictor of better overall survival (HR = 0.299, 95% CI: 0.172-0.519, P < 0.001).We determined the frequency of driver mutations in a large series of Chinese NSCLC patients. EGFR TKIs might improve the survival outcomes of EGFR-mutated lung adenocarcinoma patients who experienced disease recurrence.
| S-EPMC4741453 | biostudies-literature
Project description:Background Lung cancer is the most prevalent cancer worldwide and accounts for approximately 20% of cancer-related death in China every year. High-grade lung cancer poses a significant threat to patients, and developing a novel treatment for these patients requires an understanding of its underlying mechanism. Methods Chinese patients with lung cancer were enrolled. The tumor samples were collected by surgery or puncture and applied for next-generation sequencing. A panel of pan-cancer genes was targeted, and the sequencing depth was set to over 1,000 to improve the sensitivity of detecting mutations. Short-length mutations (substitution, insertion, and deletion), copy number variation, and gene fusion were called. Gene mutations were compared between low-grade, middle-grade, and high-grade tumors using Fisher’s exact test. The enriched pathways in each grade of tumors were also inferred. Results The study included 173 Chinese patients with non-small cell lung cancer, of whom 98 (56.6%) patients were female and 75 (43.4%) were male, with a mean age of 56.8 years. All patients were microsatellite stable; 66.4% were at the early stages (Stages 0, I, and II) with a tumor mutational burden of approximately 2.5 (confidence interval = [0, 48.3]). Compared to low-grade tumors, high-grade tumors had a significantly higher percentage of mutations in TP53 (75.9% vs 34.4%, p = 1.86e-3) and PIK3CA (24.1% vs. 0%, p = 3.58e-3). Pathway analysis found that high-grade tumors were enriched with mutations in bacterial invasion of epithelial cells (31% vs. 0%, p = 5.8e-4), Epstein–Barr virus infection (79.3% vs. 37.5%, p = 1.72e-3), and the Wnt signaling pathway (75.9% vs. 34.4%, p = 1.91e-3). High-grade tumors had a significantly higher tumor mutational burden than low-grade tumors (p-value = 0.0017). However, actionable mutations with high-level evidence were lower in high-grade tumors. Conclusion Patients with high-grade tumors from lung cancer may be more affected by bacteria and Epstein–Barr virus than low-grade tumors. High-grade tumors were specially mutated in TP53 and PIK3CA and may benefit more from immunotherapy. Further research on the underlying mechanism of high-grade lung cancer is necessary to develop new therapeutic options. Lung cancer, tumor grade, genomic mutations, Epstein–Barr virus, pathway analysis
| S-EPMC10067928 | biostudies-literature
Project description:BackgroundMolecular testing for alterations in oncogenic driver genes and targeted therapies have become standard procedures for non-small cell lung cancer (NSCLC) patients. However, little evidence has shed light on the pattern of co-existence of driver genes in NSCLC, and whether they may have different tumor features affecting immunotherapy is still unclarified.MethodsGenomic alterations in 14 lung cancer-related genes were conducted in 3440 Chinese NSCLC patients using next-generation sequencing. Meanwhile, tumor mutational burden and immunotherapy dataset from the Memorial sloan kettering cancer center (MSKCC) and lung adenocarcinoma dataset from The Cancer Genome Atlas (TCGA) were utilized for analyzing the impact of the co-occurring alterations on patients' survival following immunotherapy.ResultsIn this cohort, 90.17% of patients had at least one somatic alteration in the 14 genes, including 51% of co-occurring alterations. TP53 and epidermal growth factor receptor (EGFR) were the most prevalent genes (54.74% and 53.55%, respectively), followed by KRAS, ERBB2, ALK, PIK3CA, ROS1, RET, MET, BRAF, KIT, FGFR1, PDGFRA, and NRAS. The prevalence of TP53, EGFR, and ERBB2 in our cohort were significantly higher than that from the TCGA database, whereas KRAS, BRAF, and PDGFRA were significantly lower than the latter. Furthermore, the patients who harbored multiple alterations (8.86%, 31/350) in eight driver genes survived longer and have a higher tumor mutation burden compared to the patients with a single alteration. Similar result was found between the patients with co-occurring alteration of EGFR and other driver genes and the patients with single EGFR alteration. Meanwhile, we found a distinct immune cell infiltration feature between patients with single and multiple driver gene alterations, as well as between patients with only EGFR alteration and co-occurring groups.ConclusionThis study identified a unique driver gene feature and found patients harboring co-occurring alterations of EGFR and other driver genes may benefit from immunotherapy, which may provide more therapeutic selections for EGFR-mutated NSCLC patients and merit additional investigation.
