Identification of GALNT14 as a novel neuroblastoma predisposition gene

Abstract

Although several genes have been associated to neuroblastoma (NB) predisposition and aggressiveness, further genes are likely involved in the overall risk of developing this pediatric cancer. We thus carried out whole-exome sequencing on germline DNA from two affected second cousins and two unlinked healthy relatives from a large family with hereditary NB. Bioinformatics analysis revealed 6999 variations that were exclusively shared by the two familial NB cases. We then considered for further analysis all unknown or rare missense mutations, which involved 30 genes. Validation and analysis of these variants led to identify a GALNT14 mutation (c.802C > T) that properly segregated in the family and was predicted as functionally damaging by PolyPhen2 and SIFT. Screening of 8 additional NB families and 167 sporadic cases revealed this GALNT14 mutation in the tumors of two twins and in the germline of one sporadic NB patient. Moreover, a significant association between MYCN amplification and GALNT14 expression was observed in both NB patients and cell lines. Also, GALNT14 higher expression is associated with a worse OS in a public dataset of 88 NB samples (http://r2.amc.nl). GALNT14 is a member of the polypeptide N-acetylgalactosaminyl-transferase family and maps closely to ALK on 2p23.1, a region we previously discovered in linkage with NB in the family here considered. The aberrant function of GALNTs can result in altered glycoproteins that have been associated to the promotion of tumor aggressiveness in various cancers. Although rare, the recurrence of this mutation suggests GALNT14 as a novel gene potentially involved in NB predisposition.

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

“…At present, the prevalence of NB in children harboring germline mutations in these other genes is unclear, but emerging data on individual genetic associations may result in consideration of NB screening among these populations in the future. Finally, GALNT14 gene mutations have been associated with NB predisposition in three individuals from two families (108). Aberrant function of galactosaminyltransferases has been associated with tumor aggressiveness in various cancers, suggesting that GALNT14 may be involved in NB predisposition or pathogenesis.…”

Critical Role of a Novel Biological Marker GALNT14 Expression in Different Cancer Types

“…We can see breast, ovarium, lungs and skin in previous researches [2][3][4][5]. It has also been associated with neuroblastoma and colorectal cancer in gene expression experiments performed [6,7]. GALNT14 expression is a potential biomarker for different cancers including breast cancer and it is likely to play a role in the regulation of apoptotic activity of insulin-like growth factor binding protein-3.…”

“…Overexpression of GALNT14 plays a critical role in cell migration, invasion and proliferation of breast cancer by stimulating the epithelial mesenchymal transition of breast cancer cells [6]. In addition, GALNT14 promotes self-renewal of cells in breast cancer and supports breast cancer cells to metastasize into the lung micro-environment by inhibiting the effect of lung-derived bone morphogenetic proteins.…”

“…GALNT14 increases migration by altering the proliferation rate of breast cancer cells and thus induce metastasis. Therefore, it has been suggested that this gene is a new therapeutic target for breast cancer [6].…”

The role of omics in neuroblastoma: Patient’s risk classification and personalised therapy

“…So far, all mutations identified are in the tyrosine kinase domain and result in constitutive autophosphorylation of the ALK protein. Recently, whole exome sequencing (WES) of germline DNA revealed GALNT14 as a novel gene that is potentially involved in neuroblastoma predisposition [17] . GALNT14 is a member of the polypeptide N-acetylgalactosaminyl transferase family and maps closely to ALK on 2p23.1, a region previously linked to neuroblastoma.…”