Performance of breast cancer polygenic risk scores in 760 female CHEK2 germline mutation carriers
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Performance of breast cancer polygenic risk scores in 760 female CHEK2 germline mutation carriers. / Borde, Julika; Ernst, Corinna; Wappenschmidt, Barbara; Niederacher, Dieter; Weber-Lassalle, Konstantin; Schmidt, Gunnar; Hauke, Jan; Quante, Anne S; Weber-Lassalle, Nana; Horváth, Judit; Pohl-Rescigno, Esther; Arnold, Norbert; Rump, Andreas; Gehrig, Andrea; Hentschel, Julia; Faust, Ulrike; Dutrannoy, Véronique; Meindl, Alfons; Kuzyakova, Maria; Wang-Gohrke, Shan; Weber, Bernhard H F; Sutter, Christian; Volk, Alexander E; Giannakopoulou, Olga; Lee, Andrew; Engel, Christoph; Schmidt, Marjanka K; Antoniou, Antonis C; Schmutzler, Rita K; Kuchenbaecker, Karoline; Hahnen, Eric.
in: JNCI-J NATL CANCER I, Jahrgang 113, Nr. 7, 01.07.2021, S. 893-899.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Performance of breast cancer polygenic risk scores in 760 female CHEK2 germline mutation carriers
AU - Borde, Julika
AU - Ernst, Corinna
AU - Wappenschmidt, Barbara
AU - Niederacher, Dieter
AU - Weber-Lassalle, Konstantin
AU - Schmidt, Gunnar
AU - Hauke, Jan
AU - Quante, Anne S
AU - Weber-Lassalle, Nana
AU - Horváth, Judit
AU - Pohl-Rescigno, Esther
AU - Arnold, Norbert
AU - Rump, Andreas
AU - Gehrig, Andrea
AU - Hentschel, Julia
AU - Faust, Ulrike
AU - Dutrannoy, Véronique
AU - Meindl, Alfons
AU - Kuzyakova, Maria
AU - Wang-Gohrke, Shan
AU - Weber, Bernhard H F
AU - Sutter, Christian
AU - Volk, Alexander E
AU - Giannakopoulou, Olga
AU - Lee, Andrew
AU - Engel, Christoph
AU - Schmidt, Marjanka K
AU - Antoniou, Antonis C
AU - Schmutzler, Rita K
AU - Kuchenbaecker, Karoline
AU - Hahnen, Eric
N1 - © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - BACKGROUND: Genome-wide association studies suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in genome-wide association studies-independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2.METHODS: A total of 760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, 2 SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 germline mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 mutation carriers) BC-associated SNPs were used. All statistical tests were 2-sided.RESULTS: Both SNP sets provided concordant PRS results at the individual level (r = 0.91, P < 2.20 × 10-16). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio of 1.71 per SD of the PRS was observed (95% confidence interval = 1.36 to 2.15, P = 3.87 × 10-6). PRSs identify a subgroup of CHEK2 mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 hazard ratio = 1.23, 95% confidence interval = 0.86 to 1.78, P = .26).CONCLUSIONS: PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition.
AB - BACKGROUND: Genome-wide association studies suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in genome-wide association studies-independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2.METHODS: A total of 760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, 2 SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 germline mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 mutation carriers) BC-associated SNPs were used. All statistical tests were 2-sided.RESULTS: Both SNP sets provided concordant PRS results at the individual level (r = 0.91, P < 2.20 × 10-16). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio of 1.71 per SD of the PRS was observed (95% confidence interval = 1.36 to 2.15, P = 3.87 × 10-6). PRSs identify a subgroup of CHEK2 mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 hazard ratio = 1.23, 95% confidence interval = 0.86 to 1.78, P = .26).CONCLUSIONS: PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition.
U2 - 10.1093/jnci/djaa203
DO - 10.1093/jnci/djaa203
M3 - SCORING: Journal article
C2 - 33372680
VL - 113
SP - 893
EP - 899
JO - JNCI-J NATL CANCER I
JF - JNCI-J NATL CANCER I
SN - 0027-8874
IS - 7
ER -
