Common variants in MMP20 at 11q22.2 predispose to 11q deletion and neuroblastoma risk

Xiao Chang,Cecilia Kim,Patrick Sleiman,Lee Mcdaniel,Kelly Thomas,Haijun Qiu,Zhi Wei,Zalman Vaksman,Sharon J Diskin,Yan Zhao,Maura Diamond ,Edward F Attiyeh,Yichuan Liu,Joseph T Glessner ,Cuiping Hou,Yiran Guo,Perry Evans,Jin Li,Frank Mentch ,John M Maris,Hákon Hákonarson

doi:10.1038/s41467-017-00408-8

Abstract

MYCN amplification and 11q deletion are two inversely correlated prognostic factors of poor outcome in neuroblastoma. Here we identify common variants at 11q22.2 within MMP20 that associate with neuroblastoma cases harboring 11q deletion (rs10895322), using GWAS in 113 European-American cases and 5109 ancestry-matched controls. The association is replicated in 44 independent cases and 1902 controls. Our study yields novel insights into the genetic underpinnings of neuroblastoma, demonstrating that the inherited common variants reported contribute to the origin of intra-tumor genetic heterogeneity in neuroblastoma.

Highlights

MYCN amplification and 11q deletion are two inversely correlated prognostic factors of poor outcome in neuroblastoma
MMP20 belongs to Matrix metalloproteinase (MMP) gene family, which is involved in tooth enamel formation and defects of MMP20 have been associated with amelogenesis imperfecta[16]
The lead SNP identified in our GWAS of 11q-deletion neuroblastoma, is the top SNP reported in the GWAS of neovascular lesion size in AMD17

Summary

Introduction

MYCN amplification and 11q deletion are two inversely correlated prognostic factors of poor outcome in neuroblastoma. We identify common variants at 11q22.2 within MMP20 that associate with neuroblastoma cases harboring 11q deletion (rs10895322), using GWAS in 113 European-American cases and 5109 ancestry-matched controls. The majority of neuroblastomas behave in highly malignant fashion, with widespread metastatic dissemination typical at the time of diagnosis. These “high-risk” neuroblastoma are characterized by genomic instability resulting in segmental chromosomal alterations and high-level amplification of the MYCN gene locus. These are prognostically relevant, with MYCN amplification (MNA), 11q deletion and 1p deletion currently used as biomarkers to assign therapy, but the mechanisms by which these chromosomal rearrangements arise remain obscure. Our study provides new insights into the genetic architecture of neuroblastoma subtypes and suggests directions for subset-specific therapeutic strategies

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Results

Conclusion