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PLoS Genet. 2017 May 18;13(5):e1006787. doi: 10.1371/journal.pgen.1006787. eCollection 2017 May.

Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma.

McDaniel LD1,2, Conkrite KL1,2, Chang X3, Capasso M4,5,6, Vaksman Z1,2,7, Oldridge DA1,2,8, Zachariou A9, Horn M1,2, Diamond M1,2, Hou C3, Iolascon A4,5, Hakonarson H3,10,11, Rahman N9, Devoto M10,11,12,13, Diskin SJ1,2,7,10,14.

Author information

1
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
2
Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
3
The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
4
University of Naples Federico II, Naples, Italy.
5
Ceinge-Biotecnologie Avanzate, Naples, Italy.
6
IRCCS SDN, Istituto di Ricerca Diagnostica e Nucleare, Naples, Italy.
7
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
8
Medical Scientist Training Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America.
9
Division of Genetics and Epidemiology, Institute of Cancer Research, London, United Kingdom.
10
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
11
Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
12
University of Rome "La Sapienza", Department of Molecular Medicine, Rome, Italy.
13
Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
14
Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America.

Abstract

Neuroblastoma is a cancer of the developing sympathetic nervous system that most commonly presents in young children and accounts for approximately 12% of pediatric oncology deaths. Here, we report on a genome-wide association study (GWAS) in a discovery cohort or 2,101 cases and 4,202 controls of European ancestry. We identify two new association signals at 3q25 and 4p16 that replicated robustly in multiple independent cohorts comprising 1,163 cases and 4,396 controls (3q25: rs6441201 combined P = 1.2x10-11, Odds Ratio 1.23, 95% CI:1.16-1.31; 4p16: rs3796727 combined P = 1.26x10-12, Odds Ratio 1.30, 95% CI: 1.21-1.40). The 4p16 signal maps within the carboxypeptidase Z (CPZ) gene. The 3q25 signal resides within the arginine/serine-rich coiled-coil 1 (RSRC1) gene and upstream of the myeloid leukemia factor 1 (MLF1) gene. Increased expression of MLF1 was observed in neuroblastoma cells homozygous for the rs6441201 risk allele (P = 0.02), and significant growth inhibition was observed upon depletion of MLF1 (P < 0.0001) in neuroblastoma cells. Taken together, we show that common DNA variants within CPZ at 4p16 and upstream of MLF1 at 3q25 influence neuroblastoma susceptibility and MLF1 likely plays an important role in neuroblastoma tumorigenesis.

PMID:
28545128
PMCID:
PMC5456408
DOI:
10.1371/journal.pgen.1006787
[Indexed for MEDLINE]
Free PMC Article
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