ATM Polymorphisms Research Articles

Genetic Polymorphisms Correlated with Outcome in Multiple Myeloma Patients Receiving High Dose Melphalan.

High dose melphalan is an essential component in the treatment of patients with advanced multiple myeloma. However little is known regarding genetic polymorphisms possibly correlated with patient outcome in this setting. To identify polymorphisms predictive of survival and/or toxicity we performed a SNP analysis in 83 patients having received high dose melphalan for multiple myeloma. All patients had received one or two courses of high dose melphalan with stem cell reinfusion. DNA was obtained from peripheral blood mononuclear cells and analyzed for 230 SNPs in genes selected for their role in drug metabolism, DNA repair, cell cycling or apoptosis. There were 48 males and 35 females and the median age was 58 years. The average number of VAD courses received before high dose melphalan was 4 (3–6). 49 patients received two high dose melphalan courses. The best response to melphalan was CR in 22 pts, very good response in 14 pts, partial response in 37 patients and stable or progressive disease in 10 patients. 37 patients had experienced disease progression and 8 patients had died at last follow-up. 29 patients experienced high grade (III-IV) mucositis after high dose melphalan. The median freedom from progression was 40 months. CYP2E1 polymorphism 7632 was correlated with freedom from progression (FFP) after high dose melphalan (p=0.02). SULT1A2 704 polymorphism was correlated both with FFP (p=0.002) and with overall survival (p=0.001). Occurrence of severe mucositis after high dose melphalan therapy was correlated with XRCC1 polymorphism 1198 (24% vs 51% of high grade mucositis) as well as ATM polymorphisms. These results suggest that SNPs of genes involved in drug metabolism or repair could be used to distinguish patients subgroups with different toxicity/efficacy profiles after high dose melphalan. [Display omitted]

ATM polymorphism IVS62+60G>A is not associated with disease aggressiveness in prostate cancer

Objectives ATM is an important protein that protects the genome from double-stranded DNA breaks. Mutations and polymorphisms in the ATM gene have been associated with an increased risk of certain types of malignancies, especially breast cancer. Methods We analyzed tissue from 98 white patients with prostate cancer for the presence of IVS62+60G>A polymorphism in the ATM gene. Results The frequency of the homozygous IVS62+60G/G, heterozygous IVS62+60G/A, and homozygous IVS62+60A/A was 18.37% (18 of 98), 30.61% (30 of 98), and 51.02% (50 of 98), respectively. Using Fisher’s exact test, we found the polymorphism IVS62+60G>A was not significantly related to age, tumor grade, prostate-specific antigen level, or clinical stage ( P >0.05). No difference was found in relapse-free survival between patients with IVS62+60G/G and those with IVS62+60G/A or IVS62+60A/A ( P = 0.4533). Conclusions The results of our study indicate that this ATM polymorphism is not associated with the aggressiveness of prostate cancer in white men.

ATM Polymorphism and hereditary nonpolyposis colorectal cancer (HNPCC) ageof onset (United States)

We examined a G-to-A single nucleotide polymorphism of the ATM gene, to determine if it influences hereditary non-polyposis colorectal cancer (HNPCC) age of onset. HNPCC is caused by mutations in mismatch repair genes, especially hMLH1 and hMSH2. ATM germline mutations have been associated with breast and digestive cancers. In a smaller European study, the G-to-A polymorphism was associated with an increased risk of developing an HNPCC-related cancer within HNPCC families. We genotyped 109 mismatch repair gene (MMR) mutation carriers from 53 HNPCC families for the ATM polymorphism using PCR and single strand conformational polymorphism (SSCP) analysis. We tested the association between the ATM genotypes and HNPCC age of onset by survival analysis. The ATM polymorphism did not significantly modify HNPCC age of onset, nor overall risk, in our population. Although a modifier effect was not seen in our study, future studies that examine the polymorphism in combination with other genetic and environmental factors may elucidate an association. Revealing such associations in MMR mutation carriers may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.

ATM polymorphisms as risk factors for prostate cancer development.

The risk of prostate cancer is known to be elevated in carriers of germline mutations in BRCA2, and possibly also in carriers of BRCA1 and CHEK2 mutations. These genes are components of the ATM-dependent DNA damage signalling pathways. To evaluate the hypothesis that variants in ATM itself might be associated with prostate cancer risk, we genotyped five ATM variants in DNA from 637 prostate cancer patients and 445 controls with no family history of cancer. No significant differences in the frequency of the variant alleles at 5557G>A (D1853N), 5558A>T (D1853V), ivs38-8t>c and ivs38-15g>c were found between the cases and controls. The 3161G (P1054R) variant allele was, however, significantly associated with an increased risk of developing prostate cancer (any G vs CC OR 2.13, 95% CI 1.17–3.87, P=0.016). A lymphoblastoid cell line carrying both the 3161G and the 2572C (858L) variant in the homozygote state shows a cell cycle progression profile after exposure to ionising radiation that is significantly different to that seen in cell lines carrying a wild-type ATM gene. These results provide evidence that the presence of common variants in the ATM gene, may confer an altered cellular phenotype, and that the ATM 3161C>G variant might be associated with prostate cancer risk.

Global Analysis of ATM Polymorphism Reveals Significant Functional Constraint

ATM, the gene that is mutated in ataxia-telangiectasia, is associated with cerebellar degeneration, abnormal proliferation of small blood vessels, and cancer. These clinically important manifestations have stimulated interest in defining the sequence variation in the ATM gene. Therefore, we undertook a comprehensive survey of sequence variation in ATM in diverse human populations. The protein-encoding exons of the gene (9,168 bp) and the adjacent intron and untranslated sequences (14,661 bp) were analyzed in 93 individuals from seven major human populations. In addition, the coding sequence was analyzed in one chimpanzee, one gorilla, one orangutan, and one Old World monkey. In human ATM, 88 variant sites were discovered by denaturing high-performance liquid chromatography, which is 96%-100% sensitive for detection of DNA sequence variation. ATM was compared to 14 other autosomal genes for nucleotide diversity. The noncoding regions of ATM had diversity values comparable to other genes, but the coding regions had very low diversity, especially in the last 29% of the protein sequence. A test of the neutral evolution hypothesis, through use of the Hudson/Kreitman/Aguadé statistic, revealed that this region of the human ATM gene was significantly constrained relative to that of the orangutan, the Old World monkey, and the mouse, but not relative to that of the chimpanzee or the gorilla. ATM displayed extensive linkage disequilibrium, consistent with suppression of meiotic recombination at this locus. Seven haplotypes were defined. Two haplotypes accounted for 82% of all chromosomes analyzed in all major populations; two others carrying the same D126E missense polymorphism accounted for 33% of chromosomes in Africa but were never observed outside of Africa. The high frequency of this polymorphism may be due either to a population expansion within Africa or to selective pressure.

New mutations, polymorphisms, and rare variants in the ATM gene detected by a novel SSCP strategy.

The gene for ataxia-telangiectasia, ATM, spans about 150 kb of genomic DNA. ATM mutations are found along the entire gene, with no evidence of a mutational hot spot. Using DNA as the starting material, we screened the ATM gene in 92 A-T patients, using an optimized single-strand conformation polymorphism (SSCP) technique that detected all previously known mutations in the polymerase chain reaction (PCR) segments being analyzed. To expedite screening, we sequentially loaded the SSCP gels with three different sets of PCR products that were pretested to avoid overlapping patterns. Many of the DNA changes we detected were intragenic polymorphisms. Of an expected 177 unknown mutations, we detected approximately 70%, mostly protein truncating mutations (that would have been detectable by protein truncation testing if RNA starting material had been available). Mutations have now been defined for every exon of the ATM gene. Herein, we present 35 new mutations and 34 new intragenic polymorphisms or rare variants within the ATM gene. This is the most comprehensive compilation of ATM polymorphisms assembled to date. Defining polymorphic sites as well as mutations in the ATM gene will be of great importance in designing automated methods for detecting mutations.