Intratumor heterogeneity of epidermal growth factor receptor mutations in lung cancer and its correlation to the response to gefitinib

Taniguchi, Koki; Okami, Jiro; Kodama, Ken; Higashiyama, Masahiko; Kato, Kikuya

doi:10.1111/j.1349-7006.2008.00782.x

Cited by 225 publications

(180 citation statements)

References 30 publications

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“…An approach based on epigenetic drugs only will fail because of the expected insensitivity of cells harboring CDH1 somatic mutations or LOH. This hypothesis of insensitivity to a specific drug by a subpopulation of tumor cells, although in a different context, is elegantly illustrated by the results obtained by Taniguchi et al, 31 who described that patients with non-small-cell lung cancer constituted by 2 subpopulations of tumors cells displaying different molecular features (mutated and nonmutated for epidermal growth factor receptor [EGFR]) did not respond well to gefitinib. Moreover, the overall survival of these nonsmall-cell lung cancer patients after gefitinib treatment was significantly reduced compared with patients with EGFR-mutant tumor cells only, demonstrating the lack of benefit after this intervention.…”

Section: Discussionmentioning

confidence: 99%

Quantification of Epigenetic and Genetic 2nd Hits in CDH1 During Hereditary Diffuse Gastric Cancer Syndrome Progression

et al. 2009

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Background & Aims:Hereditary diffuse gastric cancer (HDGC) families carry CDH1 heterozygous germline mutations; their tumors acquire complete CDH1 inactivation through "2nd-hit" mechanisms. Most frequently, this occurs via promoter hypermethylation (epigenetic modification), and less frequently via CDH1 mutations and loss of heterozygosity (LOH). We quantified the different 2nd hits in CDH1 occurring in neoplastic lesions from HDGC patients. Methods: Samples were collected from 16 primary tumors and 12 metastases from 17 patients among 15 HDGC families; CDH1 mutations, LOH, and promoter hypermethylation were analyzed. E-cadherin protein expression and localization were determined by immunohistochemistry. Results: Somatic CDH1 epigenetic and genetic alterations were detected in lesions from 80% of HDGC families and in 75% of all lesions analyzed (21/28). Of the 28 neoplastic lesions analyzed, promoter hypermethylation was found in 32.1%, LOH in 25%, both alterations in 17.9%, and no alterations in 25%. Half of the CDH1 2nd hits in primary tumors were epigenetic modifications, whereas a significantly greater percentage of 2nd hits in metastases were LOH (58.3%; P ‫؍‬ .0274). Different neoplastic lesions from the same patient frequently displayed distinct 2nd-hit mechanisms. Different 2nd-hit mechanisms were also detected in the same tumor sample. Conclusion: The 2nd hit in CDH1 frequently occurs via epigenetic changes in HDGC primary tumors and LOH in metastases. Because of the concomitance and heterogeneity of these alterations in neoplastic lesions and the plasticity of hypermethylated promoters during tumor initiation and progression, drugs targeting only epigenetic alterations might not be effective, particularly in patients with metastatic HDGC.

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Section: Discussionmentioning

confidence: 99%

Quantification of Epigenetic and Genetic 2nd Hits in CDH1 During Hereditary Diffuse Gastric Cancer Syndrome Progression

et al. 2009

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“…As a consequence, the ongoing acquisition of these alterations can result in the emergence of neoplastic subclones with varying genotypes and, consequently, phenotypes,32 leading to discordance between the primary tumor and its metastases. In people, several tumors including melanoma,33 gastrointestinal stromal tumor,34 and lung cancer35 show intratumor and intertumor heterogeneity, indicating the presence of more than one clone of cancer cells within a given neoplastic mass, and the presence of different genetic alterations in different metastatic sites from a single patient, respectively. Therefore, determining if there is homogeneous mutational status between primary tumor and its metastatic sites has important clinical implications, overall to select the appropriate treatment.…”

Section: Discussionmentioning

confidence: 99%

Concordance of c‐kit Mutational Status in Matched Primary and Metastatic Cutaneous Canine Mast Cell Tumors at Baseline

