|Year : 2015 | Volume
| Issue : 4 | Page : 479-489
Cytochrome P450 1A1 genetic polymorphisms as cancer biomarkers
A Bag1, NS Jyala1, N Bag2
1 Department of Biochemistry, Government Medical College, Haldwani, Uttarakhand, India
2 Department of Horticulture, Sikkim University, Gangtok, Sikkim, India
|Date of Web Publication||10-Mar-2016|
Department of Biochemistry, Government Medical College, Haldwani, Uttarakhand
Source of Support: None, Conflict of Interest: None
Phase I metabolic enzyme CYP1A1 plays an important role in xenobiotics metabolism and has been extensively studied as a cancer risk biomarker. CYP1A1 is polymorphic and its four variants, e.g., CYP1A1* 2 A, CYP1A1* 2C, CYP1A1* 3 and CYP1A1* 4 with trivial names m1, m2, m3, and m4 respectively, are most commonly studied for cancer link. Gene- gene interaction studies combining polymorphisms of this enzyme with those of phase II detoxifying enzymes, especially glutathione S- transferases (GSTs) revealed greater risk for cancer susceptibility. Variants of CYP1A1 have also been found to be associated with chemotherapeutic adverse- effects. Results of these studies, however, remained largely contradictory mainly because of lack of statistical power due to involvement of small sample size. Strongly powered experimental designs involving gene- gene, gene- environment interactions are required in order to validate CYP1A1 as reliable cancer- biomarker.
Keywords: Biomarker, cancer, combined genotype, CYP1A1, polymorphism, toxicity marker
|How to cite this article:|
Bag A, Jyala N S, Bag N. Cytochrome P450 1A1 genetic polymorphisms as cancer biomarkers. Indian J Cancer 2015;52:479-89
| » Introduction|| |
Gain or loss of gene functions may influence disease susceptibility or treatment outcome in an individual. Altered expression of xenobiotic metabolizing enzymes, which are responsible for detoxification of xenobiotics may have obvious effects on metabolism of environmental carcinogens or drugs in human body. Thus genetic polymorphisms of these enzymes may play significant role in cancer development and varied chemotherapeutic response. These enzymes are grouped into phase I and phase II enzymes, which complement one another in the detoxification process of xenobiotics.
Cytochrome P450 enzymes (CYPs) constitute important group of phase I enzymes. They are involved in metabolism of environmental chemicals, and their genetic variations have been found to be associated with risk of several forms of cancer. CYPs are also responsible for metabolism of more than 90% of clinically prescribed drugs.
CYP1A1 enzyme, previously known as aryl hydrocarbon hydroxylase, is a major phase I enzyme. Unlike majority of CYPs that are expressed mainly in human liver, CYP1A1 is expressed predominantly in extra hepatic tissues, e.g., lung, breast, ovarian follicles etc., Since CYP1A1 plays key role in the activation of pro-carcinogens, e.g., polycyclic aromatic hydrocarbons (PAHs) and aromatic amines, geneticpolymorphisms of this enzyme have been extensively studied for susceptibility to chemically induced cancers. CYP1A1 converts these procarcinogens to their ultimate DNA binding forms. For example, benzo[a] pyrene, a weak carcinogenic PAH is converted to 7,8-epoxide with the action of CYP1A1, which is then hydrolyzed by microsomal enzyme epoxide hydroxylase (EPHX1) to form benzo[a]pyrene-7,8-dihydrodiol. This compound then undergoes another epoxidation by CYP1A1 to form benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide, which is much more potent carcinogen and can form guanine adducts on DNA. If this DNA damage remains un- repaired, it may lead to carcinogenesis.
CYP1A1 is inducible by some carcinogenic substances. Induction of CYP1A1 is initiated by binding of specific ligand like PAHs to aryl hydrocarbon receptor (AHR), which is then translocated into the nucleus by AHR nuclear translocator (ARNT). AHR/ARNT heterodimer then binds to xenobiotic response element (XRE) of CYP1A1 gene leading to transcription.
Other than activation of xenobiotics, CYP1A1 also plays a key role in estrogen metabolism. It catalyzes the hydroxylation of 17-β estradiol. Hence, CYP1A1 polymorphisms may be related to gynecological cancer risk also.
