Abstract 929: Genetic associations with sporadic neuroendocrine tumor risk
Authors: Ter-Minassian Monica , Wang Zhaoxi , Asomaning Kofi , Liu Chen-Yu , Zhai Rihong , Su Li , Frauenhoffer Christine , Hooshmand Susanne , Lin Xihong , Christiani David , Kulke Matthew 
Published: February 2011

BACKGROUND: Genetic risk factors for sporadic neuroendocrine tumors remain poorly understood. To identify genetic variants associated with neuroendocrine tumor risk, we first performed a large-scale assessment of common genetic variants in candidate cancer genes in a discovery set of cases and controls. We then sought to replicate these associations in an independent cohort of neuroendocrine tumor cases and controls.

METHODS: We designed an Illumina GoldenGate custom 1536 loci panel on a BeadArray chip (San Diego, CA) containing tagging and functional single nucleotide polymorphisms (SNPs) in 355 genes implicated in neuroendocrine tumors or in broader, established cancer-related signaling pathways. Using this panel, we evaluated potential risk associations in a discovery set of 274 cases and 329 controls. We then evaluated the top associated SNPs in an independent replication set of 235 neuroendocrine tumor cases and 113 controls using Sequenom iPlex. Subjects were all Caucasian in both sets. We evaluated potential risk associations using multiple logistic regression, after adjusting for the significant confounders of age and gender with the dominant model and test for trend.

RESULTS: Evaluation of 1536 SNPs in our discovery cohort revealed 18 SNPs with risk associations at a p-value&lt;0.01, including SNPs in genes TSC2, IL1RN, CYP1B1, FRAP1(mTOR), BIRC5, AKAP9, IL12A, BCL2, APAF1, DAD1, CASP7, MS4A6A, TERT, ADH1C, IFNGR2 and IL17RB. Evaluation of risk associations with these 18 SNPs in our independent replication cohort of cases and controls revealed that Il12A rs2243123 replicated with an aOR = 1.47 (1.03, 2.11) p-trend=0.036, which was similar to the aOR= 1.43 (1.08, 1.89) p-trend=0.011 in the initial discovery set. We also observed associations with DAD1 rs8005354, at aOR= 1.43 (1.02, 2.02) p-trend= 0.04, comparable to the value in the discovery set aOR=1.31 (1.03, 1.67) p-trend= 0.028. A prior association observed with TSC2 rs13337626 did not replicate, however we did observe an association with TSC2 rs8050755 at aOR =2.05 (1.13, 3.73) p-dominant =0.02, compared to the discovery set aOR=1.513 (1.047, 2.187) p-dominant=0.027. We evaluated whether these risk associations might differ in the subgroups of small bowel carcinoid and pancreatic neuroendocrine using a combined (discovery set + replication set) analysis. In the combined tumor subgroup analysis of 181 small bowel cases or 99 pancreatic NET vs. 432 controls, IL12A rs2243123 was associated with both small bowel (aOR= 1.40 (1.06, 1.84) p-trend=0.02) and pancreatic NET (aOR= 1.59 (1.14, 2.21) p-trend= 0.006), whereas DAD1 rs8005354 was associated only with small bowel NET (aOR= 1.33 (1.03, 1.71) p-trend=0.03) and TSC2 rs8050755 only with pancreatic NET (aOR=1.68 (1.13, 2.5) p-trend=0.01).

CONCLUSION: Our findings suggest that genetic variation in IL12A, DAD1, and TSC2 is associated with neuroendocrine tumor risk as shown in two independent cohorts.

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 929.