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Kleiblova, Petra; Stolarova, Lenka; Krizova, Katerina; Lhota, Filip; Hojny, Jan; Zemankova, Petra; Havranek, Ondrej; Vocka, Michal; Cerna, Marta; Lhotova, Klara; Borecka, Marianna; Janatova, Marketa; Soukupova, Jana; Sevcik, Jan; Zimovjanova, Martina; Kotlas, Jaroslav; Panczak, Ales; Vesela, Kamila; Cervenkova, Jana; Schneiderova, Michaela; Burocziova, Monika; Burdova, Kamila; Stranecky, Viktor; Foretova, Lenka; [...]

Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer

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  • Medientyp: E-Artikel
  • Titel: Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer
  • Beteiligte: Kleiblova, Petra; Stolarova, Lenka; Krizova, Katerina; Lhota, Filip; Hojny, Jan; Zemankova, Petra; Havranek, Ondrej; Vocka, Michal; Cerna, Marta; Lhotova, Klara; Borecka, Marianna; Janatova, Marketa; Soukupova, Jana; Sevcik, Jan; Zimovjanova, Martina; Kotlas, Jaroslav; Panczak, Ales; Vesela, Kamila; Cervenkova, Jana; Schneiderova, Michaela; Burocziova, Monika; Burdova, Kamila; Stranecky, Viktor; Foretova, Lenka; [...]
  • Erschienen: Wiley, 2019
  • Erschienen in: International Journal of Cancer
  • Sprache: Englisch
  • DOI: 10.1002/ijc.32385
  • ISSN: 0020-7136; 1097-0215
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:p>Germline mutations in checkpoint kinase 2 (<jats:italic>CHEK2</jats:italic>), a multiple cancer‐predisposing gene, increase breast cancer (BC) risk; however, risk estimates differ substantially in published studies. We analyzed germline <jats:italic>CHEK2</jats:italic> variants in 1,928 high‐risk Czech breast/ovarian cancer (BC/OC) patients and 3,360 population‐matched controls (PMCs). For a functional classification of VUS, we developed a complementation assay in human nontransformed RPE1‐<jats:italic>CHEK2</jats:italic>‐knockout cells quantifying CHK2‐specific phosphorylation of endogenous protein KAP1. We identified 10 truncations in 46 (2.39%) patients and in 11 (0.33%) PMC (<jats:italic>p</jats:italic> = 1.1 × 10<jats:sup>−14</jats:sup>). Two types of large intragenic rearrangements (LGR) were found in 20/46 mutation carriers. Truncations significantly increased unilateral BC risk (OR = 7.94; 95%CI 3.90–17.47; <jats:italic>p</jats:italic> = 1.1 × 10<jats:sup>−14</jats:sup>) and were more frequent in patients with bilateral BC (4/149; 2.68%; <jats:italic>p</jats:italic> = 0.003), double primary BC/OC (3/79; 3.80%; <jats:italic>p</jats:italic> = 0.004), male BC (3/48; 6.25%; <jats:italic>p</jats:italic> = 8.6 × 10<jats:sup>−4</jats:sup>), but not with OC (3/354; 0.85%; <jats:italic>p =</jats:italic> 0.14). Additionally, we found 26 missense VUS in 88 (4.56%) patients and 131 (3.90%) PMC (<jats:italic>p</jats:italic> = 0.22). Using our functional assay, 11 variants identified in 15 (0.78%) patients and 6 (0.18%) PMC were scored deleterious (<jats:italic>p</jats:italic> = 0.002). Frequencies of functionally intermediate and neutral variants did not differ between patients and PMC. Functionally deleterious <jats:italic>CHEK2</jats:italic> missense variants significantly increased BC risk (OR = 3.90; 95%CI 1.24–13.35; <jats:italic>p</jats:italic> = 0.009) and marginally OC risk (OR = 4.77; 95%CI 0.77–22.47; <jats:italic>p</jats:italic> = 0.047); however, carriers low frequency will require evaluation in larger studies. Our study highlights importance of LGR detection for <jats:italic>CHEK2</jats:italic> analysis, careful consideration of ethnicity in both cases and controls for risk estimates, and demonstrates promising potential of newly developed human nontransformed cell line assay for functional <jats:italic>CHEK2</jats:italic> VUS classification.</jats:p>
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