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[Cancer Research 65, 1642-1646, March 1, 2005]
© 2005 American Association for Cancer Research

Priority Reports

Somatic Mutations of the HER2 Kinase Domain in Lung Adenocarcinomas

Hisayuki Shigematsu1,9, Takao Takahashi1, Masaharu Nomura1, Kuntal Majmudar1, Makoto Suzuki5, Huei Lee6, Ignacio I. Wistuba7, Kwun M. Fong8, Shinichi Toyooka9, Nobuyoshi Shimizu9, Takehiko Fujisawa5, John D. Minna1,2,3 and Adi F. Gazdar1,4

1 Hamon Center for Therapeutic Oncology Research, Departments of 2 Internal Medicine, 3 Pharmacology, and 4 Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; 5 Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan; 6 Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan; 7 Department of Pathology and Thoracic/Head and Neck Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas; 8 Prince Charles Hospital, Brisbane, Australia; and 9 Department of Cancer and Thoracic Surgery, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan

Requests for reprints: Adi F. Gazdar, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas TX, 75390-8593. Phone: 214-648-4921; Fax: 214-648-4940; E-mail: adi.gazdar{at}utsouthwestern.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Mutations in the epidermal growth factor receptor gene (EGFR) in lung cancers predict for sensitivity to EGFR kinase inhibitors. HER2 (also known as NEU, EGFR2, or ERBB2) is a member of the EGFR family of receptor tyrosine kinases and plays important roles in the pathogenesis of certain human cancers, and mutations have recently been reported in lung cancers. We sequenced the tyrosine kinase domain of HER2 in 671 primary non–small cell lung cancers (NSCLC), 80 NSCLC cell lines, and 55 SCLCs and other neuroendocrine lung tumors as well as 85 other epithelial cancers (breast, bladder, prostate, and colorectal cancers) and compared the mutational status with clinicopathologic features and the presence of EGFR or KRAS mutations. HER2 mutations were present in 1.6% (11 of 671) of NSCLC and were absent in other types of cancers. Only one adenocarcinoma cell line (NCI-H1781) had a mutation. All HER2 mutations were in-frame insertions in exon 20 and target the identical corresponding region as did EGFR insertions. HER2 mutations were significantly more frequent in never smokers (3.2%, 8 of 248; P = 0.02) and adenocarcinoma histology (2.8%, 11 of 394; P = 0.003). In 394 adenocarcinoma cases, HER2 mutations preferentially targeted Oriental ethnicity (3.9%) compared with other ethnicities (0.7%), female gender (3.6%) compared with male gender (1.9%) and never smokers (4.1%) compared with smokers (1.4%). Mutations in EGFR, HER2, and KRAS genes were never present together in individual tumors and cell lines. The remarkable similarities of mutations in EGFR and HER2 genes involving tumor type and subtype, mutation type, gene location, and specific patient subpopulations targeted are unprecedented and suggest similar etiologic factors. EGFR, HER2, and KRAS mutations are mutually exclusive, suggesting different pathways to lung cancer in smokers and never smokers.

Key Words: HER2 • EGFR • KRAS • mutation • lung cancer


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Activating mutations of protein kinases contribute to the development of human cancers (1) and have led to the development of kinase inhibitors that target these oncogenic forms (2). The inhibitors include imatinib mesylate (Gleevec, STI571), a small molecule inhibitor of the Abl and KIT tyrosine kinases (TK) for patients with chronic myelogenous leukemia or gastrointestinal stromal tumors (3, 4), and gefitinib (Iressa, ZD1839) and erlotinib (Tarceva, OSI-774) inhibitors of epidermal growth factor receptor (EGFR) which are used for the treatment of non–small cell lung cancer (NSCLC). Recent reports of mutations in the TK domain of EGFR have generated considerable interest because they predict for sensitivity to gefitinib or erlotinib (5–7). The promising results of these TK inhibitors invoke the concept of "oncogene addiction," which hypothesizes that cancer cells are both transformed and physiologically dependent on activated oncogenes for their survival (8, 9). Thus, oncogenic activation of protein kinases including EGFR family members should be targets for cancer therapies.

