Research Papers:

Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

Vito Alessandro Lasorsa, Daniela Formicola, Piero Pignataro, Flora Cimmino, Francesco Maria Calabrese, Jaume Mora, Maria Rosaria Esposito, Marcella Pantile, Carlo Zanon, Marilena De Mariano, Luca Longo, Michael D. Hogarty, Carmen de Torres, Gian Paolo Tonini, Achille Iolascon and Mario Capasso _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:21840-21852. https://doi.org/10.18632/oncotarget.8187

Metrics: PDF 2728 views  |   HTML 4011 views  |   ?  


Vito Alessandro Lasorsa1,2, Daniela Formicola1,2, Piero Pignataro1,2, Flora Cimmino1,2, Francesco Maria Calabrese3, Jaume Mora4, Maria Rosaria Esposito5, Marcella Pantile5, Carlo Zanon5, Marilena De Mariano6, Luca Longo6, Michael D. Hogarty7, Carmen de Torres4, Gian Paolo Tonini5, Achille Iolascon1,2 and Mario Capasso1,2,8

1 University of Naples Federico II, Department of Molecular Medicine and Medical Biotechnology, Naples, Italy

2 CEINGE Biotecnolgie Avanzate, Naples, Italy

3 University of Bari, Department of Biology, Bari, Italy

4 Hospital Sant Joan de Déu, Developmental Tumor Biology Laboratory and Department of Oncology, Esplugues de Llobregat, Barcelona, Spain

5 Pediatric Research Institute (IRP), Fondazione Città della Speranza, Neuroblastoma Laboratory, Padua, Italy

6 U.O.C. Bioterapie, IRCCS AOU San Martino-IST, National Cancer Research Institute, Genoa, Italy

7 Children’s Hospital of Philadelphia, Division of Oncology, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America

8 IRCCS SDN, Istituto di Ricerca Diagnostica e Nucleare, Naples, Italy


Mario Capasso, email:

Flora Cimmino, email:

Keywords: NGS, neuroblastoma, high risk, somatic mutation, cancer driver genes

Received: December 22, 2015 Accepted: February 09, 2016 Published: March 18, 2016


The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma.

Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines.

We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK.

Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%.

Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression.

Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants.

In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 8187