Identification and Functional Characterization of EGFR V769M, a Novel Germline Variant Associated With Multiple Lung Adenocarcinomas.
Ontology highlight
ABSTRACT:
SUBMITTER: Hellmann MD
PROVIDER: S-EPMC7446373 | biostudies-literature | 2017
REPOSITORIES: biostudies-literature
Publications
Identification and Functional Characterization of <i>EGFR</i> V769M, a Novel Germline Variant Associated With Multiple Lung Adenocarcinomas.
Hellmann Matthew D MD Hayashi Takuo T Reva Boris B Yu Helena A HA Riely Gregory J GJ Adusumilli Prasad S PS Travis William D WD Wilkins Olivia O Bramletta Nicole N Chandramohan Raghu R Fleischut Megan Harlan MH Kris Mark G MG Robson Mark E ME Arcila Maria E ME Paik Paul K PK Ladanyi Marc M
JCO precision oncology 20170531
Similar Datasets
Project description: Not available
| S-EPMC7446426 | biostudies-literature
Project description:Multiple endocrine neoplasia (MEN) syndromes are characterized by tumors involving two or more endocrine glands. Two MEN syndromes have long been known: MEN1 and MEN2,caused by germline mutations in MEN1 or RET, respectively. Recently, mutations in CDKN1B,encoding the cyclin-dependent kinase (Cdk) inhibitor p27, were identified in patients having a MEN1-like phenotype but no MEN1 gene mutations. Currently, the molecular mechanisms mediating the role of p27 in tumor predisposition are ill defined. We here report a novel germline missense variant in CDKN1B (c.678C>T, p.P69L) found in a patient with multiple endocrine tumors. We previously reported a nonsense p27 mutation (c.692G>A, p.W76X) in two patients with MEN1-like phenotype. Functional assays were used to characterize p27P69L and p27W76X in vitro. We show that p27P69L is expressed at reduced level and is impaired in both binding toCdk2 and inhibiting cell growth. p27W76X, which is mislocalized to the cytoplasm, can no longer efficiently bind Cyclins-Cdks, nor inhibit cell growth or induce apoptosis. In the patient’s tumor tissues, p27P69L associates with reduced/absent p27 expression and in one tumor with loss-of heterozygosity.Our results extend previous findings of CDKN1B mutations in patients with MEN1-related states and support the hypothesis of a tumor suppressor role for p27 in neuroendocrine cells.
| S-EPMC3051264 | biostudies-literature
Project description:We have examined the microRNA expression in 154 lung adenocarcinoma samples and 20 paired normal lung tissue samples and investigated the microRNA expression to clinical variables, EGFR- and KRAS- mutational status and time to progression. 174 samples are analyzed. 154 from lung adenocarcinoma tumor tissue and 20 from paired normal lung tissue samples. No replicates or control samples included.
| S-ECPF-GEOD-48414 | biostudies-other
Project description:BackgroundStudies regarding the outcomes of salvage lung resections of epidermal growth factor receptor (EGFR)-mutant advanced lung adenocarcinomas (ALAs) following treatment with EGFR tyrosine kinase inhibitors (TKIs) are limited, hence the objective of this study was to investigate such outcomes.MethodsA total of 29 patients with EGFR-mutant ALA who underwent salvage surgery after EGFR-TKI treatment from October 2013 through January 2019 were enrolled. The patients were divided into two groups according to the surgical indications. Their perioperative parameters and surgical outcomes, including progression-free survival (PFS) and overall survival (OS), were then analyzed.ResultsThe initial stages of the patients were stage IIIB (seven patients), IVA (17 patients), and IVB (five patients). Their surgical indications included residual tumor (25 patients) and progressive disease (PD) (four patients). They all underwent surgery via minimally invasive approaches and the median follow-up was 33.9 months. Within that follow-up duration, the median PFS after surgery was 36.4 months, and the median OS was still not reached. There were no significant differences in PFS or OS according to the different EGFR-TKIs used, the different durations of EGFR-TKI treatment before surgery, or the different surgical indications. However, the patients presenting with pleural seeding before EGFR-TKI treatment had significantly poorer PFS and OS than the other patients (P < 0.001).ConclusionsSalvage surgery following EGFR-TKI treatment of ALAs is a safe procedure with acceptable intra- and postoperative results. However, studies involving more cases and longer follow-up periods are needed to clarify its benefits.Key pointsSalvage surgery following EGFR-TKI treatment of ALAs is a safe procedure with acceptable intra- and postoperative results. Our results support the use of surgery following treatment with EGFR-TKIs such as afatinib in advanced lung cancer.
