Ann Thorac Surg 2008;85:1430-1432. doi:10.1016/j.athoracsur.2007.10.012
© 2008 The Society of Thoracic Surgeons
Case Reports
Novel Germline Mutation: EGFR V843I in Patient With Multiple Lung Adenocarcinomas and Family Members With Lung Cancer
Koei Ikeda, MD, PhDa,
Hiroaki Nomori, MD, PhDa,*,
Takeshi Mori, MD, PhDa,
Jiichiro Sasaki, MD, PhDb,
Toshiaki Kobayashi, MD, PhDc
a Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
b Department of Respiratory Medicine, Kumamoto University Hospital, Kumamoto, Japan
c Department of Assistive Diagnostic Technology, National Cancer Center Hospital, Tokyo, Japan
Accepted for publication October 2, 2007.
* Address correspondence to Dr Nomori, Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan (Email: hnomori{at}qk9.so-net.ne.jp).
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Abstract
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A novel germline transmission of the epidermal growth factor receptor (EGFR) mutation V843I in a family with multiple members with lung cancer is reported. The proband was a 70-year-old woman with multiple adenocarcinomas who exhibited secondary EGFR mutations, either L858R or L861Q, in the specimens of resected tumors, in addition to a germline EGFR V843I mutation. These observations suggest that the germline EGFR V843I mutation might have altered EGFR signaling in the multicentric development of adenocarcinoma, bronchoalveolar carcinoma, and atypical adenomatous hyperplasia and also might have had a role in the development of lung cancer in multiple members of her family.
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Introduction
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Recent advances in high-resolution computed tomography (CT) have increased the detection of multicentric adenocarcinoma (AD) [1]. However, the cause of multicentric development of lung AD is unknown. Recently a germline epidermal growth factor receptor (EGFR) mutation, T790M, found to be a drug-resistant mutation of EGFR tyrosine kinase inhibitors, was reported in one family that included several patients with lung cancer [2]. We report a novel germline mutation, EGFR V843I, in a woman with multiple lung ADs and family members with lung cancer.
The patient was a 70-year-old woman. Her father and a brother (I-1 and II-1, respectively; Fig 1) had died of lung cancer. Her brother also had stomach and prostate gland cancer. In the case patient, multiple pulmonary nodules were demonstrated on CT scans obtained during a routine medical examination (Fig 2). A CT-guided needle biopsy of the bilateral nodules revealed AD. Right upper and middle lobectomies were performed, followed by wedge resection of the left pulmonary nodules 2 months later. Pathologic examination revealed 3 ADs (Figs 2A–C), 4 bronchioloalveolar carcinomas (BACs) (Fig 2D), and 3 lesions of atypical adenomatous hyperplasia (AAH) (Fig 2E). The AD had metastasized to the lymph nodes of the right upper lobe. We classified AD in the posterior segment of the right upper lobe (Fig 2B) as T1N1M0, stage IIA, because the nodule was the largest and the pathologic findings showed intratumoral lymphatic invasion. The other resected tumors were classified as T1N0M0, stage IA. The patient refused adjuvant chemotherapy. She has been alive without recurrence for 8 months after surgery.
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Fig 1. Pedigree of family of case patient (II-4). Boxes and circles indicate males and females, respectively; numbers at left above indicate age at death or time of mutation analysis; and oblique line shows deceased family members.
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Fig 2. Findings at computed tomography. (A) Adenocarcinoma (arrow) in apical segment of right upper lobe. (B) Adenocarcinoma (arrow) in posterior segment of right upper lobe. (C) Adenocarcinoma (arrow) in left upper lobe. (D) Bronchioloalveolar carcinoma (arrow) in right middle lobe. (E) Atypical adenomatous hyperplasia (arrow) in left upper lobe.
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DNA extraction and direct sequencing were performed by SRL Laboratory Inc, Tokyo, Japan. DNA was extracted from formalin-fixed, paraffin-embedded specimens of three resected ADs (Figs 2A-C), one BAC (Fig 2D), and one AAH (Fig 2E). The tumor cells were microscopically dissected from their 5-µm sections for DNA extraction. Direct sequencing from EGFR exon 18, exon19, exon 20, and exon 21 was performed. In addition, mutation analyses were performed on resected adjacent healthy lung tissue and peripheral blood mononuclear cells. After obtaining written informed consent from family members, germline mutations in the peripheral blood mononuclear cells were analyzed in her two brothers (II-2 and II-5; Fig 1) and one sister (II-3; Fig 1), none of whom had lung cancer.
