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Updated: Jul 12, 2025
miRNA Expression Analyses in Prostate Cancer Clinical Tissues
Published on: September 8, 2015
Clinicopathological and molecular analysis of microsatellite instability in prostate cancer: a multi-institutional
Huizhi Zhang1, Xiaoqun Yang2, Jialing Xie2
1Department of Pathology, Ningbo Clinical Pathology Diagnosis Center, Ningbo, China.
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.
Insights
Microsatellite instability (MSI), or mismatch repair-deficiency (dMMR), is rare in prostate cancer. This study identified key histological and molecular features of MSI/dMMR prostate cancers, aiding in patient selection for genetic screening and targeted therapies.
Area of Science:
- Oncology
- Genetics
- Pathology
Background:
- Microsatellite instability (MSI), also known as mismatch repair-deficiency (dMMR), is an uncommon molecular subtype of prostate cancer (PCa).
- The clinicopathological and molecular characteristics of MSI/dMMR prostate cancers are not well-defined.
- Understanding these features is crucial for accurate diagnosis and treatment strategies.
Purpose of the Study:
- To comprehensively characterize the histological and molecular features of prostate cancers exhibiting MSI/dMMR.
- To identify potential pathological indicators for selecting patients who may benefit from genetic screening.
- To explore the genomic landscape of MSI/dMMR PCa for actionable mutations.
Main Methods:
- Analysis of 1,141 primary treatment-naive prostate cancers using immunohistochemistry for mismatch repair proteins (MLH1, PMS2, MSH2, MSH6).
- Histopathological evaluation of identified MSI/dMMR cases, including grade, histology, and tumor-infiltrating lymphocytes.
- Polymerase chain reaction (PCR) and next-generation sequencing (NGS) for MSI status, tumor mutational burden, and gene mutations.
Main Results:
- Eight cases (0.7%) of MSI/dMMR prostate cancer were identified.
- MSI/dMMR tumors frequently showed high histological grade (GG4-5), ductal histology, pleomorphic giant-cell features, and significant lymphocytic infiltration.
- These tumors exhibited high tumor mutational burden, frequent DNA damage-repair gene alterations, and common mutations in MAPK, PI3K, and WNT/β-catenin pathways.
Conclusions:
- Specific pathological features are associated with MSI/dMMR in prostate cancer, suggesting their utility in identifying candidates for genetic screening.
- MSI/dMMR prostate cancers are enriched for actionable mutations, underscoring the importance of NGS.
- Offering NGS to patients with suspected MSI/dMMR PCa can guide standard-of-care treatment decisions.