HER2 (also known as NEU, EGFR2, or ERBB2) is one of the members of the EGFR family, which includes EGFR (or ERBB1), EGFR3 (or HER3/ERBB3) and EGFR4 (or HER4/ERBB4). Although the genes contain extracellular, transmembrane and intarcellular domains, the regions of greatest homology are the kinase domains contained within an intracellular domain. However, the genes have distinct properties: HER2 has strong kinase activity but has no identified ligand and ERBB3 lacks kinase activity due to substitutions in critical TK domain residues (10). All are capable of forming homodimers (with the possible exception of ERBB3) and heterodimers. EGFR and HER2 are dysregulated in many human cancers and play important roles in cancer development and progression (11). Overexpression of HER2 with amplification is found in a subset of breast and ovarian cancers and correlates with poor prognosis (12, 13). In lung cancers, overexpression of HER2 has been reported in about 20% (14–17) whereas gene amplification occurs less frequently than in breast cancers. Trastuzumab (Herceptin), a humanized monoclonal antibody that binds the extracellular domain of HER2, is effective for HER2 overexpressing breast cancer patients when used with other cytotoxic agents (18). By contrast, clinical trials using Trastuzumab in NSCLC patients have reported modest or disappointing clinical benefits (19–21). Recently, mutations of HER2 were reported in lung adenocarcinomas and offer the potential of additional therapy targeted at the altered protein (22). In this report, we searched for mutations of HER2 in a large number of primary lung tumors from four countries (Japan, Taiwan, the United States, and Australia). Because mutations in the EGRF gene target adenocarcinoma histology, female gender, never smoking status, and Oriental ethnicity (6, 7, 23), we determined whether there was a relationship between HER2 mutations and some or all of these factors. In addition, we correlated the mutation status of HER2, EGFR, and KRAS genes.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Tumor Samples. A total of 671 primary NSCLCs were obtained from patients undergoing curative intent surgical resections from four countries (Table 1). All cases from Japan and Taiwan were of Oriental ethnicity. United States. cases comprised 137 Caucasian, 8 Hispanic, 6 African American, and 4 Oriental (ethnicity was not available for two cases). Australian cases were all Caucasian except for one Oriental. A total of 36 neuroendocrine lung tumors including bronchial carcinoids (n = 25) and large cell neuroendocrine carcinomas (n = 5) from the United States and SCLC (n = 6) from Japan were also studied. Eighty-five carcinomas arising at other sites (breast, n = 28; bladder, n = 15; prostate, n = 14; and colorectal cancer, n = 28) were obtained from the hospitals affiliated with the University of Texas Southwestern Medical Center. Institutional Review Board permission and informed consent were obtained at each collection site. Clinical information including gender, age, histology, clinical stage, and smoking history were available. Clinical staging was based on the revised International System for Staging Lung Cancer (24). We also studied 80 NSCLC cell lines established by us (25) except for NCI-H3255 which was initiated by and obtained from Dr. Bruce Johnson (Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA; ref. 26). The list of cell lines studied and their mutational status may be obtained from the senior author.


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  		Table 1. KRAS, EGFR, and HER2 mutation in resected NSCLC

 
DNA Extraction and Sequencing of HER2, EGFR, and KRAS. Genomic DNA was obtained from primary tumors and cell lines by overnight digestion with SDS and proteinase K (Life Technologies, Inc., Rockville, MD) at 37C followed by standard phenol-chloroform (1:1) extraction and ethanol precipitation.

