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 of a chemotherapeutic response (rather than progression-free and overall survival) with high accuracy in test and validation cohorts (82.5% and 77.8%). The three-miRNA signature in surgically resected primary lung ADC tissues may by clinically useful for predicting responsiveness to platinum-based doublet chemotherapy after recurrence (Saito, 2014). 5. Metabolome. In collaboration with Frank Gonzalez (Laboratory of Metabolism), we identified diagnostic and prognostic urine metabolomic biomarkers (Mathe, 2014). We are currently evaluating their utility in pre-diagnostic samples from the well-characterized prospective Southern Community Cohort Study (SCCS), comprising 178 lung cancer cases and 351 controls. In the SCCS cohort, creatine riboside and N-acetylneuraminic acid (NANA) were identified as risk biomarkers (Haznadar et al, manuscript in preparation). To evaluate if these biomarkers may complement LDCT screening, we will measure them in the urine of 307 cases and 614 controls from the National Lung Screening Trial (NLST) and evaluate if they can distinguish benign from malignant nodules with a higher specificity than LDCT alone. We have started to integrate the lung cancer molecular markers to generate classifiers predictive of disease outcome. The prognostic value of HOXA9 promoter methylation alone and in combination with mRNA and miRNA biomarkers was assessed in two independent cohorts of stage I lung ADC. Four protein-coding gene, miR-21 expression, and HOXA9 promoter methylation were each independently associated with outcome, and when combined, identified high-risk, stage I patients (HR, 10.2; p = 3x10). We propose that a prognostic classifier comprising three types of genomic and epigenomic data may help guide the postoperative management of stage I lung ADC patients at high risk of recurrence (Robles, 2015). MOLECULAR TAXONOMY OF COLORECTAL CANCER (CRC). The expression of miR-34a/b/c was found to be significantly increased in tumors compared to adjacent noncancerous tissues from 159 American and 113 Chinese colon cancer patients, counter to the proposed tumor suppressor role for these miRNAs. Increased miR-34b/c was associated with more advanced tumors and poor cancer-specific mortality. Expression of miR-34 family was associated with TP53 transcriptional activity, consistent with the proposed regulation of miR-34a/b/c by TP53, but not with TP53 mutation status. Expression of miR-34b/c in cancer stroma was associated with poor prognosis in CRC (Hiyoshi, 2015). Distant metastasis is the major cause of mortality in CRC. CRC metastasis-specific miRNAs were determined in pairs of primary CRC (pCRC) and Liver Metastasis (LM). Twenty-three miRNAs were identified that were differentially expressed between pCRC and LM (P .001; FDR .5). A metastasis-specific miRNA signature and novel tissue- and serum-based CRC metastasis-specific miRNA biomarkers were discovered and validated. These unique miRNAs may be clinically applicable to predict prognosis and distant metastasis in CRC (Hur, 2015). CRC represents a group of histopathologically and molecularly heterogeneous diseases, which may contain signet-ring cell and/or mucinous components with unknown prognostic significance. In 1,336 rectal and colon cancer patients we found that even a minor (50 % or less) signet-ring cell component, but not mucinous component, was associated with higher patient mortality, independent of other molecular and clinicopathological features (Inamura, 2015). We evaluated the prognostic association of hypomethylation in long interspersed nucleotide element-1 (LINE-1) with respect to microsatellite instability (MSI-high) status in 1211 CRCs. We found a stronger association of LINE-1 hypomethylation with inferior survival in MSI-high compared to MSS (stable) CRCs. (Inamura, 2014).
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