MLH1 Loss in Primary Prostate Cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Mismatch repair-deficient (MMRd) prostate cancers are a distinct subtype.
• Loss of MLH1 is an uncommon cause of MMRd in prostate cancer.

Purpose of the Study:

• To describe the molecular characteristics of two primary prostate cancer cases with MLH1 loss.
• To evaluate diagnostic challenges and utility of different testing methods for MLH1-deficient prostate cancer.

Main Methods:

• Immunohistochemistry for MLH1 protein expression.
• Microsatellite instability (MSI) testing using standard PCR, long mononucleotide repeat (LMR) assay, and next-generation sequencing.
• Tumor genomic profiling including copy-number analysis and mutation detection.
• Germline testing for Lynch syndrome.

Main Results:

• Two cases of prostate cancer with MLH1 loss were identified.
• Standard MSI testing showed microsatellite stability, while LMR assay and sequencing detected MSI.
• Genomic analysis revealed biallelic or monoallelic MLH1 loss without promoter hypermethylation.
• Tumor mutation burden was modestly elevated, consistent with MMRd.
• Germline testing was negative for Lynch syndrome.

Conclusions:

• MLH1-deficient prostate cancers present diagnostic challenges with standard MSI testing.
• Immunohistochemistry, LMR assays, and advanced sequencing are valuable for detecting MMRd prostate cancer.
• These findings underscore the importance of comprehensive molecular profiling for rare cancer subtypes.