It has been found that 40% of human CYP450 forms that are involved in xenobiotic metabolism are polymorphic. The CYP1A1 gene is located at 15q24.1 and has seven exons and six introns. A total of 11 variant alleles have been identified for CYP1A1, CYP1A1*1 to CYP1A1*11. Different nomenclature systems have been developed for CYP1A1 alleles, which have often created confusion regarding identity of a particular CYP1A1 allele. In the present article nomenclature system recommended in http://www.imm.ki.se/CYPalleles has been followed. Other than 11 alleles, some additional single nucleotide polymorphisms (SNPs) have also been detected and cited in this homepage, for which haplotypes have not been determined. Among these variants, four alleles, CYP1A1*2A (3698 T >C), CYP1A1*2C (2454 A >G), CYP1A1*3 (3204 T >C) and CYP1A1*4 (2452C >A), with trivial names m1, m2, m3 and m4 respectively, have been studied mostly for the association with cancer. CYP1A1*1 is the wild type allele. CYP1A1*2C and CYP1A1*4 are lying only two bases apart, both on exon seven. The m2 polymorphism leads to an amino acid substitution of Val for Ile (I462V) in the heme-binding region; m4 causes substitution of Asn for Thr (T461N) in the same region of the enzyme. While m2 mutation leads to an enhanced enzymatic activity in comparison to its wild type allele, effect of m4 is not clearly understood. Both m1 and m3 do not cause any amino acid substitution as m1 is on 3' non- coding region and m3 is on intron seven. However, m1 allele may lead to an elevated enzyme activity. The m1 mutation is also known as Msp I polymorphism as it gains a Msp I restriction site.
Distribution of CYP1A1 polymorphisms in different populations, Caucasians, African- Americans and Asians has been described in an exhaustive review by Masson et al. They found in pool analysis that the m1 variant allele is most prevalent in Asian populations (13%) and it was present in much lower frequency in Caucasians (1%). And in African- Americans the frequency was intermediate between that of Asians and Caucasians (6%). Likewise, m2 homozygous variant allele was found to be common among Asians (5%) and very rare in Caucasians (0.7%) and absent in African Americans., The I462V polymorphism when linked with Msp I polymorphism is designated as CYP1A1*2B, a common genotype in Caucasians. The m1 and m2 allele have been found to be in linkage disequilibrium (LD) in many other populations also.,CYP1A1*3 variant is prevalent in African- Americans. Asian studies rarely observed the presence of m4 variant ,, while it is more common among whites.
In the present review we summarize the studies on CYP1A1 genetic polymorphisms as cancer susceptibility biomarkers. Here we also include the studies exploring CYP1A1 as marker for chemotherapeutic outcome. Studies were identified through electronic databases primarily from MEDLINE using keywords “CYP1A1 polymorphisms and cancer”.
Association with cancer susceptibility
Head and neck cancer
Association of C---- YP1A1 polymorphisms with risk of head and neck cancer has been extensively studied. The main etiological factor of head and neck cancer includes excessive intake of tobacco either by smoking or by chewing. Smoking related laryngeal and hypopharyngeal squamous cell carcinoma (SCC) risk was evaluated by Tai et al. in a Chinese population. Significant relation between m1 and m2 polymorphisms and increased cancer risk was observed. Further, combined effect of smoking and m1 polymorphism was also found in this study. A positive association between m1 polymorphism and laryngeal SCC was also noted in Caucasians of Portugal.
CYP1A1I462V has been found to be linked with oral cancer., However, in many studies no relation was established between this polymorphism and oral cancer risk.,m1 was not found to be linked with oral cancer risk., In a meta- analysis and pooled analysis Varela-Lema et al. found a positive association of *2A as well as *2C polymorphism with oral and pharyngeal cancer in ever smokers. Gajecka et al, found CYP1A1*4 variant to be associated with laryngeal SCC. In India oral cancer is one of the leading cancers in men. Sreelekha et al, found a positive association of m2 polymorphism with oral cancer in Indians while findings of Chatterjee et al, did not reveal any association of m2 with leukoplakia. The Msp I genotype was not found to be associated with oral pre- cancer or cancer in Indians by Anantharaman et al. In a recent meta- analysis Zhuo et al, found Msp I polymorphism as a risk factor in Caucasians, not for Asians.
Lung cancer is the leading cause of cancer death in men and second major lethal cancer in women. This disease has been found to be conclusively associated with tobacco smoking. Tobacco smoke comprises of nearly 60 carcinogenic compounds including PAH(s). It was estimated that 85% lung cancer in men and 45% cases in women were caused due to tobacco smoking. However, other environmental carcinogens, like smoky coal combustion etc., with carcinogenic constituents also can contribute to the development of lung cancer significantly.
It is known today that not all but only a fragment of smoker population (<20%) develops lung cancer, which indicates involvement of genetic variants in lung cancer development. A number of studies have been carried out on the association between CYP1A1 variants with lung cancer risk in last few decades although results were contradictory. While varying gene frequencies in different ethnicities might be one of the plausible explanations for these conflicting results, the main factor responsible is a lack of adequate statistical power as these are low penetrance alleles and require large sample size from a specific ethnicity.
