Hidenori Kouso

Combined evaluation of Rad51 and ERCC1 expressions for sensitivity to platinum agents in non-small cell lung cancer

DNA repair enzyme expression in tumor cells possibly affects sensitivity to anti‐cancer agents. The aim of this study was to determine the relationship between expression status of DNA repair enzymes and chemosensitivity in patients with non‐small cell lung cancer (NSCLC). NSCLC tissues prepared from the surgical specimens of 41 patients were subjected to immunohistochemical analysis for Rad51 and ERCC1 proteins and to a chemosensitivity test using the MTT assay. The relationships between the expression status of the DNA repair enzymes and ex vivo chemosensitivity to various agents were evaluated. A positive expression for Rad51 and ERCC1 was observed in 17 cases (41%) and 20 cases (49%), respectively. The positivity of Rad51 was closely related to a certain histologic type of squamous cell carcinoma and poor differentiation, and the positivity of ERCC1 tended to be related to squamous cell carcinoma. In chemosensitivity tests, sensitivities to CDDP and CBDCA were significantly lower when both 2 enzymes were positive (p = 0.012 and 0.04 in CDDP, 0.014 and 0.03 in CBDCA). Both Rad51 and ERCC1 expressions showed no significant relationship with sensitivities to paclitaxel, etoposide, vinorelbine, gemcitabine, 5‐FU, or irinotecan. In conclusion, combined expression of Rad51 and ERCC1 expression is associated with resistance to platinum agents in the ex vivo study of clinical NSCLC, and evaluation of expression status of both DNA repair enzymes would be a predictor for clinical response to platinum‐based chemotherapies.

Never-smoking Nonsmall Cell Lung Cancer as a Separate Entity : Clinicopathologic Features and Survival

To propose ‘never‐smoking nonsmall cell lung cancer (NSCLC)’ as a separate entity, the clinicopathologic differences of operable NSCLC between never‐smoking patients and patients with a history of smoking were investigated.

Effects of excision repair cross-complementation group 1 (ERCC1) single nucleotide polymorphisms on the prognosis of non-small cell lung cancer patients

BACKGROUND Excision repair cross-complementation group 1 (ERCC1) is the lead enzyme in the nucleotide excision repair process. Two polymorphisms of ERCC1, T19007C (rs11615) and C8092A (rs3212986), have been reported to affect both the carcinogenesis and the survival of the patients who received platinum-based chemotherapy, but the mechanism by which these polymorphisms influence the survival is unclear. In this study, we determined the function of these ERCC1 polymorphisms in the survival of NSCLC patients. METHOD The ERCC1 T19007C and C8092A single nucleotide polymorphisms (SNPs) were evaluated in 122 Japanese non-small cell lung cancer (NSCLC) patients who underwent a complete resection and analyzed the clinicopathological significance of these SNPs. None of the patients received peri-operative platinum-based chemotherapy. The relationship between these SNPs and ERCC1 protein expression and the platinum sensitivity of the primary tumors were also examined. RESULT Regarding T19007C SNP, the distribution of the CC, CT, and TT genotypes was 45%, 48% and 7%, respectively. As for C8092A SNP, the distribution of CC and CA genotypes was 70% and 30%, respectively. The patients with C8092A CA genotype were significantly poorer disease-free survival (DFS) and overall survival (OS) than those with the CC genotype (p=0.037 and 0.004). In addition, no relationship was observed between T19007C SNP and DFS or OS. These two SNPs also did not correlate with either ERCC1 protein expression or platinum sensitivity. CONCLUSION The ERCC1 C8092A polymorphism may influence the NSCLC prognosis regardless of the ERCC1 protein expression and platinum sensitivity.

Induction of epithelial-mesenchymal transition-related genes by benzo[a]pyrene in lung cancer cells

It is believed that epithelial‐mesenchymal transition (EMT) occurs during the development and progression of cancer; however, the correlation between tobacco smoking and EMT remains to be elucidated.

Serum carcinoembryonic antigen level is associated with epidermal growth factor receptor mutations in recurrent lung adenocarcinomas

The presence of epidermal growth factor receptor (EGFR) gene mutations is a good indicator of the clinical efficacy of gefitinib in patients with nonsmall cell lung cancer. It was recently reported that the serum carcinoembryonic antigen (CEA) level could be a predictive factor for the efficacy of gefitinib treatment; therefore, it is suggested that the EGFR gene mutation is associated with the serum CEA level. The current study analyzed the association between EGFR gene mutations and clinical features, including the serum CEA level, in patients with recurrent lung adenocarcinomas.

CHFR expression is preferentially impaired in smoking-related squamous cell carcinoma of the lung, and the diminished expression significantly harms outcomes.

