Germ-line and somatic presentations of the EGFR T790M mutation in lung cancer.
Journal: 2009/March - Journal of Thoracic Oncology
ISSN: 1556-1380
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J Thorac Oncol 4(1): 139-141

Germ-Line and Somatic Presentations of the <em>EGFR</em> T790M Mutation in Lung Cancer

To the Editor

Somatic mutations in the kinase domain of the epidermal growth factor receptor (EGFR) gene are found in about 10% of lung adenocarcinomas that have been sequenced from Western countries and in about 30% of those that have been sequenced from Asia.1EGFR mutations are associated with sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. However, many patients who initially respond to treatment with gefitinib or erlotinib develop resistance to these inhibitors and subsequently relapse. This process has been associated with point mutations in the kinase domain of mutant EGFR.2,3 The most common EGFR mutation associated with treatment resistance involves a C-to-T change at nucleotide 2369 in exon 20, which results in threonine-to-methionine substitution at the amino acid position 790 (T790M). This amino acid change does not seem to diminish EGFR’s catalytic activity, but the presence of the T790M mutation is predicted to impair binding of either gefitinib or erlotinib to the EGFR adenosine triphosphate-binding pocket.2,3 In addition, emerging data suggest that the T790M change may potentiate oncogenic activity. For example, a T790M germ-line mutation was found in one family with a high incidence of lung cancer,4 and somatic T790M mutations have been occasionally detected in tumors from patients who never received EGFR inhibitors.5 In fact, it may be likely that all T790M mutations are present in a small subset of tumor cells before treatment and they expand selectively with EGFR tyrosine kinase inhibitors treatment. Using deoxyribonucleic acid (DNA) extracted from formalin-fixed and paraffin-embedded tissues from 240 patients with lung adenocarcinomas that had never received treatment with EGFR inhibitors, we sequenced the EGFR exons 18 to 21 and identified 2 tumor cases (1%) harboring the T790M mutation. Here, we report those two cases with an unusual presentation of the T790M mutation, including a germ-line and a somatic mutation (Figure 1).

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Epidermal growth factor receptor (EGFR) T790M Mutation in Two Patients with Lung Cancer. Panel A, shows the pedigree of the patient with the germ-line EGFR T790M mutation (the patient is indicated by the arrow, and lung cancer is indicated by solid symbols). Panel B, shows a diagram of the patient’s lungs illustrating the three synchronous lung tumors and representative microphotographs from histologic analysis (hematoxylin and eosin, magnification X400). Tumor 1 (T1) was an invasive adenocarcinoma located in the right lower lobe, tumor 2 (T2) was a pure (noninvasive) bronchioloalveolar carcinoma (BAC) located in the right middle lobe, and tumor 3 (T3) was a large-cell neuroendocrine carcinoma (LCNEC) located in the left lower lobe with hilar lymph node metastasis. Deoxyribonucleic acid (DNA) was extracted from about 1000 microdissected cells from four sites in T1 and 1 site each from the T2 and T3 lymph node metastases (red circles) and then examined for EGFR mutations in exons 18 to 21. In addition, microdissected connective pleural tissue (two sites), nonmetastatic lymph node (two sites), and normal bronchial epithelium adjacent to T1 and T2 (7 sites) were also examined (sites not indicated). All the specimens, nonmalignant and malignant, demonstrated the T790M mutation. Panel C, shows examples of nucleotide sequence tracings illustrating heterozygosity with respect to the T790M mutation in DNA extracted from the peripheral mononuclear blood cells and the tissue sites examined. Panel D, shows the pedigree of the patient with the somatic EGFR T790M mutation (the patient is indicated by the arrow, and lung cancer is indicated by the solid symbols). Panel E, shows a diagram of the patient’s lungs illustrating the tumor and representative microphotographs from histologic analysis of the normal epithelium and tumor (hematoxylin and eosin, magnification X400). In this case, the T790M mutation was detected in four of the four tumor sites (T, red circles) and three of the five normal bronchial epithelium sites (NE, mutant: red circles, wild-type: yellow circles). Microdissected tissue from two pleural (P, green circles) and lymph node (LN, blue circles) sites without tumor involvement had the wild-type allele. Panel F, shows examples of nucleotide sequence tracings illustrating heterozygosity with respect to the T790M variant in normal bronchiolar epithelium and tumor specimen sites. The lymph node sites and pleural tissues had the wild-type allele.

The first case of T790M-associated lung cancer occurred in a 72-year-old female never smoker presented with 3 synchronous lung tumors, 2 adenocarcinomas, and 1 large-cell neuroendocrine carcinoma with hilar lymph node metastasis (Figures 1AC). In addition to the malignant tissue from the three tumors, microdissected cells from normal bronchiolar epithelium, pleural connective tissue, and nonmetastatic lymph nodes showed the presence of both the EGFR T790M and wild-type alleles. No other EGFR mutations were detected in the patient’s tissue specimens. We confirmed the presence of a germ-line mutation by sequencing the DNA extracted from the patient’s peripheral mononuclear blood cells. Although we were unable to examine DNA from other family members, this patient represents, to our knowledge, the second case4 of a T790M germ-line mutation ever reported and confirms the possibility that this phenomenon confers lung cancer susceptibility.

The second case of T790M-associated lung cancer occurred in a 62-year-old female never smoker diagnosed with stage IA adenocarcinoma; no other EGFR activating mutation was seen (Figures 1DF). The T790M mutation was not detected in the DNA extracted from multiple microdissected tissue samples, including nonmalignant pleural connective tissue, lung hilar lymph nodes, and breast connective tissue obtained during a previous breast cancer resection showing that mutation was somatic. However, EGFR mutation analysis of microdissected epithelium obtained from bronchiolar structures adjacent to the tumor showed the T790M mutation in three out of five histologically normal epithelium sites. We previously demonstrated that EGFR kinase domain mutations in exons 19 and 21 are sometimes detected in normal bronchial and bronchiolar epithelium adjacent to EGFR mutant lung tumors, indicating that the development of such mutations may be an early event in the pathogenesis of lung adenocarcinoma as a filed cancerization phenomenon.6 The presence of the T790M mutation in the normal bronchial epithelium in this patient confirms this mutation’s potential oncogenic effect, and its role in preneoplastic lesions, which is supported by the report that in vitro human bronchial epithelial cells overexpressing the T790M mutation showed a growth advantage over cells expressing the wild-type form.7

Although the EGFR T790M mutation has been identified in the context of EGFR resistance to tyrosine kinase inhibitors, it is usually found in conjunction with a classific EGFR TK domain activating mutation. In the two cases described in this report, only the T790M mutation was found. The presence of the mutation alone and also its presence in prenoplastic lesions, indicate that the T790M mutation can occasionally be found in patients whose lung tumors exhibit primary drug resistance and that this mutation may have an oncogenic effect in lung respiratory epithelial cells.

ACKNOWLEDGMENTS

This work was supported, in part, by a grant from the Specialized Program of Research Excellence (SPORE) in Lung Cancer (grant P50 CA70907), National Cancer Institute, Bethesda, MD, and Department of Defense (grant W81XWH-04-1-0142). The authors thank Dr. Margaret Spitz for contributing the DNA specimen extracted from blood.

Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
gro.nosrednadm@abutsiwii

Footnotes

Disclosure: The authors declare no conflict of interest.

Footnotes

REFERENCES

REFERENCES

References

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