A functional landscape for chromosome 17q in neuroblastoma: balancing replication stress and genomic stability.

Abstract

Neuroblastoma is characterised by extensive genomic instability despite a marked paucity of recurrent somatic mutations. Instead, the disease is predominantly driven by chromosomal alterations, including segmental chromosomal imbalances, small structural variants, and oncogene amplification. A major unmet challenge is identifying key oncogenic drivers, beyond MYCN amplification, hidden within these recurrent DNA copy number alterations. Extra wild-type gene copies can alter expression levels and thus contribute to tumour development and affect survival. Increasing evidence suggests that these copy number-affected genes confer resistance to replication stress, a hallmark of high-risk neuroblastoma tumours. Among the most frequent and prognostically significant alterations is the gain of chromosome 17q. In this review, we discuss selected top-ranked candidate genes on 17q implicated in replication fork dynamics and DNA damage repair that we previously identified through an integrative functional genomics study. Improved understanding of the mechanisms by which 17q copy number-driven genes regulate replication stress responses and DNA damage repair may expose fundamental vulnerabilities in aggressive neuroblastoma and guide the development of novel targeted therapeutic strategies.