Loss of tumor suppressors and activation of oncogenes lead to carcinogenesis. Abnormal expression of CHFR, a novel checkpoint gene, or of Aurora kinases, key regulators of mitosis, has been detected in a variety of solid tumors. Recently, CHFR has been revealed to ensure chromosomal stability by controlling the expression level of Aurora‐A in vitro. However, the frequency of aberrant expression of these proteins and the association with clinicopathologic parameters remain poorly defined in nonsmall‐cell lung cancer (NSCLC). In this study, we investigated the immunohistochemical protein expression of CHFR and Aurora‐A in 157 NSCLC cases and evaluated the association between clinicopathologic parameters statistically. The relationship between CHFR protein and mRNA levels and the association between this relationship and promoter methylation of the CHFR gene were also examined in 20 frozen sections of NSCLC. Overexpression of Aurora‐A and reduced expression of CHFR were found in 94 cases (59.8%) and 62 cases (39%) of NSCLC, respectively, and those were significantly correlated with tumor differentiation and size. Moreover, diminished CHFR expression was significantly associated with smoking‐related squamous cell carcinoma cases and poor prognosis. Multivariate analysis revealed that CHFR expression was an independent prognostic factor. A statistical correlation was evident between CHFR protein and mRNA expression. In conclusion, our results suggest the aberrant expression of Aurora‐A and/or of CHFR contributed to the increase in the malignant potential of NSCLC. We also revealed that CHFR expression was predominantly impaired in smoking‐related squamous cell carcinoma and might be a useful prognostic marker in NSCLC.

Liver Metastasis from Thyroid Carcinoma 32 Years After Resection of the Primary Tumor: Report of a Case

Follicular thyroid carcinoma is a differentiated cancer originating from the follicular cells in the thyroid gland. A 73-year-old woman, who had undergone curative resection of thyroid carcinoma 32 years earlier, was referred to our hospital after ultrasonography showed a solid mass in the liver. Laboratory data revealed positive hepatitis B core antibody, but all other values were normal. Computed tomography showed a round tumor, about 1.5 cm in diameter, which was enhanced early and washed out later, in segment 5 of the liver. She underwent laparotomy and partial resection of the liver. Microscopic examination showed follicular cells with minimal atypia growing in a thyroid follicular pattern with colloids, whereby a diagnosis of metastatic liver cancer from thyroid follicular carcinoma was made. This is a rare case of solitary liver metastasis appearing 32 years after eradication of primary follicular carcinoma. Although the reason for the delayed presentation of the metastatic lesion remains unclear, this case shows that patients with differentiated thyroid cancer should be followed up for their entire life.

Expression of mismatch repair proteins, hMLH1/hMSH2, in non-small cell lung cancer tissues and its clinical significance

hMLH1 and hMSH2 have been implicated to be involved in the DNA mismatch repair (MMR) system. The purpose of this study is to investigate the expression of hMLH1 and hMSH2 DNA MMR proteins in non‐small cell lung cancer (NSCLC) tissue and to elucidate their clinical significance.

Differences in the expression of epithelial–mesenchymal transition related molecules between primary tumors and pulmonary metastatic tumors in colorectal cancer

PurposeEpithelial–mesenchymal transition (EMT) is a key event in cancer metastasis. This study immunohistochemically examined the expression of EMT-related molecules in both primary colorectal cancer and pulmonary metastases, and analyzed the expression pattern.MethodsTen patients with colorectal cancer that underwent surgical resections for both the primary tumor and metastatic pulmonary tumors were included. The expression status of EMT-related molecules was examined using immunohistochemical staining.ResultsNine of the 10 cases maintained the expression of both E-cadherin and β-catenin in the primary site. The expression of E-cadherin and β-catenin in the pulmonary metastatic site was preserved in 10 and 12 out of 15 metastatic lesions, respectively. The EMT-related transcription factor, Twist, was positively expressed in all 10 cases, Smad interacting protein 1 (Sip1) in 9, Snail in 4 and Slug in 3 of the primary sites. On the other hand, staining for Twist, Sip1 and Snail at the metastatic pulmonary site, was negative in all 10 cases.ConclusionThe expression of EMT-related transcription factors in metastatic pulmonary tumors from colorectal cancer decreased in comparison to the primary tumors. These findings suggested that the expression status of EMT-related transcription factors might play an important role in the implantation of metastatic foci.

Relationship between the loss of heterozygosity and tobacco smoking in pulmonary adenocarcinoma.

A loss of heterozygosity (LOH) is a major cause of lung carcinogenesis, and it is considered to be related to tobacco smoking in central type lung cancer. We investigated the relationship between LOH in lung adenocarcinoma and tobacco smoking. In a consecutive series of 50 patients with lung adenocarcinoma who underwent a surgical resection, cancer tissue specimens and corresponding normal peripheral lung and central bronchial tissue specimens were analyzed for LOH at the regions of D3S1234 (FHIT), D3S1300 (FHIT), D9S171 (CDKN2), and D17S796 (p53) by polymerase chain reaction using four fluorescence-labeled dinucleotide markers. To examine how cells are influenced by smoking, the A549 cell line was exposed to benzo[a]pyrene (B[a]P) for 24 weeks and then was subjected to the above analysis. The LOH in cancer tissue was thus detected in four (17%) patients at D3S1234, six (14%) at D3S1300, and seven (18%) at D17S796, but no LOH was detected in any normal tissue specimens. The incidence of LOHs in cancer tissue specimens from active smokers was 21% at D3S1234, 11% at D3S1300, and 19% at D17S796, whereas that of LOHs from nonactive smokers was 0% at D3S1234, 19% at D3S1300, and 14% at D17S796. Analyzing the relationship between the pack-year index and the presence of LOH, a significant difference was found among the active smokers. Besides, in the A549 cell line exposed to B[a]P, LOH was de novo detected in one (D2S123) of the nine regions examined. The incidence of LOH could be influenced by tobacco smoking in lung adenocarcinoma, thus suggesting the presence of an important event in the carcinogenesis of this disease.