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S. Okumura



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    P2.01 - Poster Session 2 - Cancer Biology (ID 145)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.01-007 - Distinct characteristics of small cell lung cancer (SCLC) correlate with central or peripheral origin - microarray analysis of snap frozen tissue samples. (ID 1383)

      09:30 - 09:30  |  Author(s): S. Okumura

      • Abstract

      Background
      We previously reported that SCLC distinct characteristics by primary tumor location (central type or peripheral type) and TTF-1 expression. Peripheral type and/or TTF-1 expression were predictive factors of poor prognosis in SCLC. In this study, we examined whether or not SCLC distinct characteristics of gene expression by primary tumor location, using microarray analysis of snap frozen tissue samples.

      Methods
      Fourteen SCLC, diagnosed from biopsies and/or surgical materials, for which snap frozen tissue samples were available, were collected during 2004-2011 from Japanese patients. We evaluated the location of primary tumor (central or peripheral) by CT at diagnosis. Total RNAs from the snap frozen fresh tissue sample of the surgically resected SCLC (n=14, central type:3, peripheral type:11) were used to prepare cDNAs, which were hybridized to the Whole genome Human 60K Microarray chips (Agilent Technologies Inc, Tokyo, Japan). Data normalization, log transformation, statistical analysis, gene ontology (GO) analysis, and pattern study were performed with GeneSpring GX12 (Agilent Technologies Inc, Tokyo, Japan) and Ingenuity Pathway Analysis software, with the stringency of P < 0.01 and a < 2-fold change by moderated t-test corrected with Bonferroni multiple testing.

      Results
      There were a total of 31551 genes scored as differentially expressed between groups. A total of 833 genes were identified that differed significantly in expression: 424 genes were upregulated and 409 genes were downregulated in peripheral type compared with central type. Interestingly, upregulated gene analysis revealed that peripheral type SCLC had increased levels of neuroendocrine genes such as NCAM, Synaptophysin (SYN), Chromogranin A (CGA), Gastrin-releasing peptide (GRP), ASCL1, and TTF-1. Subsequently, GO and network analysis revealed that most of upregulated genes in peripheral group were related to neuron functions. Hierarchical cluster analysis clearly distinguished between central type and peripheral type.

      Conclusion
      SCLC had a distinct gene expression profile from tumor location and had higher expression of genes associated with neural function in peripheral SCLC. Defining gene expression profiles by tumor location may help elucidate distinct characteristics of SCLC between central type and peripheral type.

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    P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.02-002 - Identification of CpG island methylator phenotype predicts the prognosis of small cell lung cancer (ID 42)

      09:30 - 09:30  |  Author(s): S. Okumura

      • Abstract

      Background
      Small cell lung cancer (SCLC) accounts for 13-15% of new lung cancer cases in worldwide and has the poor therapeutic outcomes with a median survival of just over one year. A CpG island methylate phenotype (CIMP) is well known as a methylator phenotype with characteristic promoter DNA methylation alterations, in colorectal cancers, glioblastoma and breast cancers, although there has been no report about any CIMP of SCLC. We investigated whether DNA methylation profiles can provide useful molecular subtyping of SCLC in terms of etiology and prognosis of SCLC.

      Methods
      We analyzed 28 fresh frozen samples from pure SCLC patients and 13 noncancerous lung tissues. All patients underwent surgical lung resection at the Cancer Institute Hospital, nine patients among them were treated with chemotherapy before surgery. After genomic DNA was treated with sodium bisulfite, bisulfite-converted genomic DNA was analyzed using Illumina’s Infinium HumanMethylation27 BeadChip. And, total RNA was extracted from twenty-five SCLC tumor samples and mRNA expression of these samples were analyzed by Agilent’s SurePrint G3 Human CGH Microarray. Next, we matched these two data sets by Gene Symbol, and identified fifty-five most differentially methylated CpG sites (corresponding to 46 genes) with a FDR p value cut off of 0.05. Gene ontology analysis was performed using DAVID Bioinformatics Resources.

