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EGFR exon 19 insertions: a new family of sensitizing EGFR mutations in lung adenocarcinoma.

ABSTRACT: PURPOSE:Epidermal growth factor receptor (EGFR) genotyping is now standard in the management of advanced lung adenocarcinoma, as this biomarker predicts marked benefit from treatment with EGFR tyrosine kinase inhibitors (TKI). EGFR exon 19 insertions are a poorly described family of EGFR mutations, and their association with EGFR-TKI sensitivity in lung adenocarcinoma is uncertain. EXPERIMENTAL DESIGN:Patients with lung cancers harboring EGFR exon 19 insertions were studied. The predicted effects of the insertions on the structure of the EGFR protein were examined, and EGFR exon 19 insertions were introduced into Ba/F3 cells to assess oncogenicity and in vitro sensitivity to EGFR-TKIs. In patients receiving TKI, response magnitude was assessed with serial computed tomographic (CT) measurement. RESULTS:Twelve tumors harboring EGFR exon 19 insertions were identified; patients were predominately female (92%) and never-smokers (75%). The 11 specimens available for full sequencing all showed an 18-bp insertion that resulted in the substitution of a Pro for Leu at residue 747. The mutant EGFR transformed the Ba/F3 cells, which were then sensitive to EGFR-TKI. Six patients with measurable disease received TKI and five had a response on serial CT. CONCLUSIONS:EGFR exon 19 insertions are a newly appreciated family of EGFR-TKI-sensitizing mutations, and patients with tumors harboring these mutations should be treated with EGFR-TKI. While these mutations may be missed through the use of some mutation-specific assays, the addition of PCR product size analysis to multigene assays allows sensitive detection of both exon 19 insertion and deletion mutations.

SUBMITTER: He M

PROVIDER: S-EPMC3306520 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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EGFR exon 19 insertions: a new family of sensitizing EGFR mutations in lung adenocarcinoma.

He Mai M Capelletti Marzia M Nafa Khedoudja K Yun Cai-Hong CH Arcila Maria E ME Miller Vincent A VA Ginsberg Michelle S MS Zhao Binsheng B Kris Mark G MG Eck Michael J MJ Jänne Pasi A PA Ladanyi Marc M Oxnard Geoffrey R GR

Clinical cancer research : an official journal of the American Association for Cancer Research 20111221 6

<h4>Purpose</h4>Epidermal growth factor receptor (EGFR) genotyping is now standard in the management of advanced lung adenocarcinoma, as this biomarker predicts marked benefit from treatment with EGFR tyrosine kinase inhibitors (TKI). EGFR exon 19 insertions are a poorly described family of EGFR mutations, and their association with EGFR-TKI sensitivity in lung adenocarcinoma is uncertain.<h4>Experimental design</h4>Patients with lung cancers harboring EGFR exon 19 insertions were studied. The p ...[more]

PMID: 22190593

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Project description:The findings of EGFR mutations and the development of targeted therapies have significantly improved the overall survival of lung cancer patients. Still, the prognosis remains poor, so we need to know more about the genetic alterations in lung cancer. MicroRNAs are dysregulated in lung cancer, and some of them can regulate EGFR. So it is very important to predict the candidate microRNAs that target mutated EGFR and to investigate the role of these candidate microRNAs in lung cancer. In this study, we investigated the difference of microRNAs expression between lung adenocarcinoma cell lines with EGFR exon 19 deletion (H1650 and PC9) and wild-type (H1299 and A549) using the Phalanx Human Whole Genome Microarray. Then the expression of individual microRNAs was validated by qRT-PCR assays. Moreover, we detected the microRNAs expression in plasma of lung adenocarcinoma patients with EGFR exon 19 deletion and wild-type. Lastly, we explored the function of the positive microRNA in EGFR tyrosine kinase inhibitors (EGFR-TKIs ) resistance using MTT and Annexin V-APC assays. The expression of 1,732 microRNAs was evaluated, and we found that microRNAs expression was different between these two groups. Hsa-miR-141-3p, hsa-miR-200c-3p, hsa-miR-203, hsa-miR-3182, hsa-miR-934 were up-regulated and hsa-miR-3196 was down-regulated in the EGFR exon 19 deletion group compared with wild-type group. The detection of circulating microRNAs showed that miR-3196 was down-regulated in lung adenocarcinoma patients with EGFR exon 19 deletion compared with wild-type. And then the MTT assay results showed that miR-3196 had no effect on the sensitivity of erlotinib. The results of apoptosis analysis showed that inhibition of miR-3196 and erlotinib induced more apoptosis in H1299 cells than erlotinib alone, and overexpressed miR-3196 and erlotinib induced less apoptosis in PC9 cells than erlotinib alone (P<0.05). It is suggested that microRNAs associate with EGFR exon 19 deletion and miR-3196 may be further explored as a potential predictor and targeted biomarker when it is difficult to get the tumors.

Project description:BackgroundEpidermal growth factor receptor exon 20 insertions (EGFR ex20ins) occur in about 4-14% of lung adenocarcinoma (LUAD) patients with EGFR mutations. Recently some targeted drugs have been approved for the treatment of LUAD patients with EGFR ex20ins. However, the heterogeneity of EGFR ex20ins mutations and resultant challenges in identifying them have led to the underestimation of their frequency.MethodsWe investigated the molecular and clinicopathologic features of EGFR ex20ins in 3,892 Chinese LUAD patients using next-generation sequencing (NGS). The frequency and distribution of EGFR ex20ins mutations between Chinese and Western LUAD patients were also compared by integrating the data of this study and the data of previous studies.ResultsA total of 23 unique EGFR ex20ins were identified in 77 LUAD patients, accounting for 1.98% of all LUAD patients and 3.49% of EGFR mutant LUDA patients. The 2 most common EGFR ex20ins subtypes were S768_D770dup and A767_V769dup, which together accounted for 55.84% of the EGFR ex20ins cases. About 61% (14/23) of the EGFR ex20ins subtypes occurred only once. Additionally, 8 of the EGFR ex20ins subtypes were not recorded in the COSMIC database. These results showed that the EGFR ex20ins mutations were highly heterogeneous. There was no significant difference in the frequency and distribution of EGFR ex20ins mutations between Chinese and Western LUAD patients, but the frequency of EGFR ex20ins mutations was significantly lower in EGFR-mutant Chinese LUAD patients than Western LUAD patients. The co-mutation analysis showed that EGFR ex20ins occurred significantly and exclusively with certain driver genes in LUAD, including ALK fusion (χ2=7.133, P=0.008), KRAS (χ2=8.468, P=0.004), and PIK3CA (χ2=5.792, P=0.016). No gene was observed to be significantly co-mutated with EGFR ex20ins. In general, patients with EGFR ex20ins shared a similar age and gender to patients with other EGFR mutations or without EGFR ex20ins.ConclusionsOverall, our results revealed the molecular and clinicopathologic features of EGFR ex20ins in Chinese LUAD patients, which will be helpful for drug development and in clinical trials targeting EGFR ex20ins.

Dataset Information

EGFR exon 19 insertions: a new family of sensitizing EGFR mutations in lung adenocarcinoma.

Publications

EGFR exon 19 insertions: a new family of sensitizing EGFR mutations in lung adenocarcinoma.

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