Rare Tumor-Normal Matched Whole Exome Sequencing Identifies Novel Genomic Pathogenic Germline and Somatic Aberrations.

Ryan Sprissler,Hani M Babiker,Michael Hammer,Bryce Perkins,Pavani Chalasani,Laurel Johnstone,Daruka Mahadevan,Branden Lau

doi:10.3390/cancers12061618

Ryan Sprissler, Hani M Babiker + Show 6 more

Open Access

https://doi.org/10.3390/cancers12061618

Copy DOI

Abstract

Whole exome sequencing (WES) of matched tumor-normal pairs in rare tumors has the potential to identify genome-wide mutations and copy number alterations (CNAs). We evaluated 27 rare cancer patients with tumor-normal matching by WES and tumor-only next generation sequencing (NGS) as a comparator. Our goal was to: 1) identify known and novel variants and CNAs in rare cancers with comparison to common cancers; 2) examine differences between germline and somatic variants and how that functionally impacts rare tumors; 3) detect and characterize alleles in biologically relevant genes-pathways that may be of clinical importance but not represented in classical cancer genes. We identified 3343 germline single nucleotide variants (SNVs) and small indel variants—1670 in oncogenes and 1673 in tumor suppressor genes—generating an average of 124 germline variants/case. The number of somatic SNVs and small indels detected in all cases was 523:306 in oncogenes and 217 in tumor suppressor genes. Of the germline variants, six were identified to be pathogenic or likely pathogenic. In the 27 analyzed rare cancer cases, CNAs are variable depending on tumor type, germline pathogenic variants are more common. Cell fate pathway mutations (e.g., Hippo, Notch, Wnt) dominate pathogenesis and double hit (mutation + CNV) represent ~18% cases.

Highlights

Genomic analysis of tumors has dramatically reshaped cancer treatment through the identification of genetic variants that provide diagnostic and prognostic information and that aid in therapeutic selection [1]
There were 23 different rare cancer types represented in our survey, all of which met the criteria of a rare cancer (Figure 1)
Using the Whole exome sequencing (WES) data, we detected a total of 3343 germline single nucleotide variants (SNVs) and small indel variants

Summary

Introduction

Genomic analysis of tumors has dramatically reshaped cancer treatment through the identification of genetic variants that provide diagnostic and prognostic information and that aid in therapeutic selection [1]. Patients with rare cancers generally present with advanced disease and for most there is no standard of care therapy. This results in poor 5-year survival rates compared with the more common cancers [2]. While rare tumors are individually infrequent, combined together they comprise nearly 25% of all cancer cases [3]. We follow the stricter guidelines of the European tumor classification group (RARECARE) of less than 6 per 100,000 per year [4]. The low frequency of these cases presents unique challenges in pathological classification, presentation and progression of disease and by extension, therapeutic options for clinical management

Objectives

Methods

Results

Discussion

Conclusion