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Published on: March 6, 2018
The Somatic Mutational Landscape of Mismatch Repair Deficient Prostate Cancer
Bangwei Fang1,2, Yu Wei1,2, Jian Pan1,2
1Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Abstract:
Prostate cancers with mismatch repair deficiency (MMR-d) have aggressive clinical and histological features, and they are potentially responsive to immunotherapy. However, its rarity prevents the analysis of the underlying biology. Here, we collected the genomic data of 2664 primary prostate tumors and 1409 metastatic prostate tumors from the GENIE and TCGA databases. A total of 69 (2.59%) primary and 60 (4.26%) metastatic MMR-d tumors were identified among these tumors. Single nucleotide variant (SNV) frequencies of 34 candidate genes (including KMT2D (46.4%), ZFHX3 (33.3%), JAK1 (31.9%), and RNF43 (27.5%)) and 16 candidate genes (including KMT2D (33.3%) and JAK1 (28.3%)) were higher in MMR-d primary tumors and MMR-d metastatic tumors, respectively. The tumor mutation burden (TMB) was higher in primary MMR-d tumors. Homozygous deletions of EPCAM and EPAS1 were enriched in MMR-d primary tumors, while EPCAM deletions were enriched in metastatic MMR-d tumors. For genomic rearrangement events, TMPRSS2-ETS fusions were less frequent in primary MMR-d tumors. Our study indicates MMR-d prostate cancers have unique genomic features. These may play an important role in providing therapeutic targets for the treatment of this subset of prostate cancer patients.
Insights
Mismatch repair deficient (MMR-d) prostate cancers exhibit distinct genomic profiles. Understanding these features offers potential therapeutic targets for this aggressive cancer subtype.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Prostate cancers with mismatch repair deficiency (MMR-d) are aggressive and potentially immunotherapy-responsive.
- The rarity of MMR-d prostate cancer hinders biological analysis.
Purpose of the Study:
- To investigate the unique genomic features of MMR-d prostate cancers.
- To identify potential therapeutic targets for MMR-d prostate cancer.
Main Methods:
- Analysis of genomic data from 2664 primary and 1409 metastatic prostate tumors from GENIE and TCGA databases.
- Identification and characterization of MMR-d tumors.
- Assessment of single nucleotide variant frequencies, tumor mutation burden, homozygous deletions, and genomic rearrangement events.
Main Results:
- Identified 69 primary (2.59%) and 60 metastatic (4.26%) MMR-d tumors.
- Higher frequencies of specific gene mutations (e.g., KMT2D, JAK1) in MMR-d tumors.
- Enrichment of EPCAM and EPAS1 homozygous deletions in primary MMR-d tumors.
- Lower frequency of TMPRSS2-ETS fusions in primary MMR-d tumors.
Conclusions:
- MMR-d prostate cancers possess distinct genomic characteristics.
- These genomic features may represent valuable therapeutic targets for MMR-d prostate cancer patients.
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