Abstract 4871: New neuroblastoma susceptibility loci at 6q21 within HACE1 and LIN28B
Authors: Diskin Sharon J. , Capasso Mario , Latorre Valaria , Schnepp Robert , Attiyeh Edward F. , Diamond Maura , Hou Cuiping , Carpenter Erica L. , Lee Hanna , Cole Kristina A. , Asgharzadeh Shahab , Hakonarson Hakon , Devoto Marcella , Maris John M. 
Published: August 2012

Neuroblastoma is a cancer of the sympathetic nervous system that most commonly affects young children and accounts for approximately 10% of all pediatric oncology deaths. We have reported common SNPs associated with neuroblastoma within LINC00340 at 6p22 (NEJM 2008), BARD1 at 2q35 (Nature Genetics, 2009), LMO1 at 11p15 (Nature, 2010), DUSP12 at 1q23 (PLoS Genetics, 2011), and HSD17B12 at 11p11 (PLoS Genetics, 2011), and one common CNV at 1q21.1 within NBPF23 (Nature, 2009). We have further demonstrated that germline variation in LMO1 and BARD1 not only predisposes to neuroblastoma, but also plays an important role in tumor progression. To identify additional genetic risk factors for neuroblastoma, we expanded our previous genome-wide association study (GWAS) to include 2,841 patients and 7,482 control subjects from three independent case series including two cohorts of European ancestry and one African American cohort. Here, we report two new associations at 6q21, the first within the HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 gene (HACE1; rs4336470 combined P = 3.4 x 10−12; Odds Ratio: 1.27, 95% CI: 1.19-1.36), and the second within lin-28 homolog B (LIN28B; rs17065417 combined P = 8.4 x 10−9; Odds Ratio 1.38, 95% CI: 1.23-1.54). HACE1 is implicated in multiple human cancers as a critical tumor suppressor gene (Nature Genetics, 2009). LIN28B, on the other hand, acts as a repressor of the let-7 family of miRNA, is over-expressed in many human cancers, and promotes cellular transformation (Nature Genetics, 2009). More recently, LIN28B has also been identified as a key regulator of glucose homeostasis (Cell, 2011). Neuroblastoma cell lines homozygous for the LIN28B risk allele showed increased LIN28B mRNA and protein expression and down regulation of the let-7 family of micro RNAs, consistent with the risk allele conferring a growth advantage through increased LIN28B expression. Transcriptome analysis of 251 primary tumors showed that HACE1 is down regulated (p = 3.5 x 10−4) and LIN28B is up-regulated (P = 0.017) in high-risk neuroblastomas compared to more benign forms of the disease. Tumors over-expressing LIN28B showed increased activation of DNA damage response (P = 2.5 x 10−19) and metabolism (P = 3.5 x 10−25) pathways, independent of MYCN amplification. Taken together, we show that common DNA variants in HACE1 and LIN28B influence neuroblastoma susceptibility and our expression analyses suggest that both genes may play an important role in disease progression. Efforts are ongoing to understand the mechanism by which LIN28B and HACE1 influence neuroblastoma tumorigenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4871. doi:1538-7445.AM2012-4871