Germline variants in DNA repair genes are associated with aggressive
prostate cancer (PrCa). The aim of this study was to characterize
germline variants in DNA repair genes associated with lethal PrCa in
Finnish and Swedish populations. Whole-exome sequencing was performed
for 122 lethal and 60 unselected PrCa cases. Among the lethal cases, a
total of 16 potentially damaging protein-truncating variants in DNA
repair genes were identified in 15 men (12.3%). Mutations were found in
six genes with CHEK2 (4.1%) and ATM
(3.3%) being most frequently mutated. Overall, the carrier rate of
truncating variants in DNA repair genes among men with lethal PrCa
significantly exceeded the carrier rate of 0% in 60 unselected PrCa
cases (p = 0.030), and the prevalence of 1.6% (p < 0.001) and 5.4% (p
= 0.040) in Swedish and Finnish population controls from the Exome
Aggregation Consortium. No significant difference in carrier rate of
potentially damaging nonsynonymous single nucleotide variants between
lethal and unselected PrCa cases was observed (p
= 0.123). We confirm that DNA repair genes are strongly associated with
lethal PrCa in Sweden and Finland and highlight the importance of
population-specific assessment of variants contributing to PrCa
aggressiveness.