Several studies indicate association of m1 and m2 alleles with lung cancer risk in Chinese population. In a case- control study Song et al, assessed the role of CYP1A1 Msp I, CYP1A1 I462V and CYP1A1 T461N in the development of lung cancer in Chinese. They noted significantly higher risk of lung cancer for Msp I and I462V variant alleles, even when individuals were heterozygous for these variants. However, this elevated risk was restricted to squamous cell carcinoma (SCC) only, not for adenocarcinoma (AC) or other histological types of lung cancer. Similarly, smokers with at least one variant allele of m1 and m2 had twice the risk than with homozygous wild type alleles. They also found gene- smoking interaction for both of these variants when they stratified their data by pack- years; the risk of variant alleles was higher for heaviest smokers. Yang et al, tested CYP1A1 I462V mutation as a risk factor for lung cancer in Chinese women. They observed that a combined m2 genotype (Ile/Val and Val/Val) was significantly associated with lung cancer risk. A study by Wang et al, however, did not reveal any heightened risk of m1 polymorphism for lung cancer in Chinese population. In a meta- analysis Shi et al. concluded that CYP1A1 variants were associated with lung cancer in Chinese. Early Japanese studies documented m1 and m2 as risk factors for developing lung cancer. Other studies on Asians include a Korean study documenting a positive association between CYP1A1 variant and lung cancer risk  while in South Indians individuals with Msp I homozygous alleles were found to be at significantly higher risk for lung cancer. A study on North Indian population documented positive association of both Msp I and I462V variants with lung cancer susceptibility. Both the Indian studies found higher risk for respective variants in heavy smokers.
In a pooled analysis, including 1950 cases and 2617 controls Marchand et al. found association between inducible form of CYP1A1 I462V, and lung cancer. The interaction was stronger for SCC than AC. And the effect was particularly higher in never smokers and women. Other case- control studies demonstrated I462V polymorphism as a susceptibility factor for non- small cell lung carcinoma (NSCLC) in Caucasians., Larsen et al, recruited large number of individuals (1050 cases and 581 controls), and found the women carriers with Val alleles of m2 polymorphism as more prone to develop NSCLC. CYP1A1*4 was found to be associated with lung cancer in Mexicans. The role of Msp I variant in lung cancer formation has been found to be conflicting in Caucasians. In a pooled analysis of 2451 cases and 3358 controls Vineis et al, found Msp I homozygous variant was significantly associated with SCC as well as AC(s) among Caucasians, and there was a stronger association in men than in women. However, no significant association could be detected for the Asians. In a pooled analysis Taioli et al, detected that Msp I variant allele (CYP1A1*2 A and *2B) genotype was a risk factor in Caucasian never smokers. In studies from Portugal's midland  and Brazilian  populations CYP1A1*2 A, however, could not be detected as risk factor. In a case- control study Cote et al, interestingly found that the Caucasians with Ile/Val genotypes of m2 polymorphism was at decreased risk for lung cancer than those with homozygous wild type alleles (Ile/Ile). However, such protective role could not be replicated in African- Americans in the same study.
CYP1A1 gene is inducible by tobacco carcinogen hence a large number of experiments have been carried out to study the association of this gene with lung cancer risk in smokers. However, parallel studies in non-smoking populations would reveal a true disease- genotype association as any susceptibility for lung cancer in these cases will be generated in non- inducing environment. According to Song et al, non- smokers with m1 variants had elevated risk than those homozygous for wild type alleles. Ng et al. conducted their experiment in life- time non- smoking Chinese women, and found elevated risk of lung cancer for both homozygous m1 and m2 genotypes. Furthermore, lung cancer risk associated with both polymorphisms was higher in women with lower exposure to environmental tobacco smoke. Yang et al, also found such association was more pronounced among non- smokers than among smokers. Hung et al., conducted a pooled analysis of case- control experiments carried out in non- smoker Caucasians. They found that hetero- and homozygous variant alleles of I462V had higher risk for lung cancer, especially for lung adenocarcinoma. In this analysis in non- smoker Caucasians the authors ruled out any significant influence of the Msp I polymorphism in lung cancer. Although low level association of Msp I polymorphism with lung cancer could occur due to its link with I462V polymorphisms (*2B) in Caucasians.
Gastrointestinal tract cancer
CYP1A1 has been studied for its link with gastrointestinal tract cancer also. Mostly, CYP1A1 Msp I polymorphism has not been found to be related with esophageal cancer., The results were not changed for patients exposed to smoke or occupational exposure. Moreover, in the patients with alcohol habits, the non- variant genotype (TT) showed a higher (not- significant) risk for esophageal cancer in Indians. Interestingly in a case- control study in Chinese population, Wang et al, observed a protective effect of Msp I polymorphism in esophageal carcinoma. Unlike Msp I the Val allele of I462V polymorphism have often been linked to this cancer ,, with few exceptions.
