Yuya Yoshimoto1, Yasushi Sasaki2, Kazutoshi Murata3, Shin-Ei Noda4, Yuhei Miyasaka3, Junko Hamamoto5, Mio Furuya6, Junko Hirato7, Yoshiyuki Suzuki8, Tatsuya Ohno3, Takashi Tokino9, Takahiro Oike10, Takashi Nakano11. 1. Department of Radiation Oncology, Gunma Graduate School of Medicine, Maebashi, Japan; Department of Radiation Oncology, School of Medicine, Fukushima Medical University, Fukushima, Japan. 2. Center for Medical Education, Sapporo Medical University, Sapporo, Japan. 3. Department of Radiation Oncology, Gunma Graduate School of Medicine, Maebashi, Japan. 4. Department of Radiation Oncology, Saitama Medical University International Medical Center, Saitama, Japan. 5. Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan. 6. Department of Pathology, Maebashi Red Cross Hospital, Maebashi, Japan; Department of Pathology, Gunma University Hospital, Maebashi, Japan. 7. Department of Pathology, Gunma University Hospital, Maebashi, Japan; Department of Pathology, Public Tomioka General Hospital, Maebashi, Japan. 8. Department of Radiation Oncology, School of Medicine, Fukushima Medical University, Fukushima, Japan. 9. Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan. 10. Department of Radiation Oncology, Gunma Graduate School of Medicine, Maebashi, Japan. Electronic address: oiketakahiro@gmail.com. 11. Department of Radiation Oncology, Gunma Graduate School of Medicine, Maebashi, Japan; National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
Abstract
OBJECTIVE: To elucidate tumor mutation profiles associated with outcomes of uterine cervical cancer (UCC) patients treated with definitive radiotherapy. METHODS: Ninety-eight patients with newly diagnosed and pathologically confirmed UCC (82 squamous cell carcinomas, 12 adenocarcinomas, and four adenosquamous carcinomas) who were treated with definitive radiotherapy were analyzed. DNA was extracted from pre-treatment tumor biopsy specimens. The exons of 409 cancer-related genes were sequenced using a next-generation sequencer. Genetic mutations were identified and analyzed for correlations with clinical outcome. RESULTS: Recurrent mutations were observed in PIK3CA (35.7%), ARID1A (25.5%), NOTCH1 (19.4%), FGFR3 (16.3%), FBXW7 (19.4%), TP53 (13.3%), EP300 (12.2%), and FGFR4 (10.2%). The prevalence of mutations in FGFR family genes (i.e., FGFR1-4) was almost as high (24.5%) as that in PIK3CA and ARID1A, both of which are well-studied drivers of UCC. Fifty-five percent (21 of 38) of the identified FGFR mutations were located in the FGFR protein tyrosine kinase domain. Five-year progression-free survival (PFS) rates for FGFR mutation-positive patients (n = 24) were significantly worse than those for FGFR mutation-negative patients (n = 74) (43.9% vs. 68.5%, respectively; P = 0.010). Multivariate analysis identified FGFR mutations as significant predictors of worse 5 year PFS (P = 0.005), independent of clinicopathological variables. CONCLUSIONS: FGFR mutations are associated with worse PFS in UCC patients treated with definitive radiotherapy. These results warrant further validation in prospective studies.
OBJECTIVE: To elucidate tumor mutation profiles associated with outcomes of uterine cervical cancer (UCC) patients treated with definitive radiotherapy. METHODS: Ninety-eight patients with newly diagnosed and pathologically confirmed UCC (82 squamous cell carcinomas, 12 adenocarcinomas, and four adenosquamous carcinomas) who were treated with definitive radiotherapy were analyzed. DNA was extracted from pre-treatment tumor biopsy specimens. The exons of 409 cancer-related genes were sequenced using a next-generation sequencer. Genetic mutations were identified and analyzed for correlations with clinical outcome. RESULTS: Recurrent mutations were observed in PIK3CA (35.7%), ARID1A (25.5%), NOTCH1 (19.4%), FGFR3 (16.3%), FBXW7 (19.4%), TP53 (13.3%), EP300 (12.2%), and FGFR4 (10.2%). The prevalence of mutations in FGFR family genes (i.e., FGFR1-4) was almost as high (24.5%) as that in PIK3CA and ARID1A, both of which are well-studied drivers of UCC. Fifty-five percent (21 of 38) of the identified FGFR mutations were located in the FGFR protein tyrosine kinase domain. Five-year progression-free survival (PFS) rates for FGFR mutation-positive patients (n = 24) were significantly worse than those for FGFR mutation-negative patients (n = 74) (43.9% vs. 68.5%, respectively; P = 0.010). Multivariate analysis identified FGFR mutations as significant predictors of worse 5 year PFS (P = 0.005), independent of clinicopathological variables. CONCLUSIONS: FGFR mutations are associated with worse PFS in UCC patients treated with definitive radiotherapy. These results warrant further validation in prospective studies.
Authors: Giulia Petroni; Lewis C Cantley; Laura Santambrogio; Silvia C Formenti; Lorenzo Galluzzi Journal: Nat Rev Clin Oncol Date: 2021-11-24 Impact factor: 66.675