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We previously identified a novel breast cancer susceptibility variant on chromosome 4q31.22 locus (rs1429142) conferring risk among women of European ancestry. Here, we report replication of findings, validation of the variant in diverse populations and fine‐mapping of the associated locus in Caucasian population. The SNP rs1429142 (C/T, minor allele frequency 18%) showed association for the overall breast cancer risk in Stages 1–4 (n = 4,331 cases/4271 controls; p = 4.35 × 10−8; odds ratio, ORC‐allele,1.25), and an elevated risk among premenopausal women (n = 1,503 cases/4271 controls; p = 5.81 × 10−10; ORC‐allele 1.40) in European populations. SNP rs1429142 was associated with premenopausal breast cancer risk in women of African (T/C; p‐value 1.45 × 10−02; ORC‐allele 1.2) but not from Chinese ancestry. Fine‐mapping of the locus revealed several potential causal variants which are present within a single association signal, revealed from the conditional regression analysis. Functional annotation of the potential causal variants revealed three putative SNPs rs1366691, rs1429139 and rs7667633 with active enhancer functions inferred based on histone marks, DNase hypersensitive sites in breast cell line data. These putative variants were bound by transcription factors (C‐FOS, STAT1/3 and POL2/3) with known roles in inflammatory pathways. Furthermore, Hi‐C data revealed several short‐range interactions in the fine‐mapped locus harboring the putative variants. The fine mapped locus was predicted to be within a single topologically associated domain, potentially facilitating enhancer–promoter interactions possibly leading to the regulation of nearby genes. What's new? To date, genome‐wide association studies have addressed familial or postmenopausal breast cancer susceptibility variants. However, genetic predisposition for sporadic premenopausal breast cancer risk is unknown. This study reports a novel variant (at 4q31.22) associated with elevated risk for premenopausal breast cancer among women from European and African ancestry. The fine‐mapped locus was predicted to be within a single topologically associated domain, potentially facilitating enhancer‐promoter interactions leading to the regulation of nearby genes. [ABSTRACT FROM AUTHOR]

The benefits of PET imaging of tumor hypoxia in patient management has been demonstrated in many examples and with various tracers over the last years. Although, the optimal hypoxia imaging agent has yet to be found, 2-nitroimidazole (azomycin) sugar derivatives-mimicking nucleosides-have proven their potential with [ 18 F]FAZA ([ 18 F]fluoro-azomycin- α -arabinoside) as a prominent representative in clinical use. Still, for all of these tracers, cellular uptake by passive diffusion is postulated with the disadvantage of slow kinetics and low tumor-to-background ratios. We recently evaluated [ 18 F]fluoro-azomycin- β -deoxyriboside ( β -[ 18 F]FAZDR), with a structure more similar to nucleosides than [ 18 F]FAZA and possible interaction with nucleoside transporters. For a deeper insight, we comparatively studied the interaction of FAZA, β -FAZA, α -FAZDR and β -FAZDR with nucleoside transporters (SLC29A1/2 and SLC28A1/2/3) in vitro, showing variable interactions of the compounds. The highest interactions being for β -FAZDR (IC 50 124 ± 33 µM for SLC28A3), but also for FAZA with the non-nucleosidic α -configuration, the interactions were remarkable (290 ± 44 µM {SLC28A1}; 640 ± 10 µM {SLC28A2}). An improved synthesis was developed for β -FAZA. For a PET study in tumor-bearing mice, α -[ 18 F]FAZDR was synthesized (radiochemical yield: 15.9 ± 9.0% ( n = 3), max. 10.3 GBq, molar activity > 50 GBq/µmol) and compared to β -[ 18 F]FAZDR and [ 18 F]FMISO, the hypoxia imaging gold standard. We observed highest tumor-to-muscle ratios (TMR) for β -[ 18 F]FAZDR already at 1 h p.i. (2.52 ± 0.94, n = 4) in comparison to [ 18 F]FMISO (1.37 ± 0.11, n = 5) and α -[ 18 F]FAZDR (1.93 ± 0.39, n = 4), with possible mediation by the involvement of nucleoside transporters. After 3 h p.i., TMR were not significantly different for all 3 tracers (2.5⁻3.0). Highest clearance from tumor tissue was observed for β -[ 18 F]FAZDR (56.6 ± 6.8%, 2 h p.i.), followed by α -[ 18 F]FAZDR (34.2 ± 7.5%) and [ 18 F]FMISO (11.8 ± 6.5%). In conclusion, both isomers of [ 18 F]FAZDR showed their potential as PET hypoxia tracers. Differences in uptake behavior may be attributed to a potential variable involvement of transport mechanisms.