• Marilena De Mariano, Roberta Gallesio, Marco Chierici, Cesare Furlanello, Massimo Conte, Alberto Garaventa, Michela Croce, Silvano Ferrini, Gian Paolo Tonini, and Luca Longo.
• U.O.C. Bioterapie, IRCCS A.O.U. San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
• Oncotarget. 2015 Sep 22; 6 (28): 26335-46.

AbstractAlthough 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.

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