In another case- control study on Indian gastric cancer patients, Malik et al, did not find CYP1A1Msp I polymorphism as a susceptibility marker for gastric cancer. Similarly, Msp I was not found be linked with gastric cancer in other studies also,, though sample size in these studies was too small to bring a conclusive result. Notably Agudo et al, observed inverse association for m1 genotype in gastric cancer and increased risk for relatively uncommon SNP m4 in a nested case- control study developed in 10 European countries. Roth et al., observed a reduced risk of CYP1A1*2 A hetero- or homozygous variant alleles for gastric cardia cancer in Asian population. CYP1A1*2 A was found to be more pronounced among Lebanese gastric cancer patients by Darazy et al.
An over representation of the CYP1A1*2C variant was documented in a large case- control study employing 490 colorectal cancer patients and 593 controls  and in a Brazilian study.Msp I polymorphism was not linked to the development of colorectal cancer in the Scottish, while higher prevalence of *2A variant allele (T/C) was noted among such type of cancer patients without any smoking habits. Little et al., detected an inverse association of CYP1A1*4 polymorphism with colorectal cancer. According to Pande et al,TC genotype of CYP1A1 Msp I was associated with earlier onset of colorectal cancer among individuals with Lynch syndrome. However, the authors suggested that this SNP might not be the source of this age shift. Rather any other SNP at different locus in LD with the CYP1A1 SNPs could lead to this shift. A composite genotype of CYP1A1*2 A or CYP1A1*2C and GSTT1 polymorphisms was found to be associated with a decreased risk of colorectal cancer in a study involving 685 cases and 778 controls. Hou et al, found another gene combination of CYP1A1 I462V and NQO1 ser (187) linked with colorectal adenoma particularly among smokers.
Biliary tract cancers are although uncommon, they can be fatal sometimes. Park et al, in their study on a Chinese population found that CYP1A1 was significantly associated with the cancer of gall bladder and ampula of Vater. CYP1A1I462V was found to be significantly associated with increased risk of both adeno- and non- adenocarcinoma of gall bladder for Hungarian women. Although only 37 cases were involved in this study. Tsuchiya et al, found that Val allele of m2 mutation was associated with an increased risk of gall bladder cancer (GBC) in Japanese women. Pandey et al, also found CC genotype of Msp I polymorphism to be significantly associated with GBC; a gene- environment interaction was detected in men taking tobacco.
Interaction between CYP1A1 polymorphisms and cigarette smoking is thought to promote hepatocellular carcinoma (HCC) and results of the association studies on this carcinoma remain largely inconclusive. In a meta- analysis of eight studies (1,752 cases and 2,279 controls) for I462V polymorphism and eight studies (933 cases and 1,449 controls) for Msp I polymorphism Yu et al, found that neither I462V nor Msp I was associated with HCC. Although borderline significant associations with HCC risk were detected for both the genotypes among cigarette smokers.
Cancer of urinary system
Tumours of the kidney accounts for 2% of all cancers and its incidence rate is two- fold higher in men than in women. The commonest type of renal tumour is renal cell carcinoma (RCC). Main etiological factor is cigarette smoking. In a case- only analysis Smits et al, found CYP1A1 polymorphism as RCC risk factor in relation to smoking in 245 renal cancer patients. They found increased incidences (statistically non-significant) of RCC in smokers with CYP1A1*2C genotype.
Bladder cancer is strongly associated with cigarette smoking and environmental carcinogens. Therefore, polymorphisms of carcinogen metabolizing enzymes have been extensively studied for bladder cancer risk. While the variant genotype CYP1A1*2C polymorphism was found to be higher in bladder cancer patients than in normal patients  in a Turkish population wild type (Ile/Ile) was found to be a risk factor for bladder cancer. No significant association with this cancer was found for *2A genotypes in a North Indian population.
Male reproductive system
CYP1A1 polymorphisms have been widely studied for prostate cancer, the commonest cancer of men. Results of these studies are largely inconclusive. Vijayalaksmi et al, found that T/C genotype of m1 mutation was significantly associated with development of prostate cancer while A/G genotype of m2 polymorphism was found to be associated with reduced prostate cancer risk. However, no association was found between m1 and prostate cancer in many studies.,,, Interestingly, Chang et al, demonstrated that for m1, m2 and m4 polymorphisms, TAC haplotype was significantly associated with prostate cancer risk, and CAC was associated with a decreased risk.
