Yuka Kuroda1, Tatsuyuki Chiyoda2, Miho Kawaida3, Kohei Nakamura4, Eriko Aimono4, Takuma Yoshimura1, Mio Takahashi1, Keiko Saotome5, Tomoko Yoshihama1, Naomi Iwasa6, Kensuke Sakai1, Wataru Yamagami1, Hiroshi Nishihara4, Daisuke Aoki1. 1. Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan. 2. Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan. Electronic address: chiyoda@keio.jp. 3. Department of Pathology, Keio University School of Medicine, Tokyo, Japan. 4. Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan. 5. Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan; Department of Obstetrics and Gynecology, Eiju Generel Hospital, Tokyo, Japan. 6. Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan; Department of Obstetrics and Gynecology, National Hospital Organization Saitama Hospital, Saitama, Japan.
Abstract
OBJECTIVES: ARID1A mutation is frequently found in clear cell ovarian cancer (CCC) and endometrioid ovarian cancer (EC). Anti-PD-1 monotherapy has been found to have limited efficacy in epithelial ovarian cancer; however, anti-PD-1 therapy showed significant clinical benefit in some CCC. We sought to define the relationship of ARID1A mutation/ARID1A expression to the immunogenic profile of different histologic subtypes of ovarian cancer. METHODS: We performed next-generation sequencing of 160 cancer-related genes. Also, we analyzed the immunohistochemical status of ARID1A, PD-L1, and CD8 with survival in different histologic subtypes of ovarian cancer in a total of 103 cases. RESULTS: ARID1A mutation was found in 0% of the high-grade serous ovarian cancer (HGSC) (n = 36), 41.5% of the CCC (n = 41), 45.0% of the EC (n = 20), and 33.3% of the mucinous ovarian cancer (MC) (n = 6) cases. ARID1A loss was found in 19.4% of the HGSC, 75.6% of the CCC, 60.0% of the EC and 0% of the MC cases. ARID1A mutation was found to be associated with high PD-L1 (p < 0.001) or CD8 levels (p < 0.001) in CCC but not in other histologic subtypes. Meanwhile, ARID1A loss was associated with high PD-L1 or CD8 levels in CCC (p < 0.001) and HGSC (p < 0.001) but not in EC and MC. In addition, ARID1A mutation was associated with high tumor mutation burden in CCC (p = 0.006). CONCLUSIONS: ARID1A mutation/ARID1A expression is associated with immune microenvironmental factors in CCC but not in EC. ARID1A status can be a biomarker for selecting candidates for immune checkpoint blockade in CCC.
OBJECTIVES: ARID1A mutation is frequently found in clear cell ovarian cancer (CCC) and endometrioid ovarian cancer (EC). Anti-PD-1 monotherapy has been found to have limited efficacy in epithelial ovarian cancer; however, anti-PD-1 therapy showed significant clinical benefit in some CCC. We sought to define the relationship of ARID1A mutation/ARID1A expression to the immunogenic profile of different histologic subtypes of ovarian cancer. METHODS: We performed next-generation sequencing of 160 cancer-related genes. Also, we analyzed the immunohistochemical status of ARID1A, PD-L1, and CD8 with survival in different histologic subtypes of ovarian cancer in a total of 103 cases. RESULTS: ARID1A mutation was found in 0% of the high-grade serous ovarian cancer (HGSC) (n = 36), 41.5% of the CCC (n = 41), 45.0% of the EC (n = 20), and 33.3% of the mucinous ovarian cancer (MC) (n = 6) cases. ARID1A loss was found in 19.4% of the HGSC, 75.6% of the CCC, 60.0% of the EC and 0% of the MC cases. ARID1A mutation was found to be associated with high PD-L1 (p < 0.001) or CD8 levels (p < 0.001) in CCC but not in other histologic subtypes. Meanwhile, ARID1A loss was associated with high PD-L1 or CD8 levels in CCC (p < 0.001) and HGSC (p < 0.001) but not in EC and MC. In addition, ARID1A mutation was associated with high tumor mutation burden in CCC (p = 0.006). CONCLUSIONS: ARID1A mutation/ARID1A expression is associated with immune microenvironmental factors in CCC but not in EC. ARID1A status can be a biomarker for selecting candidates for immune checkpoint blockade in CCC.
Authors: Karolin Heinze; Tayyebeh M Nazeran; Sandra Lee; Pauline Krämer; Evan S Cairns; Derek S Chiu; Samuel Cy Leung; Eun Young Kang; Nicola S Meagher; Catherine J Kennedy; Jessica Boros; Friedrich Kommoss; Hans-Walter Vollert; Florian Heitz; Andreas du Bois; Philipp Harter; Marcel Grube; Bernhard Kraemer; Annette Staebler; Felix Kf Kommoss; Sabine Heublein; Hans-Peter Sinn; Naveena Singh; Angela Laslavic; Esther Elishaev; Alex Olawaiye; Kirsten Moysich; Francesmary Modugno; Raghwa Sharma; Alison H Brand; Paul R Harnett; Anna DeFazio; Renée T Fortner; Jan Lubinski; Marcin Lener; Aleksandra Tołoczko-Grabarek; Cezary Cybulski; Helena Gronwald; Jacek Gronwald; Penny Coulson; Mona A El-Bahrawy; Michael E Jones; Minouk J Schoemaker; Anthony J Swerdlow; Kylie L Gorringe; Ian Campbell; Linda Cook; Simon A Gayther; Michael E Carney; Yurii B Shvetsov; Brenda Y Hernandez; Lynne R Wilkens; Marc T Goodman; Constantina Mateoiu; Anna Linder; Karin Sundfeldt; Linda E Kelemen; Aleksandra Gentry-Maharaj; Martin Widschwendter; Usha Menon; Kelly L Bolton; Jennifer Alsop; Mitul Shah; Mercedes Jimenez-Linan; Paul Dp Pharoah; James D Brenton; Kara L Cushing-Haugen; Holly R Harris; Jennifer A Doherty; Blake Gilks; Prafull Ghatage; David G Huntsman; Gregg S Nelson; Anna V Tinker; Cheng-Han Lee; Ellen L Goode; Brad H Nelson; Susan J Ramus; Stefan Kommoss; Aline Talhouk; Martin Köbel; Michael S Anglesio Journal: J Pathol Date: 2022-02-07 Impact factor: 9.883