Takamichi Igarashi1,2, Kimihiro Shimizu3,4, Kengo Usui5, Takehiko Yokobori2,6,7, Yoichi Ohtaki2,8, Seshiru Nakazawa2,8, Kai Obayashi2,8, Toshiki Yajima2,8,6, Sumihito Nobusawa9, Takahiro Ohkawa5, Ryuji Katoh2, Yoko Motegi2, Hiroomi Ogawa2, Norifumi Harimoto1,2, Tatsuo Ichihara10, Yasumasa Mitani10, Hideaki Yokoo9, Akira Mogi2,8, Ken Shirabe1,2. 1. Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan. 2. Integrative Center of General Surgery, Gunma University Hospital, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan. 3. Integrative Center of General Surgery, Gunma University Hospital, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan. kmshimizu@gmail.com. 4. Division of General Thoracic Surgery, Department of General Surgical Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan. kmshimizu@gmail.com. 5. Genetic Diagnosis Technology Unit, RIKEN Center of Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. 6. Department of Innovative Cancer Immunotherapy, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan. 7. Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, 371-8511, Japan. 8. Division of General Thoracic Surgery, Department of General Surgical Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan. 9. Department of Human Pathology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan. 10. K.K. DNAFORM, 75-1 Ono-machi, Tsurumi-ku, Yokohama, Kanagawa, 230-0046, Japan.
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.
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 KRASG12D 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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