Abstract 3361: Are mismatch repair (MMR) defects and microsatellite instability (MSI) relevant in renal cell and prostate carcinomas? Their significance for future therapies

Abstract

Abstract Background Few studies have investigated mismatch repair (MMR) defects in renal and prostatic cancers. Normally, MMR accurately detects and corrects mistakes made during replication of a DNA strand. But, a defective MMR system is very likely to miss copy-number errors, particularly in microsatellites (short tandem base repeats). Alterations in function of MMR genes can result in microsatellite instability (MSI), known to facilitate tumor progression and poor prognosis. MMR deficiency is observed frequently in colonic and endometrial carcinoma as part of Lynch's syndrome, as well as occasionally in other neoplasms. In our study, we assayed MMR expression in a series of kidney tumors representing the spectrum of renal malignancies and in a wide-ranging group of prostate cancers (for which clinical information and Gleason grade was obtained in all cases). Materials and methods Immunohistochemical (IHC) staining of FFPE sections from 45 kidney cancers and 30 prostatic tumors was performed. The main MMR proteins of interest are MSH2 and MLH1, plus their heterodimer partners MSH6 and PMS2; staining was directed at these 4 targets. Antibody sources were Abcam, Cambridge, MA 02139 (MLH1, MSH6, PMS2) and Agilent Technologies, Wilmington, DE 19808 (MSH2). Also, PD-L1 expression was evaluated using antibody from Cell Signaling, Danvers, MA 01923. Results Forty-five cases of renal cell carcinoma (RCC) comprised 12 cases of clear cell VHL (von Hippel Lindau) related cancer, 11 papillary type 1, 11 chromophobe, and 11 HLRCC (hereditary leiomyomatosis and renal cell carcinoma). Only one case of chromophobe RCC with sarcomatoid differentiation showed complete loss of MLH1 and PMS2 (2% of 45 renal tumors). Of prostate cancers, only one of 30 tumors (3%) was completely negative for both MLH1 and PMS2; that tumor was Gleason grade 8. The remaining 29 cases were positive for all MMR proteins. Discussion Our study suggests that neither kidney nor prostate cancers are likely to possess significant MMR defects. In our series, clear cell, papillary and HLRCC tumors did not lack MMR expression; one chromophobe case negative for MMR (and presumed liable to MSI) may have developed genomic changes as disease progressed to a more aggressive, sarcomatoid pattern. Prostate cancer with MMR defects also appears to be rare, and we found no correlation with grade and stage. MMR defects lead to highly unstable microsatellite sequences and altered gene expression, so while only a small proportion of these tumors exhibited loss of MMR proteins, it is possible that in these few cases the loss may be significant and that such patients may benefit from new modalities of treatment. IHC detection of MMR defects (as predictors of probable MSI) may prove a useful prognostic tool in identification of rare renal and prostatic cancers likely to exhibit greater genetic instability and neoplastic advance. Citation Format: Xu Naizhen, Marston Linehan, Peter A. Pinto, Maria J. Merino. Are mismatch repair (MMR) defects and microsatellite instability (MSI) relevant in renal cell and prostate carcinomas? Their significance for future therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3361.