Testicular cancers are comparatively uncommon. Although aetiology of this cancer is not known fully, an unbalanced level of estrogen and androgens in utero is often thought to lead to develop this cancer. Since CYP1A1 is involved in hormonal metabolism, its polymorphisms have been studied for testicular cancer risk. In a study including large number of cancer patients (n = 652) and 199 controls of Norwegian Caucasian origin, both CYP1A1*2A and *2C polymorphic alleles were found to be associated with significantly reduced risk of testicular cancer.
Among gynecologic cancers, ovarian, endometrial and cervical cancers are most commonly studied for link with CYP1A1 polymorphisms. Since this gene has a role in the hydroxylation of estrogens to catechol intermediates that cause oxidative DNA damage, lipid peroxidation, and leads to DNA adducts  a possible effect of CYP1A1 mutations on gynecologic cancers is conceivable. An association between tobacco smoking and CYP1A1Msp I polymorphism on the risk of ovarian cancer was detected by Goodman et al. An elevated risk for ovarian cancer was demonstrated for women with Ile/Val genotype and who consumed more than medium level of caffeine. In a recent meta-analysis Huang et al, demonstrated that CYP1A1 I462V was linked to ovarian cancer and the risk was significantly increased for Caucasians and Asians. Although no significant association was found for Msp Iwith this cancer.
Esinler et al, found an association between Val allele of I462V mutation and endometrial cancer. However, no relationship was found for m1, m2 mutations with endometrial as well as ovarian cancer in several investigations.,,, Although this gene has role in oxidative metabolism of estradiol and activation of tobacco- smoke constituents, endometrial cancer is probably the only cancer type whose risk is decreased in smokers. Doherty et al, observed that presence of at least one CYP1A1 m1 or m2 variant allele was associated with a decreased risk of endometrial cancer. Also, a combination of TC + CC genotype of m1 was in decreased frequency in endometrial cancer patients and the TA haplotype of CYP1A1 m1 or m2 was increased in the patients. In a meta- analysis on m1, m2 and m4 Sergentanis et al, found no significant association for these three polymorphisms and endometrial cancer risk in Caucasian women.
Although the relationship between host genetic factors and human papillomavirus associated cancer is a debatable issue, a positive association has been documented with CYP1A1*2A, CYP1A1*2C, CYP1A1*3 polymorphisms and cervical cancer risk.,, Moreover, women with smoking habits and homozygous genotype for Msp I variant allele had a 19.4 fold higher risk for cervical cancer. However, no relation with CYP1A1 genetic polymorphisms and cervical cancer risk was detected by other studies., In a meta-analysis Sergentanis et al, found that homozygous mutant of Msp I and both heterozygous as well as homozygous mutants of I462V polymorphisms are associated with increased risk of cervical cancer.
Breast malignancy is the most prevalent cancer among women. While genetic factors like BRCA1 and BRCA2, and reproduction history constitute 30% of breast cancer causes, a low penetrance gene like CYP1A1 has been found to be responsible for the development of breast cancer. Results of the studies for breast cancer and CYP1A1 polymorphisms have remained largely inconclusive. In a recent meta- analysis of 10,520 cases and 14,567 controls Yao et al, concluded that there was no significant association between CYP1A1*2A and breast cancer risk. However, in a recent case- control study on Indian women Syamala et al, detected a familial breast cancer risk for CYP1A1*2A hetero- and homozygous variant genotypes. In yet another study involving 1140 Chinese patients of cohort design, Long et al, concluded that CYP1A1*2A might be considered as a genetic marker for breast cancer prognosis in Chinese women. Earlier studies in Caucasians did not reveal any link between CYP1A1*2C polymorphism and breast cancer risk. Finnish Caucasians also did not show any significant risk of CYP1A1*2C for breast cancer development. However, in a recent meta- analysis of 11909 breast cancer patients and 16,179 controls, Sergentanis et al, found that Caucasians homozygous for variant alleles of I462V polymorphism, not the carriers, were at elevated breast cancer risk; the same polymorphism was not detected to be associated with such risk in Chinese subjects. An Indian study  found that homozygous genotype (G/G) of m2 polymorphism was significantly associated with breast cancer. The m4 polymorphism was found to be a risk factor for breast cancer among French- Canadians by Krajinovic et al.
Interestingly many studies have demonstrated a reduced risk for breast cancer in individuals with Msp I variant alleles ,, and so with I462V polymorphism.,, This reduced risk for *2A and *2C variant alleles were found to be prevalent particularly among lean women with long-term endogenous estrogen exposure (>30% yrs of menstruation duration). In a haplotype analysis of two loci, CYP1A1 Msp I and CYP1A1 I462V, Shin et al., demonstrated that CA haplotype was associated with the lowest risk of breast cancer.
