High homogeneity of MMR deficiency in ovarian cancer
| Autor: | Barbara Schmalfeldt, Claudia Hube-Magg, Eike Burandt, Stefan Steurer, Martina Kluth, Franziska Büscheck, Ronald Simon, Linn Wölber, Guido Sauter, Christian Wilke, Peter Paluchowski, Waldemar Wilczak, Doris Höflmayer, Till S. Clauditz, Janina Rosebrock, Volkmar Müller, Christoph Fraune, Ingo von Leffern, Georgia Makrypidi-Fraune, Isabell Witzel, Uwe Heilenkötter |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
0301 basic medicine congenital hereditary and neonatal diseases and abnormalities MLH1 DNA Mismatch Repair Young Adult 03 medical and health sciences 0302 clinical medicine PMS2 Humans Medicine neoplasms Aged Mismatch Repair Endonuclease PMS2 Aged 80 and over Ovarian Neoplasms Tissue microarray business.industry nutritional and metabolic diseases Obstetrics and Gynecology Microsatellite instability Middle Aged medicine.disease Immunohistochemistry digestive system diseases DNA-Binding Proteins MSH6 Serous fluid DNA Repair Enzymes MutS Homolog 2 Protein 030104 developmental biology Oncology Tissue Array Analysis MSH2 030220 oncology & carcinogenesis Cancer research Female Microsatellite Instability MutL Protein Homolog 1 business Ovarian cancer Carcinoma Endometrioid |
| Zdroj: | Gynecologic Oncology. 156:669-675 |
| ISSN: | 0090-8258 |
| DOI: | 10.1016/j.ygyno.2019.12.031 |
| Popis: | Objective Mismatch repair (MMR) deficiency and Bethesda panel microsatellite instability (MSI) are increasingly analyzed to identify tumors that might benefit from immune checkpoint inhibitors, but tumor heterogeneity is a potential obstacle for such analyses. In ovarian cancer, data on intratumoral heterogeneity of MMR deficiency/MSI are lacking. Methods N = 582 ovarian cancers were screened for MMR deficiency by immunohistochemistry (IHC) on a tissue microarray. 10 cases suspect for MMR deficiency were identified among 478 interpretable cancers and repeated IHC on large sections combined with polymerase chain reaction (PCR)-based MSI analysis validated MMR deficiency/MSI in 9 of these tumors. Results MMR deficiency/MSI was predominantly seen in endmetrioid cancers (8 of 35, 23%) and also in 1 of 358 serous carcinomas (0.3%), but was absent in 34 mucinous carcinomas, 23 clear cell carcinomas, 17 malignant mixed Mullerian tumors (carcinosarcomas), and 11 mixed carcinomas. MMR deficiency involed protein loss of PMS2/MLH1 in 6 cases and of MSH2 and/or MSH6 in 3 cases. 7 MMR deficient cancers were MSI-high (all endometrioid), one was MSI-low (endometrioid) and one cancer with unequivocal MMR protein loss exhibited microsatellite stability (serous). MLH1 promotor methylation was observed in 4 of 5 endometrioid cancers with MLH1 protein loss. Immunostaining of all available cancer-containing tissue blocks (n = 114) of tumors with confirmed MMR deficiency/MSI revealed uniform MMR status throughout the entire tumor mass. Conclusions Our data show that MSI is present in a substantial proportion of endometrioid ovarian cancers but can also occur in other tumor subtypes. MMR deficiency/MSI typically involves the entire tumor mass, suggesting that MMR inactivation occurs early in tumorigenesis in a subset of ovarian cancers. |
| Databáze: | OpenAIRE |
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