Abstract
Background
RAS/BRAF mutations of colorectal cancer (CRC) play a crucial role in carcinogenesis and cancer progression and need to be considered for the therapeutic strategy choice. We used next-generation-sequencing (NGS) technology to assess RAS/BRAF mutation differences between primary CRC and corresponding pulmonary metastases (PMs).
Methods
We examined the mutation statuses of the KRAS 12/13/61/146, NRAS 12/13/61/146, and BRAF 600 codons in genomic DNA from fresh-frozen or formalin-fixed paraffin-embedded tissues derived from 34 primary lesions and 52 corresponding PMs from 36 patients with CRC.
Results
We found RAS mutations in 76% (26/34) of primary CRC lesions and in 86% (31/36) of PMs. While 27% (7/26) of the primary CRC RAS mutations were heterogeneous, all the RAS mutations in PMs were homogeneous. Of the mutations in PMs, 71% (22/31) were KRAS G>A transitions, of which 82% (18/22) were KRAS G12D or G13D. The RAS mutation discordance between primary tumors and PMs was 12.1% (4/33). RAS mutations with the same genotyping were detected in all synchronous and metachronous PMs from 9 patients. We found no BRAF mutations in either primary or pulmonary tissues.
Conclusion
Our NGS analysis suggests that RAS mutations of PM of patients with CRC are more common than initially thought. The presence of KRAS mutations in CRC specimens, especially G12D or G13D mutations, seems to promote PM formation.
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Acknowledgements
We are grateful for the experimental support we received from Mr. Tatsuya Yamazaki, Mr. Masaki Shinohara, and Ms. Yuriha Iwata. We would also like to thank RIKEN GeNAS for amplicon sequencing analyses with the Illumina HiSeq2500 sequencer.
Funding
This work was supported by the Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science; Grant numbers 22590516 and 19390359, by the subsidy of expenses of the Minister of Economy, Trade and Industry, Japan for small business support, and by a Research Grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology to the RIKEN Center for Life Science Technologies.
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Igarashi, T., Shimizu, K., Usui, K. et al. Significance of RAS mutations in pulmonary metastases of patients with colorectal cancer. Int J Clin Oncol 25, 641–650 (2020). https://doi.org/10.1007/s10147-019-01582-z
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DOI: https://doi.org/10.1007/s10147-019-01582-z