Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Julika Borde - , Universität zu Köln (Autor:in)
  • Corinna Ernst - , Universität zu Köln (Autor:in)
  • Barbara Wappenschmidt - , Universität zu Köln (Autor:in)
  • Dieter Niederacher - , Universitätsklinikum Düsseldorf (Autor:in)
  • Konstantin Weber-Lassalle - , Universität zu Köln (Autor:in)
  • Gunnar Schmidt - , Technische Universität Dresden (Autor:in)
  • Jan Hauke - , Universität zu Köln (Autor:in)
  • Anne S Quante - , Technische Universität München (Autor:in)
  • Nana Weber-Lassalle - , Universität zu Köln (Autor:in)
  • Judit Horváth - , Universitätsklinikum Münster (Autor:in)
  • Esther Pohl-Rescigno - , Universität zu Köln (Autor:in)
  • Norbert Arnold - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Andreas Rump - , Institut für Klinische Genetik (Autor:in)
  • Andrea Gehrig - , Technische Universität Dresden (Autor:in)
  • Julia Hentschel - , Universitätsklinikum Leipzig (Autor:in)
  • Ulrike Faust - , Universitätsklinikum Tübingen (Autor:in)
  • Véronique Dutrannoy - , Institute of Medical and Human Genetics (Autor:in)
  • Alfons Meindl - , Klinikum der Ludwig-Maximilians-Universität (LMU) München (Autor:in)
  • Maria Kuzyakova - , University of Göttingen (Autor:in)
  • Shan Wang-Gohrke - , Universitätsklinikum Ulm (Autor:in)
  • Bernhard H F Weber - , Universität Regensburg (Autor:in)
  • Christian Sutter - , Universität Heidelberg (Autor:in)
  • Alexander E Volk - , Universität Hamburg (Autor:in)
  • Olga Giannakopoulou - , University College London (Autor:in)
  • Andrew Lee - , University of Cambridge (Autor:in)
  • Christoph Engel - , Universität Leipzig (Autor:in)
  • Marjanka K Schmidt - , Netherlands Cancer Institute (Autor:in)
  • Antonis C Antoniou - , University of Cambridge (Autor:in)
  • Rita K Schmutzler - , Universität zu Köln (Autor:in)
  • Karoline Kuchenbaecker - , University College London (Autor:in)
  • Eric Hahnen - , Universität zu Köln (Autor:in)

Abstract

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.

Details

OriginalspracheEnglisch
Seiten (von - bis)893-899
Seitenumfang7
FachzeitschriftJournal of the National Cancer Institute
Jahrgang113
Ausgabenummer7
PublikationsstatusVeröffentlicht - 1 Juli 2021
Peer-Review-StatusJa

Externe IDs

PubMedCentral PMC8246885
Scopus 85111789367

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Breast Neoplasms/epidemiology, Checkpoint Kinase 2/genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Mutation, Risk Factors

Bibliotheksschlagworte