Comparative sequence analysis of patient-matched primary colorectal cancer, metastatic, and recurrent metastatic tumors after adjuvant FOLFOX chemotherapy

Kazuaki Harada,Hideaki Bando,Atsushi Ohtsu,Yoshito Komatsu,Wataru Okamoto,Katsuya Tsuchihara,Yasuyuki Kawamoto,Takayuki Yoshino,Riu Yamashita,Sachiyo Mimaki,Naoya Sakamoto,Satoshi Yuki

doi:10.1186/s12885-019-5479-6

Abstract

BackgroundIn the era of genome-guided personalized cancer treatment, we must understand chemotherapy-induced genomic changes in tumors. This study evaluated whether adjuvant FOLFOX chemotherapy modifies the mutational profile of recurrent colorectal cancer (CRC).MethodsWhole exome sequencing was performed on samples from primary CRC tumors, untreated metastatic tumors, and recurrent tumors following adjuvant FOLFOX chemotherapy. The samples were resected from four patients.ResultsThe number of mutations or the mutation spectrum in individual patients was nearly identical. Copy number variants persisted regardless of FOLFOX therapy administration. The genomic signature of oxaliplatin exposure (G > T/C > A, T > A/A > T) was not enriched after FOLFOX chemotherapy. Overlapping single nucleotide variants (SNVs) and indels remained in 26–65% of the patient-matched tumor samples. One patient harbored an AKT1 E17K mutation in the recurrent tumor, whereas PIK3CA E542K and E88Q mutations were detected in the primary and untreated metastatic tumor samples. Genes related to intracellular Ca2+ homeostasis were enriched among the genes uniquely mutated after FOLFOX chemotherapy.ConclusionsWe found that the mutation rates, mutation spectrum, and copy number variants were nearly identical regardless of the administration of FOLFOX therapy in the four CRC cases. The mutational discordance between the patient-matched tumor samples is likely caused by tumor heterogeneity and chemotherapy-induced clonal selection. These findings might be useful as pilot data for larger studies to clarify the changes in the mutational landscape induced by adjuvant FOLFOX chemotherapy.

Highlights

In the era of genome-guided personalized cancer treatment, we must understand chemotherapyinduced genomic changes in tumors
In this study, we performed whole exome sequencing on primary colorectal, metastatic, and recurrent tumor samples after adjuvant FOLFOX therapy to evaluate the influence of this cytotoxic chemotherapy regimen on the mutational profile of recurrent colorectal cancer (CRC)
In conclusion, our data showed that the mutation rates, mutation spectra, or copy number variant (CNV) were nearly identical between the primary tumor, pre-FOLFOX metastatic, and post-FOLFOX metastatic samples in four CRC cases

Summary

Introduction

In the era of genome-guided personalized cancer treatment, we must understand chemotherapyinduced genomic changes in tumors. This study evaluated whether adjuvant FOLFOX chemotherapy modifies the mutational profile of recurrent colorectal cancer (CRC). Combination chemotherapy with cytotoxic and molecular targeting agents has prolonged the survival time of patients with metastatic CRC. In the era Harada et al BMC Cancer (2019) 19:255 prognostic and predictive biomarkers or therapeutic targets have been explored. Extensive data sets of the mutational profiles of CRC have been generated [6], and large collaborations have created gene expression-based classifications that predict patient outcomes [7]. A previous exome sequencing study revealed that mutagenic chemotherapy regimens, such as adjuvant chemotherapy with the DNA-alkylating-like agent temozolomide to treat glioma, can induce new mutations and cause the malignant progression of recurrent tumors [9]

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