Genome-wide association study across pediatric central nervous system tumors implicates shared predisposition and points to 1q25.2 (PAPPA2) and 11p12 (LRRC4C) as novel candidate susceptibility loci

Abstract

Introduction Central nervous system (CNS) tumors constitute the most common form of solid neoplasms in children, but knowledge on genetic predisposition is sparse. In particular, whether susceptibility attributable to common variants is shared across CNS tumor types in children has not been investigated. The purpose of this study was to explore potential common genetic risk variants exhibiting pleiotropic effects across pediatric CNS tumors. We also investigated whether such susceptibility differs between early and late onset of disease. Method A Danish nationwide genome-wide association study (GWAS) of 1,097 consecutive patients (< 15 years of age) with CNS tumors and a cohort of 4,745 population-based controls. Results For both the overall cohort and patients diagnosed after the age of four, the strongest association was rs12064625 which maps to PAPPA2 at 1q25.2 (p = 3.400 × 10 −7 and 9.668 × 10 −8 , respectively). PAPPA2 regulates local bioavailability of insulinlike growth factor I (IGF-I). IGF-I is fundamental to CNS development and is involved in tumorigenesis across a wide range of different cancers. For the younger children, the strongest association was provided by rs11036373 mapping to LRRC4C at 11p12 (p = 7.620 × 10 −7), which encoded protein acts as an axon guidance molecule during CNS development and has not formerly been associated with brain tumors. Discussion This GWAS indicates shared susceptibility attributable to common variants across pediatric CNS tumor types. Variations in genetic loci with roles in CNS development appear to be involved, possibly via altered IGF-I related pathways.

Preliminary Study of Genome-Wide Association Identified Novel Susceptibility Genes for Hemorheological Indexes in a Chinese Population

“…SFMBT2 , a circRNA located on chromosome 10p14, had an increased expression level in gastric cancer tissues and was associated with the proliferation of gastric cancer cells [ 34 ]. LRRC4C (chromosome 11p12) was a novel candidate susceptibility gene for pediatric central nervous system tumors [ 35 ]. NELL1 (chromosome 11p15.1) was associated with bone formation and osteoclast differentiation [ 36 ], and ANO5 (chromosome 11p15.1) was related to myopathy.…”

Prognostic value of LRRC4C in Colon and Gastric Cancers correlates with Tumour Microenvironment Immunity

“…It has been shown to plays an important role in neural development and malignant transformation of glioma, and has been identified as a tumour suppressor gene for glioma 14 . Especially in recent years, there have been experiments to prove that LRRC4 is involved in nasopharyngeal carcinoma, pituitary adenoma and epithelial ovarian cancer 15 , 40 , 41 , and more importantly, a certain common germline variant in LRRC4C has been implicated in confer increased risk of developing tumors in the central nervous system during childhood 42 . Combined with our results, we have more reason to believe that LRRC4C is involved in the tumour progression of colon cancer and gastric cancer in a similar way to LRRC4.…”

Toward a methodology for evaluating DNA variants in nuclear families

“…Genome-wide association studies (GWAS) have identified novel cancer susceptibility loci for some pediatric cancer types [1][2][3][4]. However, in GWAS studies, the research participants are typically unrelated, and rare variants are not easily identified due to a lack of statistical power [5,6].…”