Acute lymphoblastic leukemia (ALL) accounts for approximately 74% of the leukemia cases among children. It is hypothesized that polymorphisms of xenobiotic metabolizing enzymes may have influence on susceptibility to childhood ALL. Swinney et al. studied association of CYP1A1 to ALL susceptibility in three ethnic groups, e.g., Caucasian, Hispanic and African- American children. Overall, an increased risk of ALL was documented for CYP1A1*2C and *2B homozygous variant alleles. There was a significant association of these two polymorphisms and also CYP1A1*2 A polymorphisms for Hispanics. Significant association of CYP1A1 m1 and m2 homozygous polymorphisms with paediatric ALL risk was found for Indian children. In a recent meta- analysis, Vijayakrishna and Houlston  conclude that a significant association exists between CYP1A1*2A and childhood ALL. For adults CYP1A1*2 A homozygous polymorphism was detected as significant risk factor for susceptibility to ALL in a Mexican population. Further, Val allele of I462V mutation was found to be associated with chronic myeloid leukemia.CYP1A1*2 A was detected for multiple myeloma in Koreans.
Sporadic studies on other types of cancer and CYP1A1 association are found in the literature. A variant allele of CYP1A1*4 mutation (C/A or A/A) was found to be a risk factor for papillary thyroid cancer.
Combined genotype and cancer association
Genetic association study is considered as a powerful approach for identification of low penetrance disease- susceptibility alleles. It has been often found that the association studies have mainly followed candidate gene approach, investigating one or a few SNP (s) leading to functional changes of a gene. However, carcinogenesis is a multi-step process involving cross- talk between a numbers of genes. It is expected that studying gene- gene interaction may better evaluate the contribution of low penetrance genes in cancer development. A higher phase I enzyme activity in combination with a lower phase II enzyme activity can be expected to generate several fold higher risk for cancer than an individual phase I/II enzyme. For xenobiotic- derived cancer CYP1A1, the phase I enzyme, has been most commonly studied in combination with glutathione S- transferase (GSTs) phase II detoxifying enzymes. Both GSTM1 and GSTT1 are involved in the metabolism of tobacco smoke constituents and a deletion polymorphism for GSTM1 or GSTT1 has been found to be linked with the risk of lung cancer. Wang et al, in their experiment on genetic association for lung cancer in a Chinese population did not find any statistically significant association either for CYP1A1 Msp I or for GSTM1 polymorphism separately, however, a strong association was observed for combination- genotype of Msp I homozygous variant and GSTM1 homozygous null. A combination of variant Msp I allele, and GSTM1 or GSTT1 null allele were recognized as a risk factor for lung cancer in other studies also.,, In a pooled analysis on non- smoker lung cancer patients Raimondi et al, concluded that a combination of CYP1A1 wild type, GSTM1 null and GSTT1 non- null genotypes might have a protective effect from lung cancer. Yang et al, identified a genotype combination of GSTP1, myeloperoxidase gene (MPO) and CYP1A1 variants as a risk factor for lung cancer development. A joint effect of GSTM1 null genotype and CYP1A1 Msp I variant on head and neck cancer was also found., A high risk for esophageal cancer was detected for individuals with CYP1A1 Val/Val and GSTM1 deletion genotype. The transformation of PAH into its ultimate carcinogenic form requires oxidation by CYP1A1 and hydrolysis by EPHX. Agudo et al, found a synergistic interaction of these two genes in gastric cancer patient, although not significant. For colorectal cancer, a combination of N- acetyltransferase NAT 2 rapid and CYP1A1*2 A heterozygous genotypes was identified as a susceptibility marker. Hou et al, studied gene- gene interaction between CYP1A1 m2 and Ser187 polymorphism of NQO1 gene in colorectal cancer, which influences activation of carcinogenic compounds in tobacco smoke. While Val462 or Ser187 was only weakly associated with colorectal adenoma, a combination of these genotypes showed increased risk for cancer, particularly among recent and heavy smokers. Estrogen metabolizing genes CYP1A1 and GST were found to interact in breast cancer cases also., Genes involved in the disposition of estrogen include catechol-o-methyltransferase (COMT), progesterone receptor (PGR), sulfotransferases (SULT1A1 and SULT1E1), CYP1A1, CYP1A2, CYP1B1, and CYP3A4. Rebbeck et al, found that synergistic interactions existed between CYP1A1*2C genotypes and SULT1A1*2 for breast cancer risk. Sulfotransferases cause sulfation of estrogen and catecholestrogens to more hydrophilic forms that leads to excretion of these compounds. A combination of CYP1A1, CYP1A2, and CYP1B1 genotypes led to a reduced risk for endometrial cancer.GSTM1 null and CYP1A1 m1 in combination were found to have higher risk for prostate cancer., Recipients of solid organ transplant were found to have high risk to develop non- melanoma skin cancer (NMSC). Polymorphisms in detoxifying enzyme may alter this risk. In their case- control study Lira et al, found that a combination of risk genotypes, i.e., GSTM1 null homozygous and carrying CYP1A1 Val462 allele had higher chance of developing NMSC. In acute lymphoblastic leukemia (ALL) polymorphisms of individual genes were not found to be risk factors, however, combination of GSTM1 null with CYP1A1 heterozygous mutant were found in individuals with high chance to develop ALL. Again, a combination of GSTT1 null genotype and CYP1A1*2B and CYP1A1*4 alleles was found to increase the risk of acute myeloid leukemia. [Table 1] shows a brief comparison between the CYP1A1 and cancer- link either alone or in combination with other genes. These findings suggest that experimental designs including polymorphisms of more than one enzyme involved in metabolic pathway of a particular xenobiotic would produce better results.