The intron-based PCR primer sequences for seven examined exons of the entire HER2 TK domains were as follows (forward and reverse, respectively): Exon 18 (5'-GTGAAGTCCTCCCAGCCCGC-3' and 5'-CTCCCATCAGAACTGCCGACC-3'), Exon 19 (5'-TGGAGGACAAGTAATGATCTCCTGG-3' and 5'-AAGAGAGACCAGAGCCCAGACCTG-3'), Exon 20 (5'-GCCATGGCTGTGGTTTGTGATGG-3' and 5'-ATCCTAGCCCCTTGTGGACATAGG-3'), Exon 21 (5'-GGACTCTTGCTGGGCATGTGG-3' and 5'-CCACTCAGAGTTCTCCCATGG-3'), Exon 22 (5'-CCATGGGAGAACTCTGAGTGG-3' and 5'-TCCCTTCACATGCTGAGGTGG-3'), Exon 23 (5'-AGACTCCTGAGCAGAACCTCTG-3' and 5'-AGCCAGCACAGCTCAGCCAC-3'), and Exon 24 (5'-ACTGTCTAGACCAGACTGGAGG-3' and 5'-GAGGGTGCTCTTAGCCACAGG-3'). All PCRs were carried out in 25-µL volume containing 100 ng of genomic DNA using HotStarTaq DNA polymerase (QIAGEN Inc., Valencia, CA). DNA was amplified for 32 to 34 cycles at 95°C for 30 seconds, 62°C to 68°C for 30 seconds, and 72°C for 30 seconds followed by 7 minutes extension at 72°C. All PCR products were incubated using exonuclease I and shrimp alkaline phosphatase (Amersham Biosciences Co., Piscataway, NJ) and sequenced directly using Applied Biosystems PRISM dye terminator cycle sequencing method (Perkin-Elmer Co., Foster City, CA). All sequence variants were confirmed by independent PCR amplifications and sequenced in both directions.

EGFR (exons 18-21) and KRAS (codons 12 and 13) mutation status were determined using the intron-based PCR primers as described previously (23). The EGFR and RAS data from some of these samples have been reported elsewhere (23).

Statistical Analyses. Fisher's exact tests were used to assess the relation between HER2 mutations and each factor. All statistical tests were two-sided and P < 0.05 were considered statistically significant.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Preliminary sequencing of the entire HER2 TK domain (exons 18-24) in 96 unselected NSCLC samples or sequencing of the first four exons of the TK domain (exons 18-21) in which EGFR mutations are limited, in 200 unselected NSCLC samples, and 28 breast carcinoma samples indicated that mutations were limited to exon 20. Because one missense mutation in exon 19 was reported previously in a NSCLC tumor (22), further analyses were limited to these two exons.

Mutations were limited to NSCLC and were absent in 36 neuroendocrine lung tumors (SCLC, large cell neuroendocrine carcinoma, and bronchial carcinoids) and tumors from other sites. A total of 11 (1.6%) mutations were detected in 671 primary NSCLC cases and one (1.3%) mutation was found in 80 NSCLC cell lines (Table 1). All mutations were in-frame duplications/insertions. Corresponding nonmalignant tissues was available from 9 of 11 mutant cases, and the HER2 mutations were confirmed as being somatic in origin. No missense mutations were found. According to the electropherograms (Fig. 1), most mutations were heterozygous, whereas NCI-H1781 (Fig. 1B) and Japan 79 (Fig. 1D) seemed to be homozygous (no wild sequence was detected). These results indicated that allelic imbalance due to the loss of wild allele or selective amplification of the mutant allele occurred in these samples.



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  		Figure 1. Electropherograms demonstrating mutational patterns. A, wild-type sequence in nonmalignant lung tissue. B, 3-bp insertion (D27: homozygous) in NCI-H1781. C, 3-bp insertion (D22: heterozygous) in primary tumor. D, 12-bp duplication/insertion (D21: homozygous) in primary tumor.

