Sự kết hợp giữa đột biến trình tự TERT và trạng thái methyl hóa MGMT dự đoán các phân nhóm lâm sàng có ý nghĩa của glioblastoma mới được chẩn đoán

Hideyuki Arita1,2, Kai Yamasaki3,1, Yuko Matsushita4,1, Taishi Nakamura1,5, Asanao Shimokawa6, Hirokazu Takami7,1, Shota Tanaka7, Akitake Mukasa7, Mitsuaki Shirahata8, Saki Shimizu9, Kaori Suzuki9, Kuniaki Saito9, Keiichi Kobayashi9, Fumi Higuchi10, Takeo Uzuka10, Ryohei Otani10, Kaoru Tamura11, Kazutaka Sumita11, Makoto Ohno4, Yasuji Miyakita4, Naoki Kagawa2, Naoya Hashimoto2, Ryusuke Hatae12, Koji Yoshimoto12, Naoki Shinojima13, Hideo Nakamura13, Yonehiro Kanemura14,15, Yoshiko Okita15, Manabu Kinoshita16, Kenichi Ishibashi17, Tomoko Shofuda18, Yoshinori Kodama19, Kanji Mori20, Yusuke Tomogane21, Junya Fukai22, Koji Fujita22, Yuzo Terakawa23, Naohiro Tsuyuguchi23, Shusuke Moriuchi24, Masahiro Nonaka15, Hiroyoshi Suzuki25, Makoto Shibuya26, Taketoshi Maehara11, Nobuhito Saito7, Motoo Nagane9, Nobutaka Kawahara5, Keisuke Ueki10, Toshiki Yoshimine2, Etsuo Miyaoka6, Ryo Nishikawa8, Takashi Komori27, Yoshitaka Narita4, Koichi Ichimura1
1Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan
2Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
3Department of Pediatric Hematology and Oncology, Osaka City General Hospital, Osaka, Japan
4Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan
5Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
6Department of Mathematics Faculty of Science, Tokyo University of Science, Tokyo, Japan
7Department of Neurosurgery, The University of Tokyo, Tokyo, Japan
8Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan
9Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan
10Department of Neurosurgery, Dokkyo Medical University, Tochigi, Japan
11Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan
12Department of Neurosurgery, Kyushu University Graduate School of Medical Science, Fukuoka, Japan
13Department of Neurosurgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
14Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan
15Department of Neurosurgery, National Hospital Organization Osaka National Hospital, Osaka, Japan
16Department of Neurosurgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
17Department of Neurosurgery, Osaka City General Hospital, Osaka, Japan
18Division of Stem Cell Research, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan
19Central Laboratory and Surgical Pathology, Osaka National Hospital, National Hospital Organization, Osaka, Japan
20Department of Neurosurgery, Kansai Rosai Hospital, Hyogo, Japan
21Department of Neurosurgery, Hyogo College of Medicine, Hyogo, Japan
22Department of Neurological Surgery, Wakayama Medical University, Wakayama, Japan
23Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan
24Department of Neurosurgery, Rinku General Medical Center, Izumisano, Japan
25Department of Pathology and Laboratory Medicine, National Hospital Organization, Sendai Medical Center, Sendai, Japan
26Central Laboratory, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan
27Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, Tokyo, Japan

Tóm tắt

Tác động dự đoán của các đột biến TERT còn gây tranh cãi trong các khối u IDH-hoang dã, đặc biệt là trong glioblastoma (GBM). Tranh cãi này có thể do sự hiện diện của các yếu tố gây nhiễu tiềm tàng như trạng thái methyl hóa MGMT hoặc phương pháp điều trị của bệnh nhân. Nghiên cứu này nhằm đánh giá tác động của trạng thái TERT đến kết quả của bệnh nhân trong mối liên hệ với nhiều yếu tố trong một loạt bệnh nhiễm glioma khuếch tán ở người lớn. Chúng tôi đã phân tích tổng cộng 951 glioma khuếch tán ở người lớn từ hai nhóm (Nhóm 1, n = 758; Nhóm 2, n = 193) về trạng thái IDH1/2, 1p/19q và TERT. Phân loại IDH/TERT kết hợp đã chia Nhóm 1 thành bốn nhóm phân tử với các kết quả khác nhau. Thời gian sống toàn bộ (OS) ở nhóm hoang dã IDH/đột biến TERT là ngắn nhất, chủ yếu bao gồm các GBM (P < 0.0001). Để điều tra mối liên quan giữa các đột biến TERT và methyl hóa MGMT đối với sự sống sót của bệnh nhân GBM, các mẫu từ một nhóm hợp nhất gồm 453 trường hợp GBM IDH-hoang dã được điều trị bằng xạ trị và temozolomide đã được phân tích. Một mô hình hồi quy Cox đa biến cho thấy rằng sự tương tác giữa TERT và MGMT có ý nghĩa đối với OS (P = 0.0064). So với các GBM đột biến TERT không methyl hóa MGMT, tỷ lệ rủi ro (HR) về OS kết hợp tương tác là thấp nhất ở GBM đột biến TERT có methyl hóa MGMT (HR, 0.266), tiếp đến là GBM kiểu hoang dã TERT có methyl hóa MGMT (HR, 0.317) và các GBM kiểu hoang dã TERT không methyl hóa MGMT (HR, 0.542). Do đó, bệnh nhân có GBM đột biến TERT và không methyl hóa MGMT có tiên lượng kém nhất. Những phát hiện của chúng tôi cho thấy sự kết hợp giữa IDH, TERT và MGMT tinh chỉnh phân loại các glioma khuếch tán loại II-IV.

Từ khóa

#glioblastoma #TERT mutation #MGMT methylation #prognosis #IDH-wild-type

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