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

• Verfasst von: Surowy, Harald [VerfasserIn]
• Verfasst von: Burwinkel, Barbara [VerfasserIn]
• Verfasst von: Marmé, Frederik [VerfasserIn]
• Verfasst von: Sohn, Christof [VerfasserIn]
• 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
• DOI: doi:10.1002/ijc.31105
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 157653393X

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.