      Results
      We selected a total of 1741 most differentially methylated CpG sites (s.d. > 0.20) across the 28 SCLC tumor tissues in each DNA methylation platform, after an elimination of the probes related with the X- and Y- chromosome. Unsupervised hierarchical clustering of methylation data from SCLC samples reveals two major subgroups with different prognosis: the 5 years disease-free interval (DFI) rate of patients in cluster 1 (11.1%) was lower than that of patients in cluster 2 (61.57%) (p = 0.001). By multivariate analysis for DFI, both postoperative chemotherapy and cluster 1 were a significant prognostic factor (p = 0.002 and 0.002; respectively). Next, among 1220 genes with methylation and expression data both available, the CpG sites were ranked on the basis of the spearman’s correlation coefficient between cluster 1 and cluster 2 into an ascending order. Finally, we identified that fifty-five CpG sites were nagetively correlated and found that apoptosis pathway was a most differentially expressed.

      Conclusion
      By comprehensive DNA methylation profiling, two distinct subgroups with different molecular and clinical phenotype were identified to evoke a CIMP of SCLC. We found some promoter markers in the apoptosis pathway could make a difference between the two groups, and we hope that our data can contribute to provide a useful resource for the construction of therapeutic strategy and the development of a new chemotherapeutic agent.

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    P3.07 - Poster Session 3 - Surgery (ID 193)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P3.07-011 - Prognostic and predictive factors for recurrence-free survival in patients with completely resected pN2 non-small cell lung cancer (ID 1001)

      09:30 - 09:30  |  Author(s): S. Okumura

      • Abstract

      Background
      The role of surgical resection remains controversial for pathologic N2 (pN2) non-small cell lung cancer (NSCLC). The objective of our study was to determine the prognostic and predictive factors for recurrence-free survival (RFS) in patients with completely resected pN2 NSCLC.

      Methods
      Between 1990 and 2009, 2439 patients with NSCLC underwent curative surgical resection at the Cancer Institute Hospital. Of these patients, 311 (12.8%) were diagnosed as having pN2 NSCLC. Surgical resection was performed in 79, 71, 70, and 91 patients in 1990–1994, 1995–1999, 2000–2004, and 2005–2009, respectively. Overall survival (OS) and RFS were calculated using the Kaplan-Meier method, and survival outcomes were assessed using the log-rank test. Univariate and multivariate Cox proportional hazards models were used to identify factors influencing RFS.

      Results
      The patient population comprised 199 male and 112 female patients, with ages ranging from 16 to 84 years (median, 61.4). Lobectomies or bilobectomies were conducted in 263 cases, and pneumonectomies were performed in 48 cases. For the entire cohort, 5-year OS and 5-year RFS rates were 46% and 24%, respectively. The median follow-up time was 44 months. OS and RFS rates were 34% and 23% in 1990–1994, 42% and 34% in 1995–1999, 45% and 20% in 2000–2004, and 59% and 20% in 2005–2009, respectively. The recent improvement in OS was remarkable, whereas the RFS rate did not improve. Multivariate analysis identified 4 independent predictors for poor RFS: multiple-zone mediastinal lymph node metastasis (hazard ratio [HR], 1.551; P = .002), ipsilateral intrapulmonary metastasis (HR, 1.038; P = .002), tumor size > 30 mm (HR, 1.007; P = .046), and clinical N1 or N2 stage (HR, 1.039; P = .041). Patients were grouped according to the number of risk factors for poor RFS. Patients with none of the identified risk factors had an RFS rate of 32%, those with 1–2 factors had an RFS rate of 25%, and those with 3–4 factors had an RFS rate of 7% (P < .001).Figure 1

      Conclusion
      In patients with surgically resected pN2 NSCLC, OS tended to improve in recent years, whereas RFS was fairly constant over the study period. The overall prognosis of patients with surgically resected pN2 NSCLC remains poor. However, prognosis is considerably better in those patients with fewer risk factors. Accordingly, surgical resection could be beneficial in select patients.