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High homogeneity of MMR deficiency in ovarian cancer.

Abstract：

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.

journal_name

Gynecol Oncol

journal_title

Gynecologic oncology

authors

Fraune C,Rosebrock J,Simon R,Hube-Magg C,Makrypidi-Fraune G,Kluth M,Büscheck F,Höflmayer D,Schmalfeldt B,Müller V,Wölber L,Witzel I,Paluchowski P,Wilke C,Heilenkötter U,von Leffern I,Clauditz TS,Wilczak W,Sauter G,S

doi

10.1016/j.ygyno.2019.12.031

subject

Has Abstract

pub_date

2020-03-01 00:00:00

pages

669-675

issue

eissn

0090-8258

issn

1095-6859

pii

S0090-8258(19)31861-X

journal_volume

156

pub_type

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High homogeneity of MMR deficiency in ovarian cancer.