Clinicopathological and molecular analysis of microsatellite instability in prostate cancer: a multi-institutional study in China

Huizhi Zhang; Xiaoqun Yang; Jialing Xie; Xiao Cheng; Jiayi Chen; Miaomiao Shen; Wenyi Ding; Suying Wang; Zhe Zhang; Chaofu Wang; Ming Zhao

doi:10.3389/fonc.2023.1277233

Clinicopathological and molecular analysis of microsatellite instability in prostate cancer: a multi-institutional study in China

Front Oncol. 2023 Oct 13:13:1277233. doi: 10.3389/fonc.2023.1277233. eCollection 2023.

Authors

Affiliations

¹ Department of Pathology, Ningbo Clinical Pathology Diagnosis Center, Ningbo, China.
² Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
³ Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.

Abstract

Background: Microsatellite instability (MSI), or mismatch repair-deficiency (dMMR), is rare in prostate cancers (PCas). The histological and molecular features of PCas with MSI/dMMR are incompletely described. Thus, we sought to identify the characteristics of PCas with MSI/dMMR.

Methods and results: We analyzed 1,141 primary treatment-naive PCas by MMR-related protein immunohistochemistry (MLH1, PMS2, MSH2, and MSH6). We identified eight cases exhibiting MSI/dMMR (0.7%, 8/1141). Of these, six tumors had both MSH2 and MSH6 protein loss, one had both MLH1 and PMS2 protein loss, and one had only MSH6 loss. Histologically, MSI/dMMR-PCas frequently demonstrated high histological grade (Grade Group 4 or 5), ductal/intraductal histology (6/8 cases), pleomorphic giant-cell features (4/8 cases), and conspicuous tumor lymphocytic infiltration (8/8 cases). Polymerase chain reaction-based analysis of seven MSI/dMMR tumors revealed two MSI-H tumors with loss of both MSH2 and MSH6 proteins. Subsequently, the seven cases underwent next-generation sequencing (NGS) analysis with a highly validated targeted panel; four were MSI. All cases had a high tumor mutation burden (median: 45.3 mutations/Mb). Overall, the MSI/dMMR-PCas showed a high frequency of DNA damage-repair pathway gene changes, including five with pathogenic somatic or germline MMR gene mutations. Activating mutations in the MAPK pathway, PI3K pathway, and WNT/β-catenin pathway were common. TMPRSS2::ERG rearrangement was identified in one case (1/7, 14.3%).

Conclusions: Several pathological features are associated with MSI/dMMR in PCas. Identification of these features may help to select patients for genetic screening. As MSI/dMMR-PCas are enriched for actionable mutations, patients should be offered NGS to guide standard-of-care treatment.

Keywords: DNA mismatch repair; DNA repair; high throughput nucleotide sequencing; microsatellite instability; prostatic neoplasms.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Ningbo Medical Science and Technology Project (2020Y30), the Project of NINGBO Leading Medical&Health Discipline (2022-F30), Zhejiang Provincial Natural Science Foundation (LY21H160052) and Zhejiang Provincial Medicine and Health Research Foundation (2023KY040). The funder did not have any role in the design and conduct of the study, the analysis and interpretation of the data, and preparation of the manuscript.