Genetic polymorphisms in microsomal epoxide hydrolase 
and susceptibility to adult acute myeloid leukaemia 
with defined cytogenetic abnormalities

Abstract

Summary. Acute myeloid leukaemia (AML) cases with different chromosomal abnormalities may reflect different aetiologies. Benzene exposure, from a number of sources including smoking, is one risk factor for AML. Individual susceptibility to benzene may depend on differences in expression of metabolizing enzymes. We tested the hypothesis that smoking as well as genetic polymorphisms in the microsomal epoxide hydrolase gene (HYL1), an enzyme involved in benzene metabolism, could be risk factors for AML with defined chromosomal abnormalities. Twenty-six AML cases with )7/del(7q) and 24 cases with t(8;21), as well as 43 cases with normal karyotype and 155 age-, sex-and residence-matched controls, were drawn from a large case-control study on adult acute leukaemia. Current smoking was significantly associated with the cytogenetic abnormalities t(8;21) or )7/del(7q) (OR ¼ 4AE9; 95%CI ¼ 2AE1-11AE5) but not with a normal karyotype, relative to individuals who were not current smokers. A putative high activity HYL1 phenotype [exon 3, residue 113 (Tyr/Tyr) and exon 4, residue 139 (His/Arg or Arg/ Arg)] was associated with a significantly increased AML risk in men with )7/del(7q) or t(8;21) (OR ¼ 4AE4; 95%CI 1AE1-17AE0) but not with a normal karyotype. This suggests that AML cases with defined chromosomal abnormalities could be related to specific carcinogen exposures and, furthermore, suggests that smoking and genetic polymorphisms in HYL1 could be risk factors for AML with )7/del(7q) or t(8;21).

The late radiotherapy normal tissue injury phenotypes of telangiectasia, fibrosis and atrophy in breast cancer patients have distinct genotype-dependent causes

“…Transforming growth factor-b1 polymorphisms were confirmed by direct sequencing. The frequencies of the variant alleles were comparable with those reported in other studies (Hu et al, 2001;McDermott et al, 2001;Lebailly et al, 2002;Quarmby et al, 2003;Johnson et al, 2004;Linnebank et al, 2004), and all SNPs were in Hardy -Weinberg equilibrium (Table 4).…”

“…The genes and corresponding SNP were chosen because XRCC1 (R399Q) and APE-1 (D126E) have been implicated in DNA repair (Hu et al, 2001;Chang-Claude et al, 2005;De Ruyck et al, 2005), TGFb1 (C-509T) and CX3CR1 (G745A) have been implicated in inflammation and fibrosis (Zugmaier et al, 1991;Randall and Coggle, 1995;Anscher et al, 1997;Li et al, 1999;Martin et al, 2000;McDermott et al, 2001;Gauldie et al, 2003), MTHFR (C667T), MS (A2756G) and DHFR (19 bp del intron 1) involved in folate metabolism (Johnson et al, 2004;Linnebank et al, 2004), epoxide hydrolase (Hyl1 Y113H) implicated in oxidative stress (Lebailly et al, 2002), and XRCC1 (R399Q) have been associated with susceptibility to breast cancer (Moullan et al, 2003). Additionally, several gene polymorphism have previously been implicated in late radiation-induced tissue damage (Awad et al, 1988;El-Gamel et al, 1999;Grainger et al, 1999;Quarmby et al, 2003;Andreassen et al, 2005;De Ruyck et al, 2005Brem et al, 2006), and TGFb1 and Hyl1 are induced following exposure to ionising radiation (Anscher et al, 1997;Martin et al, 1997).…”

“…DNA was extracted from the buccal samples using the QIAamp DNA mini kit (QIAGEN GmbH, Germany), using the standard manufacturers' protocol. DNA was PCR amplified and analysed for QTG restriction fragment length polymorphisms using published PCR primers and PCR conditions, and restriction enzymes: TGFb1 (C-509T) (Quarmby et al, 2003); X-ray repair cross-complementing 1 (XRCC1; R399Q) and apurinic/apyrimidinic endonuclease (APE-1; D126E) (Hu et al, 2001); dihydrofolate reductase (DHFR; 15 bp intron 1 deletion) (Johnson et al, 2004); the CX3CR1 (G745A) fractalkine receptor (McDermott et al, 2001); epoxide hydrolase (Hyl-1; Y113H) (Lebailly et al, 2002); and methionine synthetase (MS; A2756G) and methylenetetrahydrofolate reductase (MTHFR; C667T) (Linnebank et al, 2004).…”

Low-penetrance genetic susceptibility and resistance loci implicated in the relative risk for radiation-induced acute myeloid leukemia in mice

“…5,[7][8][9][10] Efforts to elucidate the genetic factors that modulate susceptibility to therapy-related AML have concentrated on enzymes involved in carcinogen detoxification, and polymorphic variations in the genes encoding NAD(P)H:quinone oxidoreductase, cytochrome P450 3A4, epoxide hydrolase, and glutathione S-transferase, found to be associated with susceptibility to induced AML. [11][12][13][14][15] r-AML in inbred CBA/H mice is widely considered the most appropriate mouse model of human r-AML. Mouse r-AMLs arise after a long latency (mean latency, 480 days after irradiation), indicating that malignant transformation of the target HSC is a multistage process and there is a low (less than 0.1%) incidence of de novo AML in control CBA/H mice.…”

Polimorfismos genéticos, susceptibilidade e resposta ao tratamento em crianças portadoras de leucemia linfoblástica aguda

“…Na análise do alelo rápido (mEH H139R), a freqüência do genótipo homozigoto polimórfico encontrado no grupo controle (2%) está em concordância com a freqüência encontrada em outras populações (Smith, Harrison, 1997;Huang et al, 2005 Embora esses resultados estejam em discrepância com os demais trabalhos citados anteriormente, estudos realizados em outros tipos de tumores, como adenocarcinoma de esôfago (Casson et al, 2003), câncer pulmonar (Gsur et al, 2003), carcinoma de laringe (To-Figueiras et al, 2002) e orofaringe (Amador et al, 2002), e leucemia milóide em adultos (Lebailly, et al, 2002) (Olson et al, 2004;Liu et al, 2004 (Tuimala et al, 2002). Conseqüentemente, um risco individual intrínsico de desenvolvimento de LLA na infância, ou para proteção contra LLA, pode depender do equilíbrio entre a eficiência em metabolizar carcinógenos genotóxicos e a capacidade para reparar os danos no DNA.…”