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Fraune, Christoph; Rosebrock, Janina; Simon, Ronald; Hube-Magg, Claudia; Makrypidi-Fraune, Georgia; Kluth, Martina; Büscheck, Franziska; Höflmayer, Doris; Schmalfeldt, Barbara; Müller, Volkmar; Wölber, Linn; Witzel, Isabell; Paluchowski, Peter; Wilke, Christian; Heilenkötter, Uwe; von Leffern, Ingo; Clauditz, Till Sebastian; Wilczak, Waldemar; Sauter, Guido; Steurer, Stefan; Burandt, Eike
Gynecologic oncology, March 2020, 2020-Mar, 2020-03-00, 20200301, Letnik: 156, Številka: 3Journal Article
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. 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. 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. 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. •Microsatellite instability (MSI) occurs in about 20% of endometrial ovarian cancers.•Because MSI is an early event in this tumor type, analysis of biopsies can yield representative results.•MSI should be routinely determined at least in every newly diagnosed endometrioid ovarian cancer.
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