Marconato

Zorzan

Giantin

et al. 2013

Veterinary Internal Medicne

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BackgroundMutation analysis of proto‐oncogene c‐kit (c‐kit) is advisable before starting treatment with tyrosine kinase inhibitors in dogs with mast cell tumor (MCT), including those with metastatic disease. Testing is usually performed on primary tumors, assuming that c‐kit mutation status does not change in metastasis.Hypothesis/ObjectivesTo give an insight into the mutational processes and to make a recommendation on the use of c‐kit mutational analysis in the clinical setting.AnimalsTwenty‐one client‐owned dogs with metastatic MCT.MethodsDogs undergoing resection or biopsy for both primary and matched metastatic MCT were prospectively enrolled. Total RNA or DNA was extracted from primary MCT and corresponding metastases. Exons 8, 9, and 11 were amplified by PCR and sequenced. Genetic features between primary MCT and metastases were compared. Their correlation with clinicopathologic features was investigated.ResultsConcordance (mutated or wild‐type) of mutational status, evaluable in 21 primary and matched metastatic (20 nodal and 1 splenic) MCTs, was 100%. Three new c‐kit mutations were identified. No significant correlation was detected between c‐kit mutation and clinicopathologic features.Conclusions and Clinical ImportanceProto‐oncogene c‐kit mutational status is conserved between any primary and its matched secondary tumor, suggesting that both can be used for c‐kit mutational testing. Targeted therapies might be also used to treat metastatic disease.

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“…Taniguchi et al showed that intra-tumor heterogeneity existed in proximity to the same pathological patterns. 26 Since EGFR mutations were analyzed according to the pathological patterns in this study, the mutation-positive and -negative BAC (lepidic) patterns could also be examined at the same time. All patients analyzed in this trial had early stage lung adenocarcinoma, and it is possible that the EGFR Recently, it has been reported that intra-tumor heterogeneity of EGFR mutation status is extremely rare.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Intratumor Heterogeneity of EGFR Mutations in Mixed Type Lung Adenocarcinoma

Tomonaga

Nakamura

Yamaguchi

et al. 2013

Clinical Lung Cancer

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2 Micro abstractIntra-tumor heterogeneity of epidermal growth factor receptor (EGFR) mutations in patients with mixed-type lung adenocarcinoma was analyzed according to histological patterns. Intra-tumor heterogeneity of EGFR mutations was detected in 9 of 38 tumors, and there was a significant correlation between heterogeneity of EGFR mutations and smoking history (P<0.043). Clinical Practice Points• EGFR mutations are factors predictive of response to EGFR-TKI treatment. However, lung cancer is thought to be the result of the accumulation of genetic alterations over a long course of exposure to a carcinogen, and the existence of intra-tumor heterogeneity of EGFR mutations remains unclear. Thus, the existence of intra-tumor heterogeneity was analyzed in patients with mixed-type lung adenocarcinoma according to histological patterns.• Intra-tumor heterogeneity of EGFR mutations was detected in 9 of 38 tumors, and a significant correlation between heterogeneity of EGFR 3 mutations and smoking history was found.• Response to EGFR-TKIs might be partial and insufficient in tumors having intra-tumor heterogeneity of EGFR mutations. New treatment strategies for patients with lung adenocarcinoma harboring heterogeneous EGFR mutations are needed.

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Intratumor heterogeneity of epidermal growth factor receptor mutations in lung cancer and its correlation to the response to gefitinib

Cited by 225 publications

References 30 publications

Quantification of Epigenetic and Genetic 2nd Hits in CDH1 During Hereditary Diffuse Gastric Cancer Syndrome Progression

Quantification of Epigenetic and Genetic 2nd Hits in CDH1 During Hereditary Diffuse Gastric Cancer Syndrome Progression

Concordance of c‐kit Mutational Status in Matched Primary and Metastatic Cutaneous Canine Mast Cell Tumors at Baseline

Analysis of Intratumor Heterogeneity of EGFR Mutations in Mixed Type Lung Adenocarcinoma

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