|Table 1: Association of CYP1A1 polymorphisms with cancer risk either alone or in combination with other genes|
Click here to view
Association with therapeutic outcome
An individual may have good response to cancer chemotherapeutic agent while at the same time, another person generates resistance and even adverse effects to the same drug. Genetic constitution of an individual is largely responsible for this difference; genetic polymorphisms of drug metabolizing enzymes are known to be important source of variability in drug responses. In humans important group of drug metabolizing enzymes include CYP(s) with CYP3A4, CYP2C9 and CYP2D6. A current trend of research includes CYP1A1 polymorphisms in cancer drug toxicity studies.
According to Krazinovic et al., approximately 20-40% of the childhood acute lymphoblastic leukemia (ALL) patients develop resistance to current therapeutic protocols. CYP1A1*2A and NQO1*2 variants were found to be associated with a worse therapeutic outcome in children with ALL. Therapy- related acute myeloid leukemia/myelodysplastic syndrome (t-AML/t-MDS) might occur as a result of impaired ability to detoxify chemotherapeutic drugs. According to Bolufer et al., a polymorphism profile consisting of CYP1A1*2 A, GSTT1 null and NQO1*2 is a strong modifier of t-AML/t-MDS risk. They also demonstrated that the absence of all three polymorphisms decreased the risk of this therapy related disease. Platinum drugs represent a unique and important class of anticancer compounds and are frequently used in the treatment of various types of cancer. Heubner et al, observed a statistically significant association between the 462Val allele and platinum resistance in ovarian cancer patients. Erlotinib, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is approved for second and third- line treatment of NSCLC. However, treatment with this drug has often been associated with life threatening adverse effects. In humans, erlotinib is extensively metabolized predominantly by CYP3A4, and to a lesser extent by CYP1A2 and the inducible form CYP1A1. Li et al., demonstrated that CYP1A1 along with CYP3A4 contributed to the formation of erlotinib- glutathione adducts. Also, the increased expression of CYP1A1 in the lungs of smokers may increase the risk of erlotinib associated interstitial lung disease.
For cancer chemotherapy, where cytotoxic agents are administrated at doses close to their maximum tolerable dose and therapeutic windows are relatively narrow, minor differences in individual drug handling may lead to severe toxicities. Hence, identification of predictive genetic markers for chemotherapeutic toxicity can make it possible to identify patients unlikely to respond to drug or at risk of severe drug- toxicity. Then an individualized plan for treatment with appropriate drug regimen can be prepared to achieve maximum treatment success with least amount of toxicity.
| » Discussion|| |
Despite the advent of new high- throughput techniques in the field of biomarker studies only few genetic polymorphisms possess accountability as cancer risk marker. For example GSTM1 null and NAT2 slow acetylator genotypes have been associated with increased overall risk of bladder cancer. And a few gene- drug combinations are recommended by US Food and Drug Administration (FDA) for pharmacogenetic testing. In general, only very few of the candidate gene studies depicting positive association between genetic polymorphism and cancer susceptibility could be replicated in the subsequent studies. The probable causes of this failure are discussed in several reviews., Briefly most important reason is the small sample size recruited in these studies. It is known that high penetrance genes render high risk for cancer but only <5% of all cancers can be explained in this way. Hence low penetrance common alleles with minor allele frequency (MAF)>5% have been chosen in genetic association studies. However, these alleles contribute only modestly to the risk for cancers. A large sample size is required in order to get statistically significant power (ability to detect a true association) in such cases. Published case- control studies typically have been conducted on a small sample size with fair possibility to generate false positive association for such low penetrance alleles. CYP1A1 studies are also no exception. Other than study design, publication bias for positive findings also influences the validation of a gene- disease association. Spitz and Bondy  further pointed out that selection of SNPs for association study is a challenging job. In complex diseases like cancer many genes of different cross-talking pathways can be involved. Some uncharacterized genes having plausible role can make the selection more complex. Further, an allele common in one population can be present in very low frequency in other populations with least relevance for a disease. For example, m3 variant of CYP1A1 gene is prevalent in African- Americans but not in other populations, which emphasizes the need of searching a universal marker applicable for all ethnic groups.
