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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e3181f1cab3
Letters to the Editor

Evaluation of Kras Gene Mutation and Copy Number in Thymic Carcinomas and Thymomas

Sasaki, Hidefumi MD, PhD; Yano, Motoki MD, PhD; Fujii, Yoshitaka MD, PhD

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Department of Oncology, Immunology and Surgery; Nagoya City University Graduate School of Medical Sciences; Nagoya, Japan

Disclosure: The authors declare no conflicts of interest.

Address for correspondence: Hidefumi Sasaki, MD, PhD, Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. E-mail: hisasaki@med.nagoya-cu.ac.jp

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To the Editor:

Compared with the more common epithelial cancers, current knowledge about the biology of thymic epithelial tumors is limited. Research has been hampered by the rarity of the tumor and the lack of established cell lines and animal models. Ras family plays important roles in the regulatory processes of proliferation, differentiation, and apoptosis. A recent Caucasian report demonstrated that 1 of 38 thymoma and 1 of 7 thymic carcinoma had Kras mutations.1 Because we previously reported the EGFR copy number2 and Kras mutation3 status using quantitative polymerase chain reaction (PCR) assay in non-small cell lung cancer, we evaluated the Kras gene mutation status and Kras gene amplification, which may bring important information for the surgically treated Japanese thymic epithelial tumor patients.

Thymic epithelial tumor tissues were obtained by surgical excision from 125 patients (107 thymomas and 18 thymic cancers). Kras mutation status at codon 12,13 mutation was analyzed by quantitative real-time PCR performed using LightCycler.3 Positive sample and some of the negative samples from melting analysis were directly sequenced. Using the LightCycler genotyping PCR assay, only one thymic carcinoma case was detected to have a Kras mutation. A heterozygous G to T substitution at nucleotide position 35 in exon 1 of Kras, resulting in a valine for glycine amino acid substitution at position 12 (G12V) (Figure 1). This patient was a 38-year-old woman with adenocarcinoma. She is a never smoker and had stage IVb cancer with lung metastasis. EGFR mutations were evaluated for 105 thymomas and 11 thymic carcinomas using LightCycler genotyping assay.4 However, no mutation was found within the cohort. In lung cancers, Kras mutation rate was lower in Japanese when compared with Caucasian.3 The difference between the previously published study1 and ours might be caused by the difference in ethnicity: Caucasian or Oriental. Characteristically, 70% of Kras mutations are G to T transversions,5 molecular events that are linked to exposure to tobacco smoke carcinogenesis. A previous report also showed that the mutation case from thymic carcinoma was a heterozygous G to T transversion at nucleotide position 35 in exon 1 of Kras.1 Although, in our case, the patient was a nonsmoker, other mechanisms such as passive tobacco smoking might be involved.

Figure 1
Figure 1
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Kras copy number was analyzed for 13 thymic cancer and 19 advanced thymoma patients by quantitative real-time PCR performed on 7500 Real Time PCR System (Applied Biosystems) by using a QuantiTect SYBR Green Kit (Qiagen, Inc., Valencia, CA).2 Only one of the 13 thymic cancer case was found to have increased Kras copy number (>3.0). This patient was a 76-year-old man with squamous cell carcinoma. He had stage IVb cancer with lymph node and lung metastasis. He died 2 months after surgery. He had wild-type Kras and EGFR gene. Of 19 thymomas, we detected only one case with increased Kras copy number.

Advanced thymic carcinoma is a very aggressive disease. To date, there are no established treatment options for the refractory and recurrent disease, and few prospective trials were conducted in patients with thymic carcinoma. Responses to EGFR tyrosine kinase inhibitors have been rare in unselected thymic tumors. Coupled with the data on Kras and EGFR mutations could explain the findings. Kras mutations predict for primary resistance to anti-EGFR therapies, gefitinib/erlotinib in lung cancer, and cetuximab in colon cancer. These findings could have therapeutic implications for the treatment of thymic tumors. Although Kras mutations or increased copy number are rare in thymic tumors, further assessment of Kras is needed and should be included in any therapeutic trial considering anti-EGFR therapy for thymic malignancies.

Hidefumi Sasaki, MD, PhD

Motoki Yano, MD, PhD

Yoshitaka Fujii, MD, PhD

Department of Oncology, Immunology and Surgery

Nagoya City University Graduate School of Medical Sciences

Nagoya, Japan

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REFERENCES

1.Girard N, Shen R, Guo T, et al. Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas. Clin Cancer Res 2009;15:6790–6798.

2.Endo K, Sasaki H, Yano M, et al. Evaluation of the epidermal growth factor receptor gene mutation and copy number in non-small cell lung cancer with gefitinib therapy. Oncol Rep 2006;16:533– 541.

3.Sasaki H, Okuda K, Kawano O, et al. Nras and Kras mutation in Japanese lung cancer patients: genotyping analysis using LightCycler. Oncol Rep 2007;18:623–628.

4.Sasaki H, Endo K, Konishi A, et al. EGFR mutation status in Japanese lung cancer patients: genotyping analysis using LightCycler. Clin Cancer Res 2005;11:2924–2928.

5.Sekido Y, Fong KM, Minna JD. Progress in understanding the molecular pathogenesis of human lung cancer. Biochim Biophys Acta 1998;1378:F21–F59.

© 2010International Association for the Study of Lung Cancer

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