Mismatch repair gene germline mutations in patients with prostate cancer.

Objectives: To investigate the prevalence of pathogenic germline mutations of mismatch repair (MMR) genes in prostate cancer patients and its relationship with clinicopathological characteristics.

Methods: Germline sequencing data of 855 prostate cancer patients admitted in Fudan University Shanghai Cancer Center from 2018 to 2022 were retrospectively analyzed. The pathogenicity of mutations was assessed according to the American College of Medical Genetics and Genomics (ACMG) standard guideline, Clinvar and Intervar databases. The clinicopathological characteristics and responses to castration treatment were compared among patients with MMR gene mutation (MMR group), patients with DNA damage repair (DDR) gene germline pathogenic mutation without MMR gene (DDRMMR group) and patients without DDR gene germline pathogenic mutation (DDR group).

Results: Thirteen (1.52%) MMR patients were identified in 855 prostate cancer patients, including 1 case with gene mutation, 6 cases with gene mutation, 4 cases with gene mutation and 2 cases with gene mutation. 105 (11.9%) patients were identified as gene positive (except gene), and 737 (86.2%) patients were DDR gene negative. Compared with DDR group, MMR group had lower age of onset (<0.05) and initial prostate-specific antigen (PSA) (<0.01), while no significant differences were found between the two groups in Gleason score and TMN staging (both >0.05). The median time to castration resistance was 8 months (95%: 6 months-not achieved), 16 months (95%: 12-32 months) and 24 months (95%: 21-27 months) for MMR group, DDRMMR group and DDR group, respectively. The time to castration resistance in MMR group was significantly shorter than that in DDRMMR group and DDR group (both <0.01), while there was no significant difference between DDRMMR group and DDR group (>0.05).

Conclusions: MMR gene mutation testing is recommended for prostate cancer patients with early onset, low initial PSA, metastasis or early resistance to castration therapy.