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We described associations among 3’UTR genetic variants in ADME genes, clinical factors and the risk of toxicity or side effects of breast cancer chemotherapy. The SNPs in breast cancer women were tested in relation to 12 symptoms belonging to myelotoxicity (anemia, leukopenia, neutropenia), gastrointestinal side effects (vomiting, nausea), nephrotoxicity and hepatotoxicity, occurred in overall, early or recurrent settings. The cumulative risk of overall symptoms of anemia was connected with AKR1C3 rs3209896 AG, ERCC1 rs3212986 GT and > 6 cycles of chemotherapy; leucopenia was determined by ABCC1 rs129081 allele G and DPYD rs291593 allele T; neutropenia risk correlated with accumulation of genetic variants of DPYD rs291583 allele G, ABCB1 rs17064 AT and positive HER2 status. Risk of nephrotoxicity was determined by homozygote DPYD rs291593, homozygote AKR1C3 rs3209896, postmenopausal age and negative ER status. Increased risk of hepatotoxicity was connected with NR1/2 rs3732359 allele G, postmenopausal age and with present metastases. The risk of nausea and vomiting was linked to several genetic factors and premenopausal age. We concluded that chemotherapy tolerance emerges from the simultaneous interaction of many genetic and clinical factors.

The Ku heterodimer, which consists of Ku70 and Ku86 subunits, is a major sensor of DNA breaks. A truncated form of Ku86 lacking its C-terminus, termed Ku86 variant, has been detected in extracts from different human cells. Here we report that in human lymphocytes the Ku86 variant is not present in vivo but is generated in vitro upon cell lysis by a trypsin-like protease. The resulting Ku86 variant exists exclusively in complexes with Ku70, which possess strong affinity to DNA double strand termini. In different blood donors the levels of Ku86 variant correlated with the magnitude of radiation induced DNA breaks.

High mobility group (HMG) proteins 1 and 2 are abundant non-histone chromosomal proteins that bind preferentially DNA that is bent or underwound. Previous studies have shown that these proteins preferentially bind to DNA damaged by the crosslinking agents cis-diammine-dichloro-platinum(II), chromium(III) and UV-C radiation. Here we have studied the binding of HMG-1/2 proteins to a duplex oligonucleotide damaged by benzo(a)pyrene diol epoxide or N-acetoxy-acetylaminofluorene using an electrophoretic mobility shift assay. Both chemicals induce monoadducts that are known to distort DNA structure. The affinities of HMG-1/2 for DNA damaged by benzo[a]pyrene diol epoxide or N-acetoxy-acetylaminofluorene were similar to that for UV-irradiated DNA, which were an order of magnitude higher than for undamaged DNA. In contrast, DNA modified by dimethyl sulfate was not preferentially recognised by HMG-1/2.