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. 2020 Mar 14;11(3):314.
doi: 10.3390/genes11030314.

Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer

Tommi Rantapero  1 , Tiina Wahlfors  1 , Anna Kähler  2 , Christina Hultman  2 , Johan Lindberg  2 , Teuvo Lj Tammela  1 , Matti Nykter  1 , Johanna Schleutker  3   4 , Fredrik Wiklund  2
Affiliations

Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer

Tommi Rantapero et al. Genes (Basel). .

Abstract

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.

Keywords: DNA repair genes; lethal cancer; prostate cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flow chart describing processing of whole exome sequencing, quality control, variant calling and annotation, and variant prioritizing. PRCA: prostate cancer; ClinVar: database of reported associations of variants to clinical phenotypes; CADD: combined annotation dependent depletion; Revel: rare exome variant ensemble learner.
Figure 2
Figure 2
Potentially damaging variants found in the CHEK2 and ATM genes. Locations of variants are shown as lollipop structures. The variants found in the Finnish/Swedish lethal or unselected cases are indicated by circles, and variants found in selected previous studies [7,11,18,28] are indicated by triangles. The variant type is indicated by the color.
See this image and copyright information in PMC

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