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Mutation and copy number discordance in primary versus metastatic colorectal cancer (mCRC).
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2014
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EngineeringCancer PathologyFormalin-fixed TissueGeneticsPathologyTumor BiologyDiscordant ResultsMolecular ProfilingGenitourinary CancerTumor HeterogeneityCancer Cell BiologyMolecular DiagnosticsRadiation OncologyCancer ResearchMolecular OncologyCopy Number DiscordanceMedicineColorectal CancerCancer GeneticsMolecular MedicineNext-generation SequencingCancer GenomicsSystems BiologyOncology
3509 Background: Molecular profiling for CRC commonly utilizes formalin-fixed tissue of convenience, which may include tissue obtained from primary or metastatic tumors. While the alterations in KRAShave been shown to have a high degree of concordance, a detailed survey of other commonly mutated genes, copy number variations, and the influence of intervening treatment in CRC has not been conducted. Methods: Primary and metastatic tissue underwent sequencing on a 46 or 50-gene hotspot AmpliSeq panel (IonTorrent) in a CLIA-compliant setting. For a subset of patients, targeted resequencing of a panel of 202 genes by HiSeq 2000 (Illumina) to an average depth of 800 was performed by the MDACC Institute of Personalized Cancer Therapeutics, with single nucleotide variations and copy number called by in-house algorithms. Results: Sequencing was successfully completed on 115 pairs of primary and metastatic tumors (N=107 for 46/50-gene, and N=17 for 202-gene). Forty-six high level amplifications (>4 copies) were found in 28 genes in 11 of 17 pairs, with discordant results in all cases, including discordance in potentially clinically relevant amplifications: HER2, NOTCH1, FLT3, and AURKA. Overall concordance rate for mutations on the 46/50-gene panel was 78%, but varied substantially by gene. APC, TP53, NRAS, and BRAF demonstrated concordance similar to KRAS (89% concordance), while PIK3CA demonstrated a 6.8-fold higher odds of discordance between primary and metastatic site (95% CI of odds ratio (OR) of 2.1 to 22.6, P<0.001). Genes with low prevalence (<10%) such as FGFR3, STK11, and FBXW7 likewise had high levels of discordance (OR 4.4, 95% CI: 1.4 to 14.1, P=0.008). Intervening chemotherapy treatment was associated with a 3.5 fold higher odds of discordance across all genes compared to patients that did not receive therapy between resection of primary and metastatic tumors (95% CI 1.26 to 10.4, P=0.008), including KRAS, TP53, and PIK3CA(OR of 5.2, 3.5, and 3.3 respectively). Conclusions: Rates of discordance between primary and metastases mutations vary substantially by gene and prior treatment in mCRC. Prospective efforts to enrich for biomarkers need to account for tumor site and treatment variability on a gene-by-gene basis.