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

Autor: 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
Rok vydání: 2017
Předmět:
Zdroj: International journal of cancer. 142(4)
ISSN: 1097-0215
Popis: 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 diagnosed60 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 (R
Databáze: OpenAIRE