Familial Lung Adenocarcinoma Caused by the <i>EGFR</i> V843I Germ-Line Mutation

Ohtsuka, Kouki; Ohnìshì, H.; Kurai, Daisuke; Matsushima, Satsuki; Morishita, Yukio; Shinonaga, Mayumi; Goto, Hajime; Watanabe, Takashi

doi:10.1200/jco.2010.31.4492

Cited by 59 publications

(48 citation statements)

References 8 publications

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“…To understand this situation, two issues should be discussed: i) the relationship between drug-sensitive EGFR mutations and the T790M mutation, and ii) the presence of the T790M mutation as a minor population. Regarding the first issue, while the reason for this association is unknown, lung cancers with germ-line EGFR mutations such as T790M (31), V843I (34), and R776H (35) are accompanied by additional EGFR mutations in the development of lung cancer, suggesting that EGFR mutations themselves cause genetic instability, thereby predisposing cells to additional mutations within the gene (34). The second issue can be explained by the following hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Presence of the minor EGFR T790M mutation is associated with drug-sensitive EGFR mutations in lung adenocarcinoma patients

et al. 2014

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Abstract. The T790M mutation in the epidermal growth factor receptor (EGFR) gene is known to be associated with the acquired resistance of lung adenocarcinoma patients to EGFRtyrosine kinase inhibitors (EGFR-TKIs). The minor T790M mutant allele is occasionally detected in EGFR-TKI-naive tumor samples, yet findings concerning the clinical impact of the minor T790M mutation vary among previous studies. In the present study, we assessed the clinical impact of the minor T790M mutation using a novel, highly sensitive assay combining high-resolution melting (HRM), mutant-enriched PCR and co-amplification at a lower denaturation temperature (COLD)-PCR. We determined the T790M mutational status in 146 surgically resected lung adenocarcinomas without a history of EGFR-TKI treatment using mutant-enriched COLD-HRM (MEC-HRM) and standard HRM assays. The sensitivities of the MEC-HRM and standard HRM assays for the detection of T790M-mutant alleles among wild-type alleles were 0.01 and 10%, respectively. Although the T790M mutation was not detected using a standard HRM assay, we identified 19 (13%) T790M mutations using the MEC-HRM assay and defined these 19 mutations as minor T790M mutations. The proportion of T790M alleles was <0.1% in 17 (84%) of the 19 samples. Multivariate analyses revealed that a minor T790M mutation was significantly associated with the presence of EGFR exon 19 deletions or the L858R mutation (both of which are drug-sensitive EGFR mutations) (P=0.04). In conclusion, the minor EGFR T790M mutations were present in 13% of EGFR-TKI-naive surgically resected lung adenocarcinomas and were associated with drug-sensitive EGFR mutations.

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Section: Discussionmentioning

confidence: 99%

Presence of the minor EGFR T790M mutation is associated with drug-sensitive EGFR mutations in lung adenocarcinoma patients

et al. 2014

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“…Previous studies reported the germline mutations of EGFR and HER2 as driver mutations in familial lung cancer patients (13)(14)(15). In the present study, whole exome sequencing identified 8 SNVs in the EGFR gene.…”

Section: Discussionmentioning

confidence: 51%

“…In another study, 3/6 individuals in a Japanese family developed lung adenocarcinoma. The germline EGFR V843I mutation was identified in all the lung adenocarcinoma-affected members of this family (14). In a study by Yamamoto et al, it was found that mutations in HER2 may be the causative variants of familial lung adenocarcinomas (15).…”

Section: Introductionmentioning

confidence: 99%

Sequencing study on familial lung squamous cancer

Wang

et al. 2015

Oncology Letters

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Abstract. Lung cancer is the leading cause of cancer-related mortality worldwide. The majority of lung cancers are sporadic, and familial cases are extremely rare. Previous studies have mainly focused on sporadic lung cancer and identified a large quantity of driver genes. However, familial lung cancers are rarer and studied less. The present study recruited a Chinese family in which multiple members had developed lung squamous carcinoma. To find the causative mutations, whole exome sequencing was conducted using a peripheral blood sample of one lung squamous carcinoma patient, and certain variants were validated in more samples. Whole exome sequencing analysis obtained ~2.0 Gb of data (an average of 60x depth for each targeted base), and further validation experiments identified two functional variants in two cancer-related genes (c.1218delA:p.E406fs in PDE4DIP and C1342A:p.L448I in CLTCL1). This study therefore provides useful sources for the further study of hereditary lung cancer.

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“…Ohtsuka et al [14] detected a germline mutation in EGFR resulting in a valine to isoleucine substitution, V843I, in a family with multiple cases of adenocarcinoma G. H. Clamon et al of the lung. The proband was a 48 year old woman who presented with widely disseminated adenocarcinoma of the lung.…”

Section: Methodsmentioning

confidence: 98%

Germline mutations predisposing to non-small cell lung cancer

et al. 2015

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Lung cancer in multiple first degree relatives had previously been attributed to smoking and to inherited enzymes associated with increased activation of carcinogens in smoke. There was not clear agreement on the significance of the testing methods for lung cancer susceptibility. More recent studies have identified germline mutations associated with lung cancer even in the absence of smoking and other mutations with plausible explanations for their association with lung cancer caused by smoking. At this time, the clinical significance of the various germline mutations for screening and the implications for therapy are not certain. This review summarizes the currently identified germline mutations associated with lung cancer, but this growing area of research will very likely identify further significant mutations as well.

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Familial Lung Adenocarcinoma Caused by the EGFR V843I Germ-Line Mutation

Cited by 59 publications

References 8 publications

Presence of the minor EGFR T790M mutation is associated with drug-sensitive EGFR mutations in lung adenocarcinoma patients

Presence of the minor EGFR T790M mutation is associated with drug-sensitive EGFR mutations in lung adenocarcinoma patients

Sequencing study on familial lung squamous cancer

Germline mutations predisposing to non-small cell lung cancer

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