 
All 11 HER2 mutant cases had adenocarcinoma histology and seven cases occurred in female patients (Table 2). Of the 11 mutant cases, nine of the subjects were never smokers or very light smoker (0.5 pack year history). By contrast, 420 (64%) of the 660 subjects whose tumors lacked mutations were smokers. HER2 mutations preferentially targeted Oriental countries (Japan and Taiwan; 2.4%) compared with Western countries (the United States and Australia; 0.3%) and female gender (2.7%) compared with male gender (1.0%); however, these differences were not statistically significant (P = 0.06 and 0.12 respectively). They occurred frequently in never smoker (3.2%) than in smoker (0.7%) and in adenocarcinoma (2.8%) than other histologies (0%; P = 0.02 and 0.004, respectively; Table 1). In 394 adenocarcinoma cases, HER2 mutations preferentially targeted Oriental ethnicity (3.9%) compared with other ethnicities (0.7%), female gender (3.6%) compared with male gender (1.9%) and never smokers (4.1%) compared with smokers (1.4%). These findings are similar to the subpopulations of lung cancers in whom EGFR mutations occur as previously shown by us and others (7, 23). In the selected subgroup of Oriental female never smokers with adenocarcinoma histology, the frequency of EGFR mutations was 61% and of HER2 mutations was 4.3%. These results suggest that similar genetic factors and possibly carcinogen(s) or other environmental factor(s) affect the occurrence of mutations in both genes.


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  		Table 2. HER2 mutation in lung cancer

 
All of the HER2 mutations were in-frame duplications/insertions in a small stretch of exon 20 (Fig. 2; Table 2). Whereas they were of four different types, a 12-bp duplication/ insertion coding for the amino acids YVMA at codon 776 was the major pattern (6 of 11 mutations). We also detected a 9-bp duplication/insertion (2 of 11 mutations) and three individual base pair de novo insertions. Interestingly, HER2 mutations target the identical corresponding nine-codon region in exon 20 as did EGFR duplications/insertions (Fig. 2). EGFR mutations target important structures around the ATP binding cleft which is also the docking site of the TK inhibitors (9, 23), including the phosphate binding loop, the {alpha}C-helix, and the activation loop. In-frame duplications/insertions of EGFR occur at the COOH-terminal end of {alpha}C-helix, and postulated by us (9) presumably result in configurational changes causing a shift of the helical axis, narrowing the ATP binding cleft and resulting in both increased gene activation and TK inhibitor sensitivity.



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  		Figure 2. Amino acid alignments of the tyrosine kinase domain in EGFR and HER2. {blacktriangleup} and {blacktriangledown}, duplications/insertions in this study (for HER2) or previously reported by us for EGFR (23). {triangleup}, HER2 duplications/insertions described by Stephens et al. (22). *, nonconserved amino acid.

 
It is of interest to compare our findings with those previously reported (22). Stephens et al. found two types of duplications/insertions in exon 20 (total of four cases). Whereas these were different from the ones we found (Fig. 2), all duplications/insertions from both studies targeted the same eight-codon region (codons 774-781). All of the mutations they identified in lung cancers were in adenocarcinomas (similar to our findings). However, four of the five mutations in their cases were in current or former smokers, in contrast to our findings that the mutations targeted never smokers. Of interest, in their series, EGFR mutations in lung adenocarcinomas were less frequent than HER2 mutations (although we are not informed as to which exons were examined). However, Stephens et al. do not present any detailed data regarding gender, histology, ethnicity, smoking status, or even the geographic location of their lung cancers. Thus, a detailed comparison with our findings is not possible.

We previously reported that EGFR and KRAS mutations do not occur simultaneously (23). Ras/Raf/mitogen-activated protein kinase signaling is one of the important EGFR downstream pathways. The additional cases analyzed in the present study confirm and extend our previous findings. KRAS mutations were detected in 54 (8%) and EGFR mutations were detected in 149 (22%) of 671 NSCLC patients (Table 1). In 80 NSCLC cell lines, KRAS mutations were detected in 20 (25%) and EGFR mutations were detected in eight (10%; 3). Mutations in more than one of these genes were never found simultaneously in the same tumor, suggesting that activation of either EGFR, HER2, or oncogenic KRAS is sufficient for lung carcinogenesis. Of interest, HER2 is the preferential heterodimer partner for EGFR, and interactions between family members may play a role in lung cancer pathogenesis. Previously, we hypothesized that at least two distinct molecular pathways are involved in the pathogenesis of lung adenocarcinomas, one involving EGFR mutations in never smokers and the other involving oncogenic KRAS mutations in smokers (9). HER2 mutations may contribute to lung adenocarcinoma pathogenesis in never smokers. However, only 51% of adenocarcinomas in the present study had mutations in any one of the three genes, indicating a role for other as yet unknown genetic or epigenetic changes. Of interest, in the highly selected subgroup of Oriental female never smokers with adenocarcinoma histology lacking EGFR mutations, the frequency of HER2 mutations was 11%


