Mutational analysis of uterine cervical cancer that survived multiple rounds of radiotherapy
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Endang Nuryadi1,2,*, Yasushi Sasaki3,*, Yoshihiko Hagiwara1,*, Tiara Bunga Mayang Permata1,2, Hiro Sato1, Shuichiro Komatsu1, Yuya Yoshimoto1, Kazutoshi Murata1, Ken Ando1, Nobuteru Kubo1, Noriyuki Okonogi1, Yosuke Takakusagi1, Akiko Adachi1, Mototaro Iwanaga1, Keisuke Tsuchida1, Tomoaki Tamaki1, Shin-ei Noda1, Yuka Hirota1, Atsushi Shibata4, Tatsuya Ohno5, Takashi Tokino3, Takahiro Oike1 and Takashi Nakano1,5
1Department of Radiation Oncology, Gunma University Graduate School of Medicine, Gunma, Japan
2Department of Radiotherapy, Dr. Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia
3Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan
4Education and Research Support Center, Gunma University Graduate School of Medicine, Gunma, Japan
5Gunma University Heavy Ion Medical Center, Gunma, Japan
*These authors contributed equally to this work
Takahiro Oike, email: firstname.lastname@example.org
Keywords: uterine cervical cancer; radioresistance; next-generation sequencing; KRAS; SMAD4
Received: February 16, 2018 Accepted: August 04, 2018 Published: August 24, 2018
Radiotherapy is an essential component of cancer therapy. Despite advances in cancer genomics, the mutation signatures of radioresistant tumors have not yet been fully elucidated. To address this issue, we analyzed a unique set of clinical specimens from a uterine cervical cancer that repeatedly locally recurred after multiple rounds of radiotherapy. Exon sequencing of 409 cancer-related genes in the treatment-naïve tumor and the tumors that recurred after initial and secondary radiotherapy identified (i) activating mutations in PIK3CA and KRAS, and putative inactivating mutations in SMAD4, as trunk mutation signatures that persisted over the clinical course; and (ii) mutations in KMT2A, TET1, and NLRP1 as acquired mutation signatures observed only in recurrent tumors after radiotherapy. Comprehensive mining of published in vitro genomics data pertaining to radiosensitivity revealed that simultaneous mutations in KRAS and SMAD4, which have not been described previously in uterine cervical cancer, are associated with cancer cell radioresistance. The association between this mutation signature and radioresistance was validated by isogenic cell-based experiments. These results provide proof-of-principle for the analytical pipeline employed in this study, which explores clinically relevant mutation signatures for radioresistance, and demonstrate that this approach is worth pursuing with larger cohorts in the future.
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