Molecular and genetic studies in high-risk neuroblastoma

• Neuroblastoma is the most common and deadly cancer in the first year of life. Children with high-risk neuroblastoma have a very poor prognosis, despite heavy multimodal treatment, with less than 50% of 5 years of overall survival. Unfortunately, between 50-60% of high-risk neuroblastoma patients will eventually suffer a relapse with a survival rate of less than 10%. For this reason, a better understanding of the interplay between genetic abnormalities within the nervous system context is necessary to improve patient stratification or aid therapeutic strategies that can ultimately lead to increased patient survival. In order to find molecular profiles that predispose to development of high-risk neuroblastoma or contribute to the relapse, metastatic or non-responsive status of the tumor, we performed comprehensive molecular characterization of neuroblastoma tumors and cell lines by SNP-microarrays and next generation sequencing techniques in combination with functional exploration of novel recurrent somatic aberrations. Through our large-scale studies, we confirmed the genetic stability of neuroblastoma PDOXs over serial passaging, explored intra-tumoral heterogeneity of neuroblastoma and monitored a set of primary/relapsed neuroblastoma tumors, highlighting the recurrence of alterations of MAPK signaling, cell cycle progression and telomere activity pathways. Furthermore, we detected and investigated a recurrent structural alteration in LSAMP which appears to be a tumor suppressor gene in neuroblastoma. We also characterized a highly aggressive subgroup of neuroblastoma tumors, which presented a high-grade amplification of two loci at 12q, and our in vitro results indicated possible tumor inhibition routes through CDK4 and MDM2 inhibition. To conclude, genome-wide analyses with powerful techniques, such as next generation sequencing, are useful not only for research purposes but also as a clinical tool.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

Cancer

neural crest

neuroblastoma

heterogeneity

relapse

sequencing

CNVs

SVs

SNVs

LSAMP

CDK4

MDM2

Publikations- och innehållstyp

vet (ämneskategori)

dok (ämneskategori)