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

BMC Cancer

Wataru Okamoto¹  Hideaki Bando²  Satoshi Yuki³  Naoya Sakamoto³  Yasuyuki Kawamoto³  Kazuaki Harada³  Takayuki Yoshino⁴  Katsuya Tsuchihara⁵  Riu Yamashita⁵  Sachiyo Mimaki⁵  Yoshito Komatsu⁶  Atsushi Ohtsu⁷ 

[1] Biobank Translational Research Support Section, Translational Research Management Division, Clinical Research Support Office, National Cancer Center Hospital East;Department of Drug Therapy, Aichi Cancer Center;Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University;Department of Gastrointestinal Oncology, National Cancer Center Hospital East;Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center;Hokkaido University Hospital Cancer Center, Kita 14;National Cancer Center Hospital East;

关键词: Colorectal cancer;    Whole exome sequencing;    Mutagenicity;    Adjuvant chemotherapy;    Chemo-resistance;   

DOI  :  10.1186/s12885-019-5479-6

来源: DOAJ

【 摘 要 】

Abstract Background In 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). Methods Whole 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. Results The 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. Conclusions We 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.

【 授权许可】

Unknown