Molecular oncology of lung cancer

Toyooka, Shinichi; Mitsudomi, Tetsuya; Soh, Junichi; Aokage, Keiju; Yamane, Masaomi; Oto, Takahiro; Kiura, Katsuyuki; Miyoshi, Shinichiro

doi:10.1007/s11748-010-0743-3

Cited by 63 publications

(47 citation statements)

References 86 publications

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“…Of note, the profile of molecular alterations is quite different among the histological subtypes of lung cancer [6][7][8]. For example, epidermal growth factor receptor (EGFR) mutations [9], K-ras mutations and P16 methylation [8] are frequently found in non-small cell lung cancer (NSCLC), but not in SCLC [10]. In contrast, TP53 mutations [8,11] or RASSF1A methylation [12] is frequently found in SCLC, compared with NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer

et al. 2012

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Small-cell lung cancer (SCLC) is an aggressive tumor with a dismal prognosis among primary lung cancers. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family is comprised of tumor-suppressive miRNAs, and its reduced expression by methylation has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the alteration and tumor-suppressive impact of miR-34s in SCLC.The methylation of miR-34a and miR-34b/c was observed in 4 (36 %) and 7 (64 %) of 11 SCLC cell lines, respectively. Among the 27 SCLC clinical specimens, miR-34a and miR-34b/c were methylated in 4 (15 %) and 18 (67 %), respectively. In contrast, 13 (28 %) miR-34a methylated cases and 12 (26 %) miR-34b/c methylated cases were found in 47 NSCLC primary tumors. The frequency of miR-34b/c methylation was significantly higher in SCLC than in NSCLC (p < 0.001). The expressions of miR-34swere reduced in methylated cell lines and tumors and restored after 5-aza-2'-deoxycytidine treatment, indicating that methylation was responsible for the reduced expression of miR-34s. Because the frequency of methylation was higher in miR-34b/c, we focused on miR-34b/c for a functional analysis.We examined the effect of miR-34b/c introduction on cell proliferation, migration and invasion. The

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Section: Introductionmentioning

confidence: 99%

Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer

et al. 2012

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“…EGFR, a gene that is frequently overexpressed in 40-80% of NSCLC cases, serves an important role in tumor cell survival and proliferation (16,17). Recent clinical trials with EGFR inhibitors have demonstrated positive results in patients with NSCLC, particularly by increasing the progression-free survival (PFS) time among patients harboring EGFR mutations compared with patients with wild-type EGFR (7-12).…”

Section: Discussionmentioning

confidence: 99%

Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer

et al. 2016

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Abstract. Epidermal growth factor receptor (EGFR) is overexpressed in >60% of non-small cell lung cancer (NSCLC) cases. In combination with radiotherapy or chemotherapy, first-line treatments with antibodies against EGFR, including cetuximab and necitumumab, have demonstrated benefits by increasing overall survival (OS), particularly in patients who overexpress EGFR. The present study evaluated the interobserver agreement among three senior pathologists, who were blinded to the clinical outcomes and assessed tumor samples from 85 patients with NSCLC using the H-score method. EGFR immunohistochemistry was performed using a qualitative immunohistochemical kit. The reported (mean ± standard deviation) H-scores from each pathologist were 111±102, 127±103 and 128.53±104.03. The patients with average H-scores ≥1, ≥100, ≥200 and between 250-300 were 85.9, 54.1, 28.2 and 12.9, respectively. Patients who had an average H-score >100 had a shorter OS time compared with those with lower scores. Furthermore, patients with EGFR mutations who were treated with EGFR-tyrosine kinase inhibitors (TKIs) and had an average H-score >100 had a longer OS time compared with those with an average H-score <100. The interobserver concordance for the total H-scores were 0.982, 0.980 and 0.988, and for a positive H-score ≥200, the interobserver concordance was 0.773, 0.710 and 0.675, respectively. The determination of EGFR expression by the H-score method is highly reproducible among pathologists and is a prognostic factor associated with a poor OS in all patients. Additionally, the results of the present study suggest that patients with EGFR mutations that are treated with EGFR-TKIs and present with a high H-score have a longer OS time.

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“…Va rious molecules are being investigated as putative markers of CSCs in malignancies including lung cancer [5]. CD133, which was initially described as a surface antigen specific for human hematopoietic stem cells [6,7], is now being used to identify and isolate putative CSC populations from malignant tumors including cancers of the brain, prostate, liver, pancreas, and colon as well as melanomas [8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Prognostic impact of cancer stem cell-related markers in non-small cell lung cancer patients treated with induction chemoradiotherapy

et al. 2012

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The expression of several cancer stem cell (CSC)-related markers has been confirmed in non-small cell lung cancer (NSCLC). The aim of this study was to clarify the clinical role of CSC-related markers in patients with NSCLC undergoing induction chemoradiotherapy (CRT). Fifty patients with clinically diagnosed N2 or N3 NSCLC who underwent induction CRT with docetaxel and cisplatin concurrently with thoracic radiation followed by surgery were examined in this study. The expressions of CSC related markers (CD133, ALDH1, ABCG2, and Bmi-1) were examined using immunohistochemical staining in surgically resected specimens. Among the 50 patients, 20 patients had no residual tumor cells in the resected specimen when examined pathologically; CSC-related marker expressions and their correlation to survival were evaluated in the other 30 patients. After a median follow-up period of 72 months, the 5-year overall survival rate of the patients with CD133-positive or ALDH1-positive specimens was significantly worse than that of the patients with both CD133-negative and ALDH1-negative expressions (44.9% vs. 90.0%, respectively; P = 0.042). In a multivariate analysis, CD133 and ALDH1 negativity (P = 0.047) and cN2-3 single station metastasis (P = 0.03) were significant independent prognostic factors for prolonged survival. The expressions of CSC-related markers after CRT were 3 significantly correlated with a poor prognosis in patients with NSCLC. The development of therapeutic strategies including adjuvant therapy that take CSC-related marker positivity into consideration is likely to be a key factor in further improvements of the prognosis of patients undergoing trimodality therapy.

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Molecular oncology of lung cancer

Cited by 63 publications

References 86 publications

Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer

Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer

Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer

Prognostic impact of cancer stem cell-related markers in non-small cell lung cancer patients treated with induction chemoradiotherapy

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