Xue Xiao1, Dandan Dong2, Wenjing He3, Linhong Song2, Qiao Wang3, Jun Yue3, Lan Xie4. 1. Individualized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, 32 West Second Section, First Ring Road, Chengdu, Sichuan, China. Electronic address: xiaoxue@med.uestc.edu.cn. 2. Department of Pathology, Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, 32 West Second Section, First Ring Road, Chengdu, Sichuan, China. 3. Department of Gynecology and Obstetrics, Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, 32 West Second Section, First Ring Road, Chengdu, Sichuan, China. 4. Department of Gynecology and Obstetrics, Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology of China, 32 West Second Section, First Ring Road, Chengdu, Sichuan, China. Electronic address: xielan@med.uestc.edu.cn.
Abstract
OBJECTIVE: The role of mismatch repair (MMR) deficiency in ovarian cancer (OC) pathogenesis and its association with other clinicopathologic features, such as microsatellite instability (MSI) and expression of checkpoint proteins, remain largely elusive. METHODS: We performed Immunohistochemistry (IHC) for MLH1, MSH2, MSH6 and PMS2 on full-section slides from 419 OCs to assess the MMR status. The clinical relevance of MMR deficiency was analyzed in combination with clinical data. The MSI status (by MSI assay) and expression of CD3, CD8, PD-1 and PD-L1 (by IHC) were compared in OCs with different MMR status. RESULTS: We found that 2.6% OCs were MMR-negative, 4.3% OCs were MMR-low, and 63.6% of MMR-negative OCs were of endometrioid subtype. A significantly higher proportion of MMR-negative OCs were diagnosed at stage I or II compared to MMR-proficient OCs (p=0.0041). MSI was observed in all tested MMR-negative OCs, 14.3% of tested MMR-low OCs and 3.2% of tested MMR-proficient OCs. In addition, MMR-negative OCs had better progression free survival compared to MMR-proficient and MMR-low OCs (p=0.0046). Furthermore, the majority of OCs were PD-1-positive in intratumoral lymphocytes regardless of MMR status; while MMR-negative OCs exhibited significantly increased CD3+ and CD8+ tumor-infiltrating lymphocytes, and PD-L1+ intratumoral immune cells compared to MMR-proficient OCs. CONCLUSION: Our data suggests that MMR deficient OC is a unique molecular subgroup, characterized by early stage of diagnosis, MSI phenotype, and increased tumor-infiltrating lymphocytes. These patients may be good candidates for anti-PD-1/PD-L1 therapy.
OBJECTIVE: The role of mismatch repair (MMR) deficiency in ovarian cancer (OC) pathogenesis and its association with other clinicopathologic features, such as microsatellite instability (MSI) and expression of checkpoint proteins, remain largely elusive. METHODS: We performed Immunohistochemistry (IHC) for MLH1, MSH2, MSH6 and PMS2 on full-section slides from 419 OCs to assess the MMR status. The clinical relevance of MMR deficiency was analyzed in combination with clinical data. The MSI status (by MSI assay) and expression of CD3, CD8, PD-1 and PD-L1 (by IHC) were compared in OCs with different MMR status. RESULTS: We found that 2.6% OCs were MMR-negative, 4.3% OCs were MMR-low, and 63.6% of MMR-negative OCs were of endometrioid subtype. A significantly higher proportion of MMR-negative OCs were diagnosed at stage I or II compared to MMR-proficient OCs (p=0.0041). MSI was observed in all tested MMR-negative OCs, 14.3% of tested MMR-low OCs and 3.2% of tested MMR-proficient OCs. In addition, MMR-negative OCs had better progression free survival compared to MMR-proficient and MMR-low OCs (p=0.0046). Furthermore, the majority of OCs were PD-1-positive in intratumoral lymphocytes regardless of MMR status; while MMR-negative OCs exhibited significantly increased CD3+ and CD8+ tumor-infiltrating lymphocytes, and PD-L1+ intratumoral immune cells compared to MMR-proficient OCs. CONCLUSION: Our data suggests that MMR deficient OC is a unique molecular subgroup, characterized by early stage of diagnosis, MSI phenotype, and increased tumor-infiltrating lymphocytes. These patients may be good candidates for anti-PD-1/PD-L1 therapy.
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