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  		Table 3. EGFR, HER2, and KRAS mutation status in NSCLC cell lines

 
Oncogenic mutations activate kinases by disrupting the autoinhibitory mechanisms that normally stabilize their inactive forms (1). They target structures around the ATP binding cleft that are involved in phosphorylation events. These structures include the phosphate binding and activation loops. Of interest, very different kinases, such as the receptor tyrosine kinase PDGFR family and the intracellular serine/threonine kinase BRAF share similar oncogenic hotspots (1). Deletions and duplications/insertions on either side of the {alpha}C-helix are also characteristic of EGFR mutations, and we have postulated that such mutations alter the angle of the ATP binding cleft, resulting in greater activity (9). Of interest, with one exception, all of the HER2 mutations in lung cancers described by us and by Stephens et al. (22) have been in-frame duplications/insertions targeting a region of eight codons in exon 20 on the COOH-terminal side of the {alpha}C-helix. With one exception they occur adjacent to or replaced nonconserved residues (Fig. 2). Whereas the activating function of these specific mutations has not been clarified, the remarkable similarities between the mutations in EGFR and HER2 suggest that they are functional. However, the function of the very rare, often unique, point mutations found in NSCLC and other cancers is less certain.

In summary, we found a relatively modest frequency of somatic HER2 gene mutations limited to the adenocarcinoma subtype of lung cancer. The mutations targeted never or light smokers, Oriental ethnicity and female gender. The remarkable similarities of mutations in EGFR and HER2 genes involving tumor type and subtype, mutation type, gene location, and specific patient subpopulations targeted are unprecedented in molecular medicine. These finding suggest the necessity of epidemiologic studies focused on finding a common underlying etiology. HER2 mutant cell line NCI-H1781 is resistant in vitro to gefitinib (26), which preferentially inhibits the TK activity of EGFR. The identification of NCI-H1781 with its HER2 mutation provides an important new resource for preclinical therapeutic studies looking a HER2 targeted agents. However, broad spectrum TK inhibitors may also offer the advantage of simultaneously targeting multiple members of the EGFR family thereby interfering with the cooperation that exists between receptors (27).


   Acknowledgments
 
Grant support: Specialized Program of Research Excellence in Lung Cancer grant P50CA70907 and Early Detection Research Network, National Cancer Institute grant 5U01CA8497102 (Bethesda, MD).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/29/04. Revised 12/17/04. Accepted 12/23/04.


   References
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 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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W. Xu and L. Neckers
Targeting the Molecular Chaperone Heat Shock Protein 90 Provides a Multifaceted Effect on Diverse Cell Signaling Pathways of Cancer Cells
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M. P. Cunningham, H. Thomas, Z. Fan, and H. Modjtahedi
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T. Shimamura, H. Ji, Y. Minami, R. K. Thomas, A. M. Lowell, K. Shah, H. Greulich, K. A. Glatt, M. Meyerson, G. I. Shapiro, et al.
Non-Small-Cell Lung Cancer and Ba/F3 Transformed Cells Harboring the ERBB2 G776insV_G/C Mutation Are Sensitive to the Dual-Specific Epidermal Growth Factor Receptor and ERBB2 Inhibitor HKI-272.
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F. Cappuzzo, L. Bemis, and M. Varella-Garcia
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Wnt/{beta}-Catenin Signaling Mediates Antineoplastic Effects of Imatinib Mesylate (Gleevec) in Anaplastic Thyroid Cancer
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O. C. Ioachimescu and A. C. Mehta
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