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Verfasst von:Surowy, Harald [VerfasserIn]   i
 Burwinkel, Barbara [VerfasserIn]   i
 Marmé, Frederik [VerfasserIn]   i
 Sohn, Christof [VerfasserIn]   i
Titel:A low-frequency haplotype spanning SLX4/FANCP constitutes a new risk locus for early-onset breast cancer (<60 years) and is associated with reduced DNA repair capacity
Verf.angabe:Harald Surowy, Dominic Varga, Barbara Burwinkel, Frederik Marmé, Christof Sohn, Manuel Luedeke, Antje Rinckleb, Christiane Maier, Helmut Deissler, Meta Volcic, Lisa Wiesmüller, Annette Hasenburg, Maximilian Klar, Josef Hoegel, Walther Vogel
Umfang:12 S.
Fussnoten:First published: 16 October 2017 ; Gesehen am 19.06.2018
Titel Quelle:Enthalten in: International journal of cancer
Jahr Quelle:2017
Band/Heft Quelle:142(2017), 4, S. 757-768
ISSN Quelle:1097-0215
Abstract:Only a fraction of breast cancer (BC) cases can be yet explained by mutations in genes or genomic variants discovered in linkage, genome-wide association and sequencing studies. The known genes entailing medium or high risk for BC are strongly enriched for a function in DNA double strand repair. Thus, aiming at identifying low frequency variants conferring an intermediate risk, we here investigated 17 variants (MAF: 0.01-0.1) in 10 candidate genes involved in DNA repair or cell cycle control. In an exploration cohort of 437 cases and 1189 controls, we show the variant rs3810813 in the SLX4/FANCP gene to be significantly associated with both BC (≤60 years; OR = 2.6(1.6-3.9), p = 1.6E-05) and decreased DNA repair capacity (≤60 years; beta = 37.8(17.9-57.8), p = 5.3E-4). BC association was confirmed in a verification cohort (N = 2441). Both associations were absent from cases diagnosed >60 years and stronger the earlier the diagnosis. By imputation we show that rs3810813 tags a haplotype with 5 additional variants with the same allele frequency (R2 > 0.9), and a pattern of association very similar for both phenotypes (cases <60 years, p < 0.001, the Bonferroni threshold derived from unlinked variants in the region). In young cases (≤60 years) carrying the risk haplotype, micronucleus test results are predictive for BC (AUC > 0.9). Our findings propose a risk variant with high penetrance on the haplotype spanning SLX4/FANCP to be functionally associated to BC predisposition via decreased repair capacity and suggest this variant is carried by a fraction of these haplotypes that is enriched in early onset BC cases.
DOI:doi:10.1002/ijc.31105
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Verlag: http://dx.doi.org/10.1002/ijc.31105
 Verlag: https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.31105
 DOI: https://doi.org/10.1002/ijc.31105
Datenträger:Online-Ressource
Sprache:eng
K10plus-PPN:157653393X
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