| S-EPMC8520796 | biostudies-literature
Project description:The findings of mutations and the development of targeted therapies have improved lung cancer management. Still, the prognosis remains poor, and we need to know more about the genetic and epigenetic alterations in lung cancer. MicroRNAs are involved in crucial biological processes like carcinogenesis by regulating gene expression at the post-transcriptional level. In this project, we have studied the microRNA expression of lung adenocarcinomas and corresponding normal lung tissue and correlated the expression with clinical data and EGFR- and KRAS-mutational status. Agilent microarrays have been used, examining microRNA expression in 154 surgically resected lung adenocarcinomas and 20 corresponding normal lung tissue samples. Findings were confirmed by RT-qPCR in the same cohort and in an independent cohort of 103 lung cancer patients. EGFR and KRAS mutation analyses were also performed. 129 microRNAs were significantly differentially expressed in lung adenocarcinomas compared with normal lung tissue, and 17 microRNAs were differentially expressed between EGFR-mutated and EGFR wildtype tumors. We identified microRNAs associated with time to progression. We have identified several aberrantly expressed microRNAs that discriminate lung adenocarcinomas from normal lung tissue, and hence may be potential biomarkers for early detection. We have found microRNAs that are differentially expressed between EGFR-mutated and EGFR wildtype lung adenocarcinomas, suggesting that microRNAs can be used as molecular biomarkers in classification. We hypothesize that microRNA expression can be used as biomarkers for clinical course.
| S-EPMC4235315 | biostudies-literature
Project description:PurposeThe application of pan-cancer next-generation sequencing panels in the clinical setting has facilitated the identification of low frequency somatic mutations and the testing of new therapies in solid tumors using the "basket trial" scheme. However, little consideration has been given to the relevance of nonsynonymous germline variants, which are likely to be uncovered in tumors and germline and which may be relevant to prognostication and prediction of treatment response.Experimental designWe analyzed matched tumor and normal DNA from 34 melanoma patients using an Ion Torrent cancer-associated gene panel. We elected to study the germline variant Q472H in the kinase insert domain receptor (KDR), which was identified in 35% of melanoma patients in both a pilot and an independent 1,223 patient cohort. Using patient-derived melanoma cell lines and human samples, we assessed proliferation, invasion, VEGF levels, and angiogenesis by analyzing tumor microvessel density (MVD) using anti-CD34 antibody.ResultsSerum VEGF levels and tumor MVD were significantly higher in Q472H versus KDR wild-type (WD) patients. Primary cultures derived from melanomas harboring the KDR variant were more proliferative and invasive than KDR wild type. Finally, using a VEGFR2 antibody, we showed that KDR Q472H cells were sensitive to targeted inhibition of VEGFR2, an effect that was not observed in KDR WT cells.ConclusionsOur data support the integration of germline analysis into personalized treatment decision-making and suggest that patients with germline KDR variant might benefit from antiangiogenesis treatment. Clin Cancer Res; 22(10); 2377-85. ©2015 AACR.
