ZIA BC 011495 (ZIA) | |||
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Title | Integrative Molecular Epidemiology of Human Cancer | ||
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 (20.0%) Inflammatory Bowel Disease (20.0%) |
Colon/Rectum (20.0%) Lung (80.0%) |
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Research Type | |||
Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors Resources and Infrastructure Related to Detection, Diagnosis, or Prognosi |
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Abstract | |||
Global changes in gene expression accompany the development of cancer. Thus, inherited variants in miRNA-binding sites are likely candidates for conferring inherited susceptibility. Using an in silico approach, we compiled a comprehensive list of SNPs predicted to modulate miRNA binding in genes from several key lung cancer pathways. We then investigated whether these SNPs were associated with lung cancer risk in two independent populations. In general, SNPs in miRNA-binding sites are rare. However, some allelic variation was observed. We found that rs1126579 in CXCR2 was associated with a reduced risk of lung cancer in both European American [ORTT vs. CC 0.56 (0.37-0.88); P = 0.008] and Japanese [ORTT vs. CC 0.62 (0.38-1.00); P = 0.049] populations. Furthermore, we found that the SNP disrupted a novel binding site for miR-516a-3p, led to a moderate increase in CXCR2 mRNA and protein expression, and increased MAPK signaling. Moreover, analysis of rs1126579 with serum levels of IL8, its endogenous ligand, supported an interaction whereby rs1126579-T and high serum IL8 conferred synergistic protection from lung cancer. Our findings demonstrate a function for a 3'UTR SNP in modulating CXCR2 expression, signaling, and susceptibility to lung cancer (Ryan et al. 2015). In collaboration with Mayo Clinic, we are investigating oncogenic fusions in never smokers in relation to childhood exposure to secondhand tobacco smoke (SHS). The EML4-ALK fusion gene is more frequently found in younger, never smoking patients with lung cancer. Meanwhile, never smokers exposed to SHS during childhood are diagnosed at a younger age compared with never smoking patients with lung cancer who are not exposed. We, therefore, hypothesized that SHS, which can induce DNA damage, is associated with the EML4-ALK fusion gene. We compared the frequency of the EML4-ALK fusion gene among 197 never smoker patients with lung cancer with and without a history of exposure to SHS during childhood at Mayo Clinic. The EML4-ALK fusion gene was detected in 33% of cases from never smokers with a history of SHS exposure during childhood, whereas 47% of never smoking lung cancer cases without a history of childhood SHS exposure tested positive for the fusion gene. The EML4-ALK fusion gene is not enriched in tumors from individuals exposed to SHS during childhood. These data suggest that childhood exposure to SHS is not a significant etiologic cause of the EML4-ALK fusion gene in lung cancer (Ryan et al. 2014). With our collaborators at Lombardi Comprehensive Cancer Center, we examined the associations between telomere length variation (TLV), mean telomere length in blood lymphocytes and lung cancer risk in 191 lung cancer patients and 207 healthy individuals. We discovered that TLV is significantly associated with lung cancer risk and the associations were modulated by age. Telomere fluorescent in situ hybridization was used to measure telomere features using short-term cultured blood lymphocytes. Logistic regression was used to estimate the strength of association between telomere features and lung cancer risk. TLV across all chromosomal ends was significantly associated with lung cancer risk; adjusted odds ratios 4.67 [95% confidence interval (CI): 1.46-14.9] and 0.46 (95% CI: 0.25-0.84) for younger (age less than or equal to 60) and older (age greater than 60) individuals, respectively. TLV and mean telomere length jointly affected lung cancer risk: when comparing individuals with short telomere length and high TLV to those with long telomere length and low TLV, adjusted odd ratios were 8.21 (95% CI: 1.71-39.5) and 0.33 (95% CI: 0.15-0.72) for younger and older individuals, respectively. Thus, we propose that TLV in combination with mean telomere length might be useful in identifying high-risk population for lung cancer LDCT screening (Sun et al. 2015). Cigarette smoke is the most important risk factor for lung cancer. Recent studies have implicated cigarette smoke in the d |