Genetic susceptibility to therapy-related leukemia after Hodgkin lymphoma or non-Hodgkin lymphoma: role of drug metabolism, apoptosis and DNA repair.
Ontology highlight
ABSTRACT:
SUBMITTER: Ding Y
PROVIDER: S-EPMC3317523 | biostudies-literature | 2012 Mar
REPOSITORIES: biostudies-literature
Publications
Genetic susceptibility to therapy-related leukemia after Hodgkin lymphoma or non-Hodgkin lymphoma: role of drug metabolism, apoptosis and DNA repair.
Ding Y Y Sun C-L CL Li L L Li M M Francisco L L Sabado M M Hahn B B Gyorffy J J Noe J J Larson G P GP Forman S J SJ Bhatia R R Bhatia S S
Blood cancer journal 20120302 3
Similar Datasets
Project description:Female Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211 155 germline single-nucleotide polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate, <20%), of which 1 SNP in the PVT1 oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a fourfold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients.
| S-EPMC6405334 | biostudies-literature
Project description:Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10-8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10-9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10-8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.
| S-EPMC10337695 | biostudies-literature
Project description:Genetic susceptibility to DNA oxidation, carcinogen metabolism, and altered DNA repair may increase non-Hodgkin lymphoma (NHL) risk, whereas vegetables- and antioxidant-related nutrients may decrease risk. We evaluated the interaction of a priori-defined dietary factors with 28 polymorphisms in these metabolic pathways. Incident cases (n = 1,141) were identified during 1998-2000 from four cancer registries and frequency-matched to population-based controls (n = 949). We estimated diet-gene joint effects using two-phase semi-parametric maximum-likelihood methods, which utilized genotype data from all subjects as well as 371 cases and 311 controls with available diet information. Adjusted odds ratios (95% confidence intervals) were lower among common allele carriers with higher dietary intakes. For the GSTM3 3-base insertion and higher total vegetable intake, the risk was 0.56 (0.35-0.92, p interaction = 0.03); for GSTP1 A114V and higher cruciferous vegetable intake, the risk was 0.52 (0.34-0.81, p interaction = 0.02); for OGG1 S326C and higher daily zinc intake, the risk was 0.71 (0.47-1.08, p interaction = 0.04) and for XRCC3 T241M and higher green leafy vegetable intake, the risk was 0.63 (0.41-0.97, p interaction = 0.03). Calculation of the false positive report probability determined a high likelihood of falsely positive associations. Although most associations have not been examined previously with NHL, our results suggest the examined polymorphisms are not modifiers of the association between vegetable and zinc intakes and NHL risk.
| S-EPMC2804920 | biostudies-literature
Project description:Non-Hodgkin lymphoma (NHL) is a hematological malignancy of the immune system, and, as with autoimmune and inflammatory diseases (ADs), is influenced by genetic variation in the major histocompatibility complex (MHC). Persons with a history of specific ADs also have increased risk of NHL. As the coexistence of ADs and NHL could be caused by factors common to both diseases, here we examined whether some of the associated genetic signals are shared. Overlapping risk loci for NHL subytpes and several ADs were explored using data from genome-wide association studies. Several common genomic regions and susceptibility loci were identified, suggesting a potential shared genetic background. Two independent MHC regions showed the main overlap, with several alleles in the human leukocyte antigen (HLA) class II region exhibiting an opposite risk effect for follicular lymphoma and type I diabetes. These results support continued investigation to further elucidate the relationship between lymphoma and autoimmune diseases.
| S-EPMC3129413 | biostudies-literature
Project description:The damage caused by oxidative stress and exposure to cigarette smoke and alcohol necessitate DNA damage repair and transport by multidrug resistance-1 (MDR1). To explore the association between polymorphisms in these genes and non-Hodgkin lymphoma risk, we analyzed 15 polymorphisms of 12 genes in a population-based study in Korea (694 cases and 1700 controls). Four genotypes of DNA repair pathway genes (XRCC1 399 GA, OGG1 326 GG, BRCA1 871 TT, and WRN 787 TT) were associated with a decreased risk for NHL [odds ratio (OR)XRCC1 GA=0.80, p=0.02; OROGG1 GG=0.70, p=0.008; ORBRCA1 TT=0.71, p=0.048; ORWRN TT=0.68, p=0.01]. Conversely, the MGMT 115 CT genotype was associated with an increased risk for NHL (OR=1.25, p=0.04). In the MDR1 gene, the 1236 CC genotype was associated with a decreased risk for NHL (OR=0.74, p=0.04), and the 3435 CT and TT genotypes were associated with an increased risk (OR3435CT=1.50, p<0.0001; OR3435TT=1.43, p=0.02). These results suggest that polymorphisms in the DNA repair genes XRCC1, OGG1, BRCA1, WRN1, and MGMT and in the MDR1 gene may affect the risk for NHL in Korean patients.