Holmes et al., recommended some strategies to be followed in present day pharmacogenetic research. These included the need of high quality updated systematic reviews and meta- analyses in order to obtain conclusive data. Also, a careful look at precisely measurable intermediary risk markers like DNA adducts, cytogenetic damages and mutations, rather than cancer as an end point, would lead to a more comprehensive understanding of the genetic basis for cancer development. While susceptibility biomarkers contribute to the identification of high- risk subgroups in the population, intermediate biomarkers measure early non- persistent biological events that take place after exposure and before the cancer development. Intermediate (effect) markers include chromosomal aberrations, changes in DNA adducts, protein expression etc., and another category of biomarker, the exposure biomarkers, could be used to understand environmental influence on cancers, e.g., urinary adducts formed by aflatoxin, a strong human carcinogen.
| » Conclusion|| |
This is need of the hour to identify genetically susceptible individuals so that preventive measurements could be undertaken in order to reduce cancer load in the population. Further, identification of toxicity markers can reduce chemotherapy related death cases. Variations in metabolic enzymes have long been hypothesized as risk factors for the genetic susceptibility of cancer development, or chemotherapeutic drug toxicity and drug resistance. CYP1A1 for its key role in xenobiotic metabolism, have been extensively studied as a cancer marker though large discrepancies prevail in the results of these studies. More thorough studies recruiting large sample size, gene- gene, gene- environment interactions are required to understand the potential of CYP1A1 as candidate gene for cancer susceptibility or drug toxicity biomarker.
| » Acknowledgement|| |
Authors are grateful to the Department of Biotechnology, Uttarakhand for financial support.
| » References|| |
Agundez JA. Cytochrome P450 gene polymorphism and cancer. Curr Drug Metab 2004;5:211-24.
Ekhart C, Rodenhuis S, Smits PH, Beijnen JH, Huitema AD. An overview of the relations between polymorphisms in drug metabolizing enzymes and drug transporters and survival after cancer drug treatment. Cancer Treat Rev 2009;35:18-31.
Hankinson O. The role of the aryl hydrocarbon receptor nuclear translocator protein in aryl hydrocarbon receptor action. Trends Endocrinol Metab 1994;5:240-4.
Spink DC, Eugster HP, Lincoln DW II, Schuetz JD, Schuetz EG, Johnson JA, et al.
17 beta-estradiol hydroxylation catalyzed by human cytochrome P450 1A1: A comparison of the activities induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in MCF-7 cells with those from heterologous expression of the cDNA. Arch Biochem Biophys 1992;293:342-8.
Roman LJ, Masters BS. The cytochrome P450 and nitric oxide synthases. In: Devlin TM, editor. Textbook of Biochemistry with clinical correlations. Hoboken, NJ: John Wiley and Sons; 2006. p. 430.
Bartsch, H, Nair U, Risch A, Rojas M, Wikman H, Alexandrov K. Genetic polymorphism of CYP
genes, alone or in combination, as a risk modifier of tobacco- related cancers. Cancer Epidemiol Biomark Prev 2000;9:3-28.
Song N, Tan W, Xing D, Lin D. CYP 1A1 polymorphism and risk of lung cancer in relation to tobacco smoking: A case- control study in China. Carcinogenesis 2001;22:11-6.
Masson LF, Sharp L, Cotton SC, Little J. Cytochrome P-450 1A1 gene polymorphisms and risk of breast cancer: A HuGE review. Am J Epidemiol 2005;16:901-15.
Hung RJ, Boffetta P, Brockmoller J, Butkiewicz D, Cascorbi I, Clapper ML, et al
. CYP1A1 and GSTM1 genetic polymorphisms and lung cancer risk in Caucasian non-smokers: A pooled analysis. Carcinogenesis 2003;24:875-82.
Mota P, Moura DS, Vale MG, Coimbra H, Carvalho L, Regateiro F. CYP1A1 m1 and m2 polymorphisms: Genetic susceptibility to lung cancer. Rev Port Pneumol 2010;16:89-98.
Shaffi SM, Shah MA, Bhat IA, Koul P, Ahmad SN, Siddiqi MA. CYP1A1 polymorphisms and risk of lung cancer in the ethnic Kashmiri population. Asian Pac J Cancer Prev 2009;10:651-6.
Duell EJ, Holly EA, Bracci PM, Liu M, Wiencke JK, Kelsey KT. A population-based, case–control study of polymorphisