Mutational analysis of uterine cervical cancer that survived multiple rounds of radiotherapy

Endang Nuryadi, Yasushi Sasaki, Yoshihiko Hagiwara, Tiara Bunga Mayang Permata, Hiro Sato, Shuichiro Komatsu, Yuya Yoshimoto, Kazutoshi Murata, Ken Ando, Nobuteru Kubo, Noriyuki Okonogi, Yosuke Takakusagi, Akiko Adachi, Mototaro Iwanaga, Keisuke Tsuchida, Tomoaki Tamaki, Shin Ei Noda, Yuka Hirota, Atsushi Shibata, Tatsuya OhnoTakashi Tokino, Takahiro Oike, Takashi Nakano

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)32642-32652
Number of pages11
JournalOncotarget
Volume9
Issue number66
DOIs
Publication statusPublished - 2018 Aug 24
Externally publishedYes

Keywords

  • KRAS
  • Next-generation sequencing
  • Radioresistance
  • SMAD4
  • Uterine cervical cancer

ASJC Scopus subject areas

  • Oncology

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