| S-EPMC4013656 | biostudies-literature
Project description:PurposeGenetic polymorphisms in DNA repair genes and hair dye use may both have a role in the development of non-Hodgkin lymphoma (NHL). We aimed to examine the interaction between variants in DNA repair genes and hair dye use with risk of NHL in a population-based case-control study of Connecticut women.MethodsWe examined 24 single nucleotide polymorphisms in 16 DNA repair genes among 518 NHL cases and 597 controls and evaluated the associations between hair dye use and risk of overall NHL and common NHL subtypes, stratified by genotype, using unconditional logistic regression.ResultsWomen who used hair dye before 1980 had a significantly increased risk of NHL, particularly for the follicular lymphoma (FL) subtype, but not for diffuse large B-cell lymphoma. The following genotypes in combination with hair dye use before 1980 were associated with FL risk: BRCA2 rs144848 AC+CC [odds ratio (OR) (95% confidence interval (CI)) 3.28(1.27-8.50)], WRN rs1346044 TT [OR(95% CI) 2.70(1.30-5.65)], XRCC3 rs861539 CT+TT [OR(95% CI) 2.76(1.32-5.77)], XRCC4 rs1805377 GG [OR(95% CI) 2.07(1.10-3.90)] and rs1056503 TT [OR(95% CI) 2.17(1.16-4.07)], ERCC1 rs3212961 CC [OR(95% CI) 1.93(1.00-3.72)], RAD23B rs1805329 CC [OR(95% CI) 2.28(1.12-4.64)], and MGMT rs12917 CC, rs2308321 AA, and rs2308327 AA genotypes [OR(95% CI) 1.96(1.06-3.63), 2.02(1.09-3.75), and 2.23(1.16-4.29), respectively]. In addition, a significant interaction with risk of overall NHL was observed between WRN rs1346044 and hair dye use before 1980 (p(interaction) = 0.032).ConclusionsOur results indicated that genetic variation in DNA repair genes modifies susceptibility to NHL in relation to hair dye use, particularly for the FL subtype and in women who began using hair dye before 1980. Further studies are needed to confirm these observations.
| S-EPMC4843788 | biostudies-literature
Project description:We conducted a population-based case-control study in Connecticut women to test the hypothesis that genetic variations in DNA repair pathway genes may modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL). Compared to those with BMI <25, women with BMI ?25 had significantly increased risk of NHL among women who carried BRCA1 (rs799917) CT/TT, ERCC2 (rs13181) AA, XRCC1 (rs1799782) CC, and WRN (rs1801195) GG genotypes, but no increase in NHL risk among women who carried BRCA1 CC, ERCC2 AC/CC, XRCC1 CT/TT, and WRN GT/TT genotypes. A significant interaction with BMI was only observed for WRN (rs1801195; P?=?0.004) for T-cell lymphoma and ERCC2 (rs13181; P?=?0.002) for diffuse large B-cell lymphoma. The results suggest that common genetic variation in DNA repair pathway genes may modify the association between BMI and NHL risk.