Specimens from all five tumors examined, healthy lung tissue, and peripheral blood mononuclear cells from the patient exhibited the EGFR V843I mutation (Figs 3a, c, and e) in exon 21 of the EGFR gene. In addition, EGFR L861Q (Fig 3b) was detected in ADs in the apical segment of the right upper lobe (Fig 2A) and in the left upper lobe (Fig 2C), and EGFR L858R (Fig 3d) in AD in the posterior segment of the right upper lobe (Fig 2B), BAC in the lateral segment of the right middle lobe (Fig 2D), and AAH in the apical anterior segment of the left upper lobe (Fig 2E) (Table 1). These mutations were not detected in the healthy lung tissue and peripheral blood mononuclear cells. Of her three affected family members, two (II-3 and II-5; Fig 1) had the germline V843I mutation and one (II-2; Fig 1) did not. All mutations were harbored in exon 21 of the EGFR gene, and there were no mutations of exon 18, 19, or 20 in any specimens examined.
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Fig 3. Nucleotide sequence tracings. Tracings (a), (c) and (e) show G to A mutation, which represents germline V843I mutation in EGFR gene. Tracing (b) shows A to T mutation, which represents L861Q mutation in tumor (reverse sequence). Tracing (d) shows T to G mutation, which represents L858R mutation in tumor (reverse sequence).
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Comment
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Frequent detection of the EGFR mutation in lung ADs with BAC features has been reported [3]. Recently, the possibility of an important role of the EGFR mutation in the carcinogenesis of lung AD has also been suggested. Tang and colleagues [4] showed that the EGFR mutation is frequently present in the normal epithelium of patients with EGFR mutant lung AD and suggested that the EGFR mutation might be a very early event in the pathogenesis of lung AD. Ji and colleagues [5] demonstrated a close relationship between the EGFR mutation and carcinogenesis of lung AD in experiments in transgenic mice.
The EGFR V843I mutation has been reported in a patient with lung AD who exhibited a partial response to therapy with gefitinib (Iressa; AstraZeneca Pharmaceuticals LP, Willmington, Delaware) [6] and in a patient with bile duct AD [7]. Our case patient had a germline EGFR V843I mutation and additional mutations L861Q and L858R in all five tumor specimens examined. Knudson [8] proposed the two-hit theory of tumor development, that is, that tumors can develop from healthy tissue with congenital first mutations following acquisition of second mutations. We speculate that multifocal development of AD, BAC, and AAH in the case patient might have occurred as a result of second-hit mutations L861Q and L858R in the setting of a germline V843I mutation.
However, the effects of the EGFR V843I mutation on EGFR signaling and the molecular importance of the double mutation on EGFR exon 21 are unknown. The patient’s father and a brother had died of lung cancer. However, another brother and a sister, each of whom had germline EGFR V843I mutation, have not developed lung cancer despite being almost 70 years old. The role of germline EGFR V843I mutation in multifocal lung carcinogenesis and the familial occurrence of lung cancer in the case patient are still unclear. In vitro experiments are needed to clarify the effects of EGFR V843I mutation on EGFR signaling, as is accumulation of clinical cases to determine the role of germline EGFR mutation in lung carcinogenesis.
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References
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- Bell DW, Gore I, Okimoto RA, et al. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR Nat Genet 2005;37:1315-1316.[Medline]
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- Tang X, Shigematsu H, Bekele N, et al. EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients Cancer Res 2005;65:7568-7572.[Abstract/Free Full Text]
- Ji H, Li D, Chen L, et al. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies Cancer Cells 2006;9:485-495.
- Shih J-Y, Gow C-H, Yu C-J, et al. Epidermal growth factor receptor mutation in needle biopsy/aspiration samples predicts response to gefitinib therapy and survival of patients with advanced non–small cell lung cancer Int J Cancer 2006;118:963-969.[Medline]
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- Knudson Jr AG. Overview: genes that predispose to cancer Mutat Res 1991;247:185-190.[Medline]
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Abstract
Introduction
