ZIA BC 011492 (ZIA) | |||
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Title | Biomarkers in Cancer Diagnosis,Prognosis, and Therapeutic Outcome | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Harris, Curtis | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,137,949 | Project Dates | 01/01/2012 - 00/00/0000 |
Fiscal Year | 2015 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (40.0%) Inflammatory Bowel Disease (20.0%) |
Colon/Rectum (40.0%) Lung (60.0%) |
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Research Type | |||
Cancer Progression & Metastasis Technology Development and/or Marker Discovery |
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Abstract | |||
MOLECULAR TAXONOMY OF LUNG AND ESOPHAGEAL CANCERS. 1. Internal Exposome: Inflammation. We retrospectively analyzed serum C-reactive protein, interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, and IL-1beta in 548 lung cancer cases prospectively enrolled in the Prostate, Lung, Colorectal and Ovarian study. A combined classifier of IL-6 and IL-8 was significantly associated with poor outcome in stage I lung cancer patients (HR, 3.39; 95% CI, 1.54-7.48, p = 0.002) and in stage 1 patients with more than or equal to 30 pack-years of smoking (HR, 3.15; 95% CI, 1.54-6.46, p = 0.002). These results support the association between inflammatory markers and lung cancer outcome and suggest that a combined serum IL-6/IL-8 classifier could be useful for guiding management of patients with stage I lung cancer (Ryan, 2014). External Exposome. In collaboration with D. Schrump, we established that cigarette smoke mediates epigenetic repression of microRNA miR-217 during esophageal adenocarcinogenesis. CSC significantly decreased miR-217 expression in immortalized esophageal epithelia and esophageal adenocarcinoma (EAC) cells, consistent with observed lower levels of miR-217 in primary EACs compared to paired normal esophageal tissues. We observed a direct interaction of miR-217 with kallikrein 7 (KLK7), consistent with a negative correlation in primary EACs. Overexpression of miR-217 significantly decreased, whereas overexpression of KLK7 increased proliferation, invasion and tumorigenicity (Xi, 2015). 2. Genome. Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. Only 15% of SCLC patients survive beyond 2 years after diagnosis. In collaboration with J. Yokota, exome sequencing was performed in primary and metastatic tumors from 38 patients with SCLC in order to identify genes frequently mutated and expressed in SCLCs that could be targetable for therapy. Expression of mutant alleles was verified by RNA sequencing. Overall, our study indicates that, in addition to previously found TP53, RB1 and PTEN, TMEM132D, SPTA1 and VPS13B could be also involved in SCLC development, with the products from their mutated alleles being potential therapeutic targets in SCLC patients (Iwakawa, 2015). 3. Epigenome. Genome-wide screening of DNA methylation and pyrosequencing analysis of HOXA9 promoter methylation were performed in two independently collected cohorts of stage I lung adenocarcinoma (ADC). Promoters of genes marked by polycomb in embryonic stem cells were methylated de novo in tumors and identified patients with poor prognosis. High HOXA9 promoter methylation was associated with worse cancer-specific survival (hazard ratio [HR], 2.6; p = 0.02) and recurrence-free survival (HR, 3.0; p = 0.01), and identified high-risk patients in stratified analysis of stages IA and IB (Robles, 2015). 4. Transcriptome. We previously developed a prognostic classifier using the expression levels of BRCA1, HIF1A, DLC1, and XPO1 that identified stage I lung ADC patients with a high risk of relapse. We now used a meta-analysis-based approach to evaluate the classifier in 12 publically available cohorts consisting of 1,069 Stage I patients. The classifier was associated with prognosis in 10/12 cohorts regardless of ethnicity or microarray platform. Pooled estimates demonstrated that patients classified as high-risk had worse overall survival in all stage I [HR, 2.66; 95% CI, 1.93-3.67; P < 0.0001] and in stratified analyses of stage IA (HR, 2.69; 95% CI, 1.66-4.35; P < 0.0001) and stage IB (HR, 2.69; 95% CI, 1.74-4.16; P < 0.0001). Thus, the 4-gene classifier provides independent prognostic stratification of stage IA and stage IB lung ADC patients beyond conventional clinical factors (Okayama, 2014). In collaboration with T. Kohno, we identified a three-microRNA signature that predicts response to platinum-based doublet chemotherapy in patients with lung ADC. A signature comprising three miRNAs (miR1290, miR196b, and miR135a*) enabled the prediction |