| S-EPMC3902049 | biostudies-literature
Project description:Inhibition of the mitochondrial metabolism offers a promising therapeutic approach for the treatment of cancer. Here, we identify the mycotoxin viriditoxin (VDT), derived from the endophytic fungus Cladosporium cladosporioides, as an interesting candidate for leukemia and lymphoma treatment. VDT displayed a high cytotoxic potential and rapid kinetics of caspase activation in Jurkat leukemia and Ramos lymphoma cells in contrast to solid tumor cells that were affected to a much lesser extent. Most remarkably, human hematopoietic stem and progenitor cells and peripheral blood mononuclear cells derived from healthy donors were profoundly resilient to VDT-induced cytotoxicity. Likewise, the colony-forming capacity was affected only at very high concentrations, which provides a therapeutic window for cancer treatment. Intriguingly, VDT could directly activate the mitochondrial apoptosis pathway in leukemia cells in the presence of antiapoptotic Bcl-2 proteins. The mitochondrial toxicity of VDT was further confirmed by inhibition of mitochondrial respiration, breakdown of the mitochondrial membrane potential (ΔΨm), the release of mitochondrial cytochrome c, generation of reactive oxygen species (ROS), processing of the dynamin-like GTPase OPA1 and subsequent fission of mitochondria. Thus, VDT-mediated targeting of mitochondrial oxidative phosphorylation (OXPHOS) might represent a promising therapeutic approach for the treatment of leukemia and lymphoma without affecting hematopoietic stem and progenitor cells.
| S-EPMC9643474 | biostudies-literature
Project description:BackgroundThis study aimed to determine whether single nucleotide polymorphisms (SNPs) in genes involved in DNA repair or metabolism of taxanes or platinum could predict toxicity or response to first-line chemotherapy in ovarian cancer.MethodsTwenty-six selected SNPs in 18 genes were genotyped in 322 patients treated with first-line paclitaxel-carboplatin or carboplatin mono-therapy. Genotypes were correlated with toxicity events (anemia, neutropenia, thrombocytopenia, febrile neutropenia, neurotoxicity), use of growth factors and survival.ResultsThe risk of anemia was increased for variant alleles of rs1128503 (ABCB1, C > T; p = 0.023, OR = 1.71, 95% CI = 1.07-2.71), rs363717 (ABCA1, A > G; p = 0.002, OR = 2.08, 95% CI = 1.32-3.27) and rs11615 (ERCC1, T > C; p = 0.031, OR = 1.61, 95% CI = 1.04-2.50), while it was decreased for variant alleles of rs12762549 (ABCC2, C > G; p = 0.004, OR = 0.51, 95% CI = 0.33-0.81). Likewise, increased risk of thrombocytopenia was associated with rs4986910 (CYP3A4, T > C; p = 0.025, OR = 4.99, 95% CI = 1.22-20.31). No significant correlations were found for neurotoxicity. Variant alleles of rs2073337 (ABCC2, A > G; p = 0.039, OR = 0.60, 95% CI = 0.37-0.98), rs1695 (ABCC1, A > G; p = 0.017, OR = 0.55, 95% CI 0.33-0.90) and rs1799793 (ERCC2, G > A; p = 0.042, OR = 0.63, 95% CI 0.41-0.98) associated with the use of colony stimulating factors (CSF), while rs2074087 (ABCC1, G > C; p = 0.011, OR = 2.09, 95% CI 1.18-3.68) correlated with use of erythropoiesis stimulating agents (ESAs). Homozygous carriers of the rs1799793 (ERCC2, G > A) G-allele had a prolonged platinum-free interval (p = 0.016).ConclusionsOur data reveal significant correlations between genetic variants of transport, hepatic metabolism, platinum related detoxification or DNA damage repair and toxicity or outcome in ovarian cancer.
| S-EPMC4359565 | biostudies-literature
Project description:BACKGROUND:Translocations are hallmarks of non-Hodgkin lymphoma (NHL) genomes. Because lymphoid cell development processes require the creation and repair of double stranded breaks, it is not surprising that disruption of this type of DNA repair can cause cancer. The members of the MRE11-RAD50-NBS1 (MRN) complex and BLM have central roles in maintenance of DNA integrity. Severe mutations in any of these genes cause genetic disorders, some of which are characterized by increased risk of lymphoma. METHODS:We surveyed the genetic variation in these genes in constitutional DNA of NHL patients by means of gene re-sequencing, then conducted genetic association tests for susceptibility to NHL in a population-based collection of 797 NHL cases and 793 controls. RESULTS:114 SNPs were discovered in our sequenced samples, 61% of which were novel and not previously reported in dbSNP. Although four variants, two in RAD50 and two in NBS1, showed association results suggestive of an effect on NHL, they were not significant after correction for multiple tests. CONCLUSION:These results suggest an influence of RAD50 and NBS1 on susceptibility to diffuse large B-cell lymphoma and marginal zone lymphoma. Larger association and functional studies could confirm such a role.
| S-EPMC2788526 | biostudies-literature