Sou Hirose1, Naoya Murakami2, Kazuaki Takahashi3, Ikumi Kuno4, Daisuke Takayanagi5, Yuka Asami6, Maiko Matsuda5, Yoko Shimada5, Shotaro Yamano7, Kuniko Sunami5, Kazushi Yoshida8, Takayuki Honda9, Tomomi Nakahara10, Tomoko Watanabe5, Masaaki Komatsu11, Ryuji Hamamoto11, Mayumi Kobayashi Kato4, Koji Matsumoto12, Kae Okuma2, Takafumi Kuroda3, Aikou Okamoto3, Jun Itami2, Takashi Kohno5, Tomoyasu Kato4, Kouya Shiraishi13, Hiroshi Yoshida14. 1. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan; Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan. 2. Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan. 3. Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan. 4. Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan. 5. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. 6. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan; Department of Obstetrics and Gynecology, Showa University School of Medicine, Tokyo, Japan. 7. Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Kanagawa, Japan. 8. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan; Department of Respiratory Medicine, The Jikei University School of Medicine, Tokyo, Japan. 9. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan; Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan. 10. Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, Tokyo, Japan. 11. Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, Tokyo, Japan; Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan. 12. Department of Obstetrics and Gynecology, Showa University School of Medicine, Tokyo, Japan. 13. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. Electronic address: kshirais@ncc.go.jp. 14. Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan. Electronic address: hiroyosh@ncc.go.jp.
Abstract
OBJECTIVE: Cervical cancer is the fourth most common cause of cancer-related deaths in Asian women, due to its poor prognosis. This study aimed to decipher genomic alteration profiles of a cohort of Japanese cervical cancer patients to understand why certain patients benefited from molecular targeted therapies and their prognostic significance. METHODS: During 2008-2018, 154 cervical cancer patients underwent a potentially curative resection procedure at the National Cancer Center Hospital. Genomic DNA samples were analyzed using Ion AmpliSeq™ Cancer Hotspot Panel v2. Alterations in the copy number of PIK3CA, ERBB2, PTEN, and STK11 were detected using the TaqMan assay. HPV-positive results were confirmed by genomic testing and in situ hybridization assay. RESULTS: The frequency of genomic alterations in PIK3CA (36%), STK11 (16%), PTEN (11%), TP53 (11%), and KRAS (8%) was >5%. KRAS mutations were preferentially detected in patients with adenocarcinomas, and the frequency of PIK3CA mutations in patients with squamous cell carcinomas was higher than that in patients with other histological cancer types. HPV-positive results were observed in 139/154 (90.3%) patients, and TP53 mutants were detected in HPV-negative specimens. In this study, the overall survival of patients with genomic alterations in STK11 was worse than in patients with wild-type STK11 (hazard ratio = 10.6, P = 0.0079) and TCGA dataset (hazard ratio = 2.46, P = 0.029). CONCLUSIONS: More than one-third of Japanese cervical cancer patients exhibit mutations targeted by molecular targeted therapies. We have proposed the prognostic value of STK11 genomic alterations.
OBJECTIVE:Cervical cancer is the fourth most common cause of cancer-related deaths in Asian women, due to its poor prognosis. This study aimed to decipher genomic alteration profiles of a cohort of Japanese cervical cancerpatients to understand why certain patients benefited from molecular targeted therapies and their prognostic significance. METHODS: During 2008-2018, 154 cervical cancerpatients underwent a potentially curative resection procedure at the National Cancer Center Hospital. Genomic DNA samples were analyzed using Ion AmpliSeq™ Cancer Hotspot Panel v2. Alterations in the copy number of PIK3CA, ERBB2, PTEN, and STK11 were detected using the TaqMan assay. HPV-positive results were confirmed by genomic testing and in situ hybridization assay. RESULTS: The frequency of genomic alterations in PIK3CA (36%), STK11 (16%), PTEN (11%), TP53 (11%), and KRAS (8%) was >5%. KRAS mutations were preferentially detected in patients with adenocarcinomas, and the frequency of PIK3CA mutations in patients with squamous cell carcinomas was higher than that in patients with other histological cancer types. HPV-positive results were observed in 139/154 (90.3%) patients, and TP53 mutants were detected in HPV-negative specimens. In this study, the overall survival of patients with genomic alterations in STK11 was worse than in patients with wild-type STK11 (hazard ratio = 10.6, P = 0.0079) and TCGA dataset (hazard ratio = 2.46, P = 0.029). CONCLUSIONS: More than one-third of Japanese cervical cancerpatients exhibit mutations targeted by molecular targeted therapies. We have proposed the prognostic value of STK11 genomic alterations.