© The Author 2006. Published by Oxford University Press.
CORRESPONDENCE |
Re: Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers
Affiliations of authors: SNP Institute, Hengyang, China (JRP, LX, KL); Egea Biosciences, LLC., San Diego, CA (JRP); GNF Institute, San Diego, CA (JZ); City of Hope National Medical Center, Duarte, CA (KL)
Correspondence to: Kai Li, MD, PhD, City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA 91010 (e-mail: kli{at}coh.org).
Shigematsu et al. (1) recently described 28 unique epidermal growth factor receptor (EGFR) gene mutations in 617 lung cancer patients and further confirmed the previously described clinical characteristics associated with these somatic mutations. We believe that the authors did not properly annotate two of these mutations (D8 and 
9). For example, they described D8 as a duplication with a nucleotide substitution; we suggest that is more likely to be a simple duplication (Fig. 1, A). In general, it is reasonable to assume that a sequence variant results from a single mutation rather than from a concatenation of multiple events. If we apply this assumption to 9, this variant can be described as two distinct deletions rather than as one deletion with two substitutions (Fig. 1, B). The two-deletion hypothesis is supported by the identification in two patients (2) of a 9-like EGFR gene mutation that has precisely the same deleted sequences as 9 except for three bases (i.e., ATC) at the 5' end (Fig. 1, C). EGFR gene mutations located between CAAGGAA repeats are predominantly in-frame deletions in lung cancers of patients who are nonsmokers. By contrast, base substitutions are the type of mutation most frequently reported in the Human Gene Mutation Database (http://www.hgmd.org) and in a database of somatic mutations in the gene encoding p53 (http://www-p53.iarc.fr). Clearly, deletions play a more important role than base substitutions in mutagenesis of the bases located between the repetitive sequences in the EGFR gene.
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Although in some Asian populations, approximately 50% of lung cancer patients harbor somatic EGFR gene mutations (3), it is too early to conclude that EGFR gene mutations are a primary cause of lung cancer. EGFR gene mutations are observed predominantly in lung cancers from nonsmokers; gain-of-function EGFR gene mutations that promote angiogenesis may facilitate cancer development from a few initial tumor cells in this particular subpopulation of patients. On the contrary, EGFR gene mutations are rarely identified in lung cancers in cigarette smokers, which are usually more malignant than lung cancers in nonsmokers (3). It has been observed that cancer patients with EGFR gene mutations have longer survival times than those without EGFR gene mutations (3). Also, the identification of an EGFR gene mutation that results in a truncated protein in a lung cancer patient (http://www.egfr.org) argues for a causal effect in carcinogenesis in this case. Furthermore, the possible causal effects of EGFR gene mutations are not consistently supported by therapeutic data. Early studies indicated that lung cancers' response to gefitinib was highly dependent on the presence of EGFR mutations. However, recent clinical trials showed that the combination of gefitinib with chemotherapy did not dramatically improve the survival of cancer patients (4). These findings suggest that EGFR gene mutations may not be a primary cause of lung carcinogenesis. When a therapeutic target is the actual cause of cancer, a high rate of clinical remission should be expected (5), but gefitinib treatment for lung cancers with an EGFR gene mutation did not induce clinical remission in a clinical trial with a large sample size (4).
Since the initial suggestion that angiogenesis is important in cancer growth, several drugs that inhibit angiogenesis have been developed. The EGFR inhibitor, gefitinib, was found to inhibit renal cancer growth by decreasing capillary density (6), suggesting the enhancing effect of EGFR-mediated angiogenesis in the development of renal cancer in this animal model. However, no studies of gefitinib have been performed in lung cancer animal models, nor have inherited gain-of-function EGFR gene mutations been identified by genetic linkage analysis except for T790
M, an EGFR gene mutation that confers drug resistance, which has been identified in one family (7). Whereas the exact roles of the EGFR gene mutations and some other angiogenic genes in lung cancer development remain to be elucidated, the exponential accumulation of somatic EGFR gene mutations, including the inherited mutation, T790M (7), has intensified the red-hot debate over the modifying effects of angiogenesis in cancer development.
REFERENCES
(1) Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339–46.
(2) Sonobe M, Manabe T, Wada H, Tanaka F. Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma. Br J Cancer 2005;93:355–63.[CrossRef][Medline]
(3) Shih JY, Gow CH, Yu CJ, Yang CH, Chang YL, Tsai MF, et al. Early detection and diagnosis: epidermal growth factor receptor mutations in needle biopsy/aspiration samples predict response to gefitinib therapy and survival of patients with advanced nonsmall cell lung cancer. Int J Cancer 2005 Sep 8; [Epub ahead of print].
(4) Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527–37.[CrossRef][Web of Science][Medline]
(5) Cortes J, Talpaz M, O'Brien S, Jones D, Luthra R, Shan J, et al. Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin Cancer Res 2005;11:3425–32.
(6) Asakuma J, Sumitomo M, Asano T, Asano T, Hayakawa M. Modulation of tumor growth and tumor induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 in renal cell carcinoma. J Urol 2004;171:897–902.[CrossRef][Medline]
(7) Bell DW, Gore I, Okimoto RA, Godin-Heymann N, Sordella R, Mulloy R, et al. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat Genet 2005 Oct 30; [Epub ahead of print].
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J Natl Cancer Inst 2006 98: 363-364.
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