Paired Tumor and Normal Whole Genome Sequencing of Metastatic Olfactory Neuroblastoma

Glen J Weiss,Shripad Sinari,Shilpi Arora,Daniel D Von Hoff,Tyler Izatt,Raghu Metpally,Angela S Baker,Robert N Raju,Ahmet Kurdoglu,Lori Phillips,John D Carpten,Winnie S Liang,Galen Hostetter,David W Craig,Irene Cherni,Alexis Christoforides,Waibhav D Tembe,Hassan Ashktorab

doi:10.1371/journal.pone.0037029

Glen J Weiss, Shripad Sinari + Show 16 more

Open Access

https://doi.org/10.1371/journal.pone.0037029

Copy DOI

Abstract

BackgroundOlfactory neuroblastoma (ONB) is a rare cancer of the sinonasal tract with little molecular characterization. We performed whole genome sequencing (WGS) on paired normal and tumor DNA from a patient with metastatic-ONB to identify the somatic alterations that might be drivers of tumorigenesis and/or metastatic progression.Methodology/Principal FindingsGenomic DNA was isolated from fresh frozen tissue from a metastatic lesion and whole blood, followed by WGS at >30X depth, alignment and mapping, and mutation analyses. Sanger sequencing was used to confirm selected mutations. Sixty-two somatic short nucleotide variants (SNVs) and five deletions were identified inside coding regions, each causing a non-synonymous DNA sequence change. We selected seven SNVs and validated them by Sanger sequencing. In the metastatic ONB samples collected several months prior to WGS, all seven mutations were present. However, in the original surgical resection specimen (prior to evidence of metastatic disease), mutations in KDR, MYC, SIN3B, and NLRC4 genes were not present, suggesting that these were acquired with disease progression and/or as a result of post-treatment effects.Conclusions/SignificanceThis work provides insight into the evolution of ONB cancer cells and provides a window into the more complex factors, including tumor clonality and multiple driver mutations.

Highlights

Called esthesioneuroblastoma, olfactory neuroblastoma (ONB) is a rare cancer comprising 2% of all sinonasal tract tumors with an incidence of 0.4 cases per million [1]
Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal tract and data on its molecular characterization is limited
We found that specific mutations in KDR, MYC, SIN3B, and NLRC4 appear only in the metastatic setting, while mutations in TP53, TAOK2 and MAP4K2 were present in the previous samples

Summary

Introduction

Called esthesioneuroblastoma, olfactory neuroblastoma (ONB) is a rare cancer comprising 2% of all sinonasal tract tumors with an incidence of 0.4 cases per million [1]. ONB is thought to arise from sensory neuroepithelial olfactory cells typically found in the upper portion of the naval cavity [1] These tumors do not have a gender predilection and can occur at any age, but have a bimodal age distribution in the 2nd and 6th decades of life [1]. Its distinct immunoprofile includes loss of keratin expression, immunopositivity for neuroendocrine markers, and S100 positive cells surrounding the nests of tumor cells. Despite all these distinguishing features, the wide variability in these tumors can lead to difficulty in diagnosis [3]. While no standard chemotherapy exists for ONB, cisplatin and etoposide or doxorubicin, or vincristine with an alkylating agent are most commonly administered [5]. We performed whole genome sequencing (WGS) on paired normal and tumor DNA from a patient with metastatic-ONB to identify the somatic alterations that might be drivers of tumorigenesis and/or metastatic progression

Methods

Results

Conclusion