| S-EPMC8525092 | biostudies-literature
Project description:BackgroundERBB2 (HER2) is a driver gene identified in non-small cell lung cancer (NSCLC). The prevalence, clinicopathology, genetic variability and treatment of HER2-positive NSCLC in Chinese population are unclear.Patients and methodsEight hundred and fifty-nine patients with pathologically confirmed NSCLC were screened for HER2 mutations using Sanger sequencing. Next-generation sequencing (NGS) was performed in positive cases. HER2 amplification was detected with FISH. Overall survival (OS) was evaluated using Kaplan-Meier methods and compared with log-rank tests.ResultsTwenty-one cases carrying HER2 mutations were identified with a prevalence of 2.4%. HER2 mutations were more frequently encountered in females, non-smokers and adenocarcinoma. NGS was performed in 19 out of 21 patients, The results showed 16 cases with additional genetic aberrations, most commonly associated with TP53 (n = 6), followed by EGFR (n = 3), NF1 (n = 3), KRAS (n = 2) and other mutations. One patient harbored HER2 amplification. Four patients with stage IV received afatinib treatment, and three showed stable disease with a median progression-free survival of 4 months and one patient was diagnosed with progressive disease.ConclusionHER2 mutations represent a distinct subset of NSCLC. NGS showed that HER2 mutations commonly co-existed with other driver genes. Afatinib treatment displayed moderate efficacy in patients with HER2 mutations.
| S-EPMC5363651 | biostudies-literature
Project description:Deep understanding of the genomic and immunological differences between Chinese and Western lung cancer patients is of great importance for target therapy selection and development for Chinese patients. Here we report an extensive molecular and immune profiling study of 245 Chinese patients with non-small cell lung cancer. Tumor-infiltrating lymphocyte estimated using immune cell signatures is found to be significantly higher in adenocarcinoma (ADC, 72.5%) compared with squamous cell carcinoma (SQCC, 54.4%). The correlation of genomic alterations with immune signatures reveals that low immune infiltration was associated with EGFR mutations in ADC samples, PI3K and/or WNT pathway activation in SQCC. While KRAS mutations are found to be significantly associated with T cell infiltration in ADC samples. The SQCC patients with high antigen presentation machinery and cytotoxic T cell signature scores are found to have a prolonged overall survival time.
| S-EPMC6467893 | biostudies-literature
Project description:ObjectiveQujing 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.MethodsIn 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.ResultsA 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.ConclusionsPatients 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.
| S-EPMC8076749 | biostudies-literature
Project description:Lung cancer, of which non-small lung cancer is the most common subtype, represents the leading cause of cancer related-death worldwide. It is now recognized that a significant proportion of these patients present alterations in certain genes that drive oncogenesis. In recent years, more of these so-called oncogenic drivers have been identified, and a better understanding of their biology has allowed the development new targeted agents. This review aims to provide an update about the current landscape of driver mutation in non-small-cell lung cancer. Alterations in Kirsten rat sarcoma, epidermal growth factor receptor, MET, anaplastic lymphoma kinase, c-ROS oncogene 1, v-raf murine sarcoma viral oncogene homolog B, neurotrophic receptor tyrosine kinase, human epidermal growth factor 2, neuregulin-1 and rearranged during transfection are discussed, as well as agents targeting these alterations. Current standards of treatment as well as promising future strategies are presented. Currently, more than fifteen targeted agents are food and Drug administration-approved for seven oncogenic drivers in non-small-cell lung cancer, highlighting the importance of actively searching for these mutations. Continuous and future efforts made in defining the biology of each of these alterations will help to elucidate their respective resistance mechanisms, and to define the best treatment strategy and therapeutic sequence.
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Project description:BackgroundThe aim of this study was to carry out a descriptive analysis of the somatic genetic profile and co-occurring mutations of non-small cell lung cancer (NSCLC) samples from patients tested with comprehensive genomic profiling (CGP).MethodsThis was a retrospective cross-sectional study of patients diagnosed with NSCLC from 2013 to 2018 in Brazil and whose samples were submitted to CGP (FoundationOne or FoundationACT) using either tumor or circulating tumor DNA (ctDNA) from plasma.ResultsWe recovered 513 CGP results from patients, 457 (89.1%) of which were from tumors and 56 (10.9%) from plasma. The median age of patients was 64 years old, of which 51.6% were males. TP53 mutations were identified in 53.6% of tumor samples, KRAS mutations in 24.2%, EGFR activating mutations were detected in 22.5%, STK11 mutations in 11.6%, PIK3CA mutations in 8.8%, ALK rearrangements in 5.4%, BRAF mutations in 5.2%, and ERBB2 alterations in 4.9%. The most commonly comutated gene was TP53. TP53 p.R337H was observed in 4.3% of samples and was associated with somatic mutations in EGFR and ERBB2 (P < 0.00001). Tumor mutational burden (TMB) analysis was available for 80.5% of samples tested, and 5.5% of samples had high TMB (≥ 20 mutations/Mb). In conclusion, this retrospective analysis of genomic data from NSCLC patients obtained by CGP showed that common abnormalities such as EGFR mutations and ALK rearrangements had similar frequency to those previously described by other groups using others strategies. Additionally, our data confirm an association between TP53 p.R337H, supposedly germline in nature, and somatic mutations in genes of the HER family.Key pointsSIGNIFICANT FINDINGS OF THE STUDY: This is the first report of the prevalence of driver mutations in Brazilian NSCLC patients using comprehensive genomic profiling (CGP). The frequency of the most common driver mutations in this population was similar to that previously described in Brazil.What this study addsTP53 was the most commonly comutated gene across samples. TP53 p.R337H was associated with somatic mutations in EGFR and ERBB2. Most samples had low TMB; only 5.5% of samples had high TMB.
