Abstract
Whole exome sequencing (WES), targeted gene panel sequencing and single nucleotide polymorphism (SNP) arrays are increasingly used for the identification of actionable alterations that are critical to cancer care. Here, we compared The Cancer Genome Atlas (TCGA) and the Genomics Evidence Neoplasia Information Exchange (GENIE) breast cancer genomic datasets (array and next generation sequencing (NGS) data) in detecting genomic alterations in clinically relevant genes. We performed an in silico analysis to determine the concordance in the frequencies of actionable mutations and copy number alterations/aberrations (CNAs) in the two most common breast cancer histologies, invasive lobular and invasive ductal carcinoma. We found that targeted sequencing identified a larger number of mutational hotspots and clinically significant amplifications that would have been missed by WES and SNP arrays in many actionable genes such as PIK3CA, EGFR, AKT3, FGFR1, ERBB2, ERBB3 and ESR1. The striking differences between the number of mutational hotspots and CNAs generated from these platforms highlight a number of factors that should be considered in the interpretation of array and NGS-based genomic data for precision medicine. Targeted panel sequencing was preferable to WES to define the full spectrum of somatic mutations present in a tumor.
Highlights
A comprehensive understanding of potentially actionable genomic aberrations in tumor samples is important in guiding precision medicine for clinical decision-making
The clinical characteristics including age, race, ethnicity, tumor grade and hormone receptor status were compared between The Cancer Genome Atlas (TCGA) and Genomics Evidence Neoplasia Information Exchange (GENIE) breast cancer invasive lobular carcinomas (ILC) and invasive ductal carcinomas (IDC) patients (Table 1)
The results showed that there was inconsistency in the genomic alterations in the GENIE and TCGA datasets
Summary
A comprehensive understanding of potentially actionable genomic aberrations in tumor samples is important in guiding precision medicine for clinical decision-making. Several technical issues need to be addressed before implementing NGS results into clinical practice These include consideration of the downstream molecular analysis of: degraded DNA extracted from formalin-fixed, paraffin-embedded (FFPE) specimens, limited amounts of fresh tissue, the degree of stromal cellularity, and variation in the sequencing depth and capture efficiency. These challenges limit the ability to identify clinically relevant aberrations present in cancer cell subpopulations[7,10,11]. The objective of our study was to investigate which platform (array versus WES and targeted panel sequencing) was most sensitive in identifying clinically significant genomic alterations using the TCGA and GENIE datasets for non-metastatic breast cancer patients
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