In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 2205-2205
Abstract:
A study on twins [N Engl J Med. 13; 78-85, 2000] estimated that the genetic contribution in colorectal cancer (CRC) accounts for 35% of cases, but only ∼5% are attributable to known inherited syndromes. Recently it has been hypothesized that the predisposition to CRC can also be due to low-risk variants such as SNPs. So far, ten variants have been identified in genome-wide association studies (GWAS). The purpose of the present study was to identify new CRC susceptibility loci by investigating two regions (chromosome [chr.] 3q and 10p) using direct sequencing and Taqman® genotyping. The genome-wide linkage analysis previously performed in our lab [BMC Cancer 8:87, 2008] in 30 families using microsatellite markers pinpointed a region on chr. 3q (3q13.31-3q27.1). This region partly overlaps with the one found by Kemp and co-workers [Hum Mol Genet. 15:2903-2910; 2006] located at 3q21-3q24. Additionally, one patient at the Karolinska Hospital with CRC at an early age of onset and no family history of CRC was diagnosed with a de novo translocation between chr. 3 and chr. 10 (t(3;10)(q22.1;p13)). The breakpoint region was mapped using fluorescence in situ hybridization (FISH) and included 7 transcripts on chr. 3 and one on chr. 10. Interestingly, the breakpoint region on chr. 3 was located within the linked region found in our genome-wide linkage study. Furthermore, 5 of the 30 families had positive logarithm of odds (LOD) scores in the breakpoint region on chr. 10. The 7 transcripts in the breakpoint on chr. 3 were sequenced in two affected members from each of the 8 families with linkage to that region and several SNPs were found. These were then investigated in association studies using a cohort of 1760 cases and 1570 controls. Two SNPs were found to be significant (p-value≤0.05): SNP1, located in NEK11, with an OR=1.097 and a ptrend-value=0.0404 and SNP2, located in NUDT16P (a pseudogene), with an OR=1.469 and a ptrend-value=0.0057. After correction for multiple testing using 10,000 permutations SNP2 remained significant (ptrend-value=0.0503). NEK11 has recently been shown to play an important role in the G2/M cell cycle checkpoint and therein may be involved in the development of human cancers. Expression array data for NUDT16P and NEK11 using colorectal tumor cells did not reveal any differences with controls. A replication of the two SNPs in a new cohort of 1500 CRC cases and 1400 controls was not successful (SNP1: OR=0.986, ptrend-value=0.97; SNP2: OR=0.934, ptrend-value=0.61). To analyze the breakpoint region on chr. 10, selected members of the 5 linked families were sequenced and one interesting SNP (located within a potential miRNA-binding site) was found. An association study in 400 cases and 400 controls did not reveal any statistical significant results. Conclusion: Several lines of evidence suggest that the locus on chr. 3q could be associated with CRC predisposition even though we have not been able to identify the causative variant so far. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2205.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-2205
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
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