| S-EPMC7919136 | biostudies-literature
Project description:The carcinogen urethane induces pulmonary tumors in mice initiated by an incredibly specific Q61L/R oncogenic mutation in the proto-oncogene Kras. Previous Whole-Exome Sequencing of urethane-induced tumors revealed a bias towards A➙T/G and G➙A substitutions. Subsequent ultra-sensitive Maximum-Depth Sequencing of Kras shortly after urethane exposure suggest a further refinement to CA➙CT/G substitutions. As C182AA➙C182T/GA substitutions in Kras result in Q61L/R mutations, the extreme bias of urethane towards these genomic driver mutations can be ascribed to the specificity of the carcinogen for CA➙CT/G substitutions. However, we previously found that changing rare codons to common in the Kras gene to increase protein expression shifted mutations in urethane-induced tumors away from Kras, or when detected in Kras, to G12D mutations that are usually rarely detected in such tumors. Moreover, the loss of p53 partially reversed this effect, generating tumors with either Q61L/R or G12D oncogenic Kras mutations, or no Kras mutations, presumably due to other genomic driver mutations. Determining the origin of these G12D and other unknown non-canonical genomic driver mutations would provide critical insight into the extreme bias of carcinogens for specific genomic driver mutations. We thus compared the types of Single Nucleotide Variations detected by previously performed Maximum-Depth Sequencing immediately after urethane exposure to the mutation signatures derived from Whole Exome Sequencing of urethane-induced tumors. This identified two types of non-canonical mutations. First, a V637E oncogenic mutation in the proto-oncogene Braf that conforms to the mutation signature of urethane, suggesting that the mutational bias of the carcinogen may account for this non-canonical mutation, similar to that for canonical Q61L/R mutations in Kras. Second, G12D and Q61H mutations in Kras that did not fit this mutation signature, and instead shared similarity with Single Nucleotide Variations detected by Maximum-Depth Sequencing from normal cells, suggesting that perhaps these mutations were pre-existing. We thus posit that when canonical Kras mutations are selected against that the carcinogen may instead promote the expansion of pre-existing genomic driver mutations, although admittedly we cannot rule out other mechanisms. Interrogating the mutation signatures of human lung cancers similarly identified KRAS genomic driver mutations that failed to match the mutation signature of the tumor. Thus, we also speculate that the selection for non-canonical genomic driver mutations during urethane carcinogenesis may reflect the process by which discordance between genomic driver mutations and mutational signatures arises in human cancers.
| S-EPMC9049545 | biostudies-literature
Project description:BackgroundTyrosine kinase inhibitors (TKIs) are clinically effective in non-small cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) oncogene mutations. Genetic factors, other than EGFR sensitive mutations, that allow prognosis of TKI treatment remain undefined.MethodsWe retrospectively screened 423 consecutive patients with advanced NSCLC and EGFR 19del or 21L858R mutations. A total of 71 patients whose progression-free survivals (PFS) were shorter than 6 months or longer than 24 months were included and stratified into separate groups. Genetic background discrepancy was analysed in the two groups using next generation sequencing (NGS).FindingsSensitive EGFR mutations of 19del or 21L858R were detected by NGS in all patients; the 21L858R mutation was the major type. The most frequent accompanying somatic mutations were TP53, RB1, MAP2K. ALK fusion, MET amplification, and BRAF V600E were found only in the short PFS group. Concurrent pretreament T790 M mutation was found in both groups, but was proportionally higher in the short PFS group. In the short PFS group, patients had significantly more driver gene mutations than in long PFS group (P = 0·018). The numbers of concomitant somatic mutations, EGFR pathway-related mutations, and tumor mutation burden (TMB) were not significantly different between the two groups.InterpretationCo-occuring driver gene mutations were negative predictive factors of TKI therapy in EGFR-mutated patients. This study highlights the importance of exploring co-occuring genomic alterations before initiation of EGFR-TKIs.
| S-EPMC6491938 | biostudies-literature