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Int J Cancer. 2018 Feb 15;142(4):757-768. doi: 10.1002/ijc.31105. Epub 2017 Oct 30.

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.

Author information

1
Institute of Human Genetics, University of Ulm, Albert-Einstein-Allee 11, Ulm, D-89081, Germany.
2
Division of Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, Heidelberg, D-69120, Germany.
3
Molecular Epidemiology, C080, German Cancer Research Center, Im Neuenheimer Feld 581, Heidelberg, D-69120, Germany.
4
Harald Surowy's current address is: Institute of Human Genetics, University of Duesseldorf, Universitaetsstr. 1, Duesseldorf, 40225, Germany.
5
Department of Obstetrics and Gynecology, Ulm University, Prittwitzstr. 43, Ulm, D-89075, Germany.
6
Dominic Varga's current address is: Department of Gynecology, Donauklinik, Krankenhausstr 11, Neu-Ulm, 89231, Germany.
7
National Centre for Tumor Diseases, Heidelberg, D-69120, Germany.
8
Helmut Deissler's current address is: HD/U Biomedical Services, Im Wiblinger Hart 62, Ulm, 89079, Germany.
9
Department of Obstetrics and Gynecology, University of Freiburg, Hugstetter Straße 55, Freiburg, D-79106, Germany.
10
Annete Hasenburg's current address is: Klinik und Poliklinik für Geburtshilfe und Frauengesundheit, University of Mainz, Langenbeckstr. 1, Mainz, 55131, Germany.

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.

PMID:
29044504
DOI:
10.1002/ijc.31105
[Indexed for MEDLINE]
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