In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 3_suppl ( 2014-01-20), p. 457-457
Abstract:
457 Background: DCC (deleted in colon cancer; 18q21.3) is frequently lost in colorectal cancers (CRC), but few mutations in DCC have been discovered, even in tumors with 18q loss of heterozygosity. DCC has been shown to be a dependence receptor, with differential signaling depending on the presence (proliferative) or absence (pro-apoptotic) of the netrin-1 ligand (NTN1). DCC-mutated CRC tend to present at advanced stage and have a poor prognosis. RET, another dependence receptor, is a possible tumor suppressor gene in CRC and associates with CRC progression. Given the apparent role of DCC and RET in CRC progression, we carried out a genetic association study to determine if specific genetic variants in these pathways associate with advanced vs. early CRC. Methods: Imputed HapMap genome-wide association study (GWAS) from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), a collection of 19 international case-control and cohort studies, was used to identify single nucleotide polymorphisms (SNPs) in DCC, NTN1, RET and interacting genes within 5kb upstream to 500mb downstream of each of the 54 genes. With the resultant 10,102 SNPs, we performed a stage-stratified analysis, comparing advanced (AJCC stage III-IV, n = 3500) to early CRC (I-II, n = 5300). An inverse-variance weighted fixed effect meta-analysis was performed with significance set at p=0.05/10102 SNPs=5x10 -6 for multiple test correction. Results: Of the examined SNPs within DCC, the lowest p-value comparing advanced vs. early CRC was 3.6x10 -3 . SNPs in DOCK1 (dedicator of cytokinesis 1), which complexes with DCC and netrin-1, were associated with advanced CRC at p=1.11x10 -3 . SNPs in NTN1 and RET reached significance only at p = 1.73x10 -2 and 1.53x10 -2 , respectively. No SNPs reached the pre-determined level of statistical significance. Conclusions: Our current analysis does not provide clear evidence for candidate SNPs associated with advanced CRC. Further approaches include expanding the analysis to include 1,000 Genome Project and ExomeChip data (~30,000 added SNPs), comparison of cases and controls, and evaluating candidate SNP-SNP interactions to better evaluate pathway pathogenesis. We plan to present an updated analysis at the symposium.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2014.32.3_suppl.457
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2014
detail.hit.zdb_id:
2005181-5
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