Germline <i>BLM</i> mutations and metastatic prostate cancer

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Biallelic loss‐of‐function <jats:italic>BLM</jats:italic> mutations result in Bloom syndrome: a genetic disorder characterized by growth deficiencies, photosensitivity, and multiple cancer susceptibilities. There are conflicting reports about whether or not heterozygous <jats:italic>BLM</jats:italic> carriers are at a higher risk of various cancers. Without <jats:italic>BLM</jats:italic> protein functionality, there is evidence of increased sister chromatid exchange and chromosomal instability.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Metastatic prostate cancer patients (N = 796) underwent germline genetic testing as part of routine care at three academic centers. Patients with heterozygous <jats:italic>BLM</jats:italic> mutations were identified. Tumor tissue was analyzed for somatic alterations in those patients who had a germline pathogenic mutation. Control data using a population sample were extracted from the Genome Aggregation Database.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Heterozygous <jats:italic>BLM</jats:italic> germline mutations in 5 of 796 patients (prevalence, 0.63%). All mutations were loss‐of‐function truncating alterations. None of the mutations were <jats:italic>BLM</jats:italic><jats:sup><jats:italic>Ash</jats:italic></jats:sup>. The control population (gnomAD) frequency of pathogenic or likely pathogenic <jats:italic>BLM</jats:italic> mutations was 0.18% (212 of 116 653). The relative risk (RR) of <jats:italic>BLM</jats:italic> mutations in metastatic prostate cancer patients was 3.4 (95% CI, 1.42‐8.33; <jats:italic>P</jats:italic> < .0062) compared to gnomAD controls. Tumor DNA sequencing in the <jats:italic>BLM</jats:italic> carriers showed no evidence of somatic <jats:italic>BLM</jats:italic> mutations. Interestingly, 3 of 5 <jats:italic>BLM</jats:italic> germline carriers had bi‐allelic <jats:italic>BRCA2</jats:italic> inactivation evident on tumor sequencing. One patient had both germline and somatic mutations in <jats:italic>BRCA2</jats:italic>. Excluding the patient with the germline <jats:italic>BRCA2</jats:italic> mutation (<jats:italic>BLM</jats:italic> prevalence, 4 of 796: 0.50%) still yielded a statistically significant finding vs the gnomAD controls (RR, 2.8; 95% CI, 1.02‐7.39; <jats:italic>P</jats:italic> < .04).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Truncating <jats:italic>BLM</jats:italic> germline mutations occur at a higher frequency in patients with advanced prostate cancer as compared to control populations. Though no biallelic loss of <jats:italic>BLM</jats:italic> was no noted in cancers, a surprising number of the <jats:italic>BLM</jats:italic> germline heterozygotes had pathogenic <jats:italic>BRCA2</jats:italic> mutations in their tumor.</jats:p></jats:sec>