With the purpose to evaluate the association between LIN28B gene polymorphisms and neuroblastoma susceptibility in Southern Chinese population, we conducted this study with 256 neuroblastoma cases and 531 cancer-free controls.
We also found that the combination of polymorphisms in CASC15, LIN28B, and LMO1 may be used to predict neuroblastoma risk (AUC=0.63, 95% CI=0.59-0.67).
Taken together, these data show that common variants in HACE1 and LIN28B influence neuroblastoma susceptibility and indicate that both genes likely have a role in disease progression.
In a genome-wide association study, we identified single-nucleotide polymorphisms (SNP) associated with neuroblastoma at the CASC15, BARD1, LMO1, DUSP12, HSD17B12, HACE1, and LIN28B gene loci, but these explain only a small fraction of neuroblastoma heritability.
Several neuroblastoma (NB) susceptibility loci have been identified within LINC00340, BARD1, LMO1, DUSP12, HSD17B12, DDX4, IL31RA, HACE1 and LIN28B by genome-wide association (GWA) studies including European American individuals.
Taken together, these data show that common variants in HACE1 and LIN28B influence neuroblastoma susceptibility and indicate that both genes likely have a role in disease progression.
Taken together, these data show that common variants in HACE1 and LIN28B influence neuroblastoma susceptibility and indicate that both genes likely have a role in disease progression.
For instance, discoveries in familial NBL have identified genetic aberrations in Phox2b and Alk that predispose to NBL, while advances in epigenetics and MYCN regulation have also offered insight into NBL pathogenesis and future treatment.
We did not find any conclusive association of the polymorphisms or mutations in PHOX2b with the development of NB, although the large confidence intervals neither substantiate nor exclude a role for this gene in the tumor etiology.
We also report a germline PHOX2B mutation in one patient treated for Hirschsprung's disease who subsequently developed a multifocal neuroblastoma in infancy.
Recent studies have shown that 1) PHOX2B is the main disease-causing gene for congenital central hypoventilation syndrome, an autosomal dominant disorder with incomplete penetrance; 2) PHOX2B is the first gene for which germline mutations have been demonstrated to predispose to neuroblastoma; and 3) Hirschsprung disease was associated with an intronic single-nucleotide polymorphism of the PHOX2B gene in a case-control study.
This case highlights the need to consider neuroblastoma in patients with CCHS and the longest PHOX2B PARMs and to individualize treatment based on co-morbidities.
Heterozygous germline mutations and deletions in PHOX2B, a key regulator of autonomic neuron development, predispose to neuroblastoma, a tumor of the peripheral sympathetic nervous system.
Consistent with its role as an important neurodevelopmental gene, forced overexpression of wild-type PHOX2B in neuroblastoma cell lines suppressed cell proliferation and synergized with all-trans retinoic acid to promote differentiation.
We undertook mutational analysis of the genes known to predispose to non-syndromic familial Wilms tumor (WT1) or neuroblastoma (PHOX2B, ALK) which excluded these as the underlying predisposition genes in the nine families.
Approximately 1-2% of neuroblastomas are inherited in an autosomal dominant fashion and a combination of co-morbidity and linkage studies has led to the identification of germline mutations in PHOX2B and ALK as the major genetic contributors to this familial neuroblastoma subset.
Our results suggest that certain PHOX2B variants associated with neuroblastoma pathogenesis, because of their inability to bind to key interacting proteins such as HPCAL1, may predispose to this malignancy by impeding the differentiation of immature sympathetic neurons.
Nevertheless, as only a few NB families but not others have been shown to carry PHOX2B mutations, the role of this gene in NB predisposition has still to be clarified.
Universal mass screening for neuroblastoma is not indicated but targeted screening of infants at risk of hereditary neuroblastoma with germline ALK or PHOX2B mutations is appropriate.
PHOX2B plays a key function in the development of neural crest derivatives, and heterozygous mutations cause a complex dysautonomia associating HSCR, Congenital Central Hypoventilation Syndrome (CCHS) and neuroblastoma (NB) in various combinations.
Furthermore, as PHOX2B mutations were mainly observed in some NB families with multifocal and syndromic NB, features that are missing in the families we have studied, we suggest they represent second-site modifications responsible for a specific phenotype rather than causal mutations of a major locus.