| S-EPMC4867268 | biostudies-literature
Project description:Precision medicine relies on targeting specific somatic alterations present in a patient's tumor. However, the extent to which germline ancestry may influence the somatic burden of disease has received little attention. We estimated the genetic ancestry of non-small-cell lung cancer (NSCLC) patients and performed an in-depth analysis of the influence of genetic ancestry on the evolutionary disease course. Compared with European Americans (EA), African Americans (AA) with lung adenocarcinoma (LUAD) were found to be significantly younger and smoke significantly less. However, LUADs from AAs exhibited a significantly higher somatic mutation burden, with a more pronounced tobacco carcinogen footprint and increased frequencies of alterations affecting cancer genes. Conversely, no significant differences were observed between lung squamous cell carcinomas (LUSC) from EAs and AAs. Our results suggest germline ancestry influences the somatic evolution of LUAD but not LUSC.
| S-EPMC7484830 | biostudies-literature
Project description: Not available
| S-EPMC5119523 | biostudies-literature
Project description:IntroductionEGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Unfortunately, they develop resistance, often due to acquisition of a second-site mutation (T790M). Current EGFR TKIs select for T790M in preclinical models of acquired resistance. We explored whether all EGFR TKIs similarly select for the T790M mutation using data from early clinical trials and established in vitro models of acquired resistance.MethodsWe analyzed the clinical characteristics of eight patients with metastatic EGFR-mutant lung adenocarcinoma who were treated first-line with XL647 and then progressed. XL647 is an ATP-competitive inhibitor of EGFR, HER2, KDR, and EPHB4. Additional molecular preclinical studies were performed to characterize resistance.ResultsFour patients displayed confirmed partial responses (PRs), three patients had unconfirmed PRs, and one patient displayed stable disease. Only one of five patients' tumor samples available for analysis after disease progression harbored the T790M mutation. Eight patients subsequently received erlotinib, with (n = 3) or without (n = 5) chemotherapy. Three of five patients treated with single-agent erlotinib derived additional benefit, staying on drug up to 9 months. EGFR-mutant PC-9 cells with acquired resistance to XL647 did not harbor the T790M mutation, displayed a distinct mRNA profile from PC-9 cells with T790M-mediated resistance, and were moderately sensitive to erlotinib in growth inhibition assays. Crystal structure analyses of XL647/EGFR T790M did not reveal a different binding mode from that of erlotinib.ConclusionsThe findings of this exploratory study suggest that different EGFR TKIs may select for distinct mechanisms of resistance. These results raise the possibility that different EGFR TKIs could be sequentially used to improve outcomes in patients with EGFR-mutant lung cancer. Further work investigating this hypothesis is warranted.
| S-EPMC3261336 | biostudies-literature
Project description:BackgroundThe detection rate of synchronous multiple lung adenocarcinomas (SMLA), which display multiple ground glass opacity nodules in the peripheral lung, is increasing due to advances in high resolution computed tomography. The backgrounds of multicentric development of adenocarcinoma are unknown. In this study, we quantitated estrogen concentration in the peripheral lungs of postmenopausal female patients with SMLA.MethodsThe tissue concentration of estrogens (estrone [E1] and estdadiol [E2]) in the noncancerous peripheral lung were measured with liquid chromatography/electrospray tandem mass spectrometry in postmenopausal female patients with lung adenocarcinoma. The expression levels of CYP19A1 in the normal lung were also quantitated with real-time PCR. Thirty patients with SMLA and 79 cases of control patients with single lung adenocarcinoma were analyzed.ResultsThe concentrations of E1 and E2 in the noncancerous tissue were significantly higher in SMLA cases than control cases (P = 0.004 and P = 0.02, respectively). The minor allele (A) of single nucleotide polymorphism rs3764221 were significantly associated with higher concentration of E1 and E2 (P = 0.002 and P = 0.01, respectively) and higher CYP19A1 mRNA expression (P = 0.03).ConclusionThe tissue estrogen concentration of peripheral lung was significantly higher in SMLA than control cases. The high concentration of estrogen may be one of the causes of multicentric development of peripheral lung adenocarcinomas.
| S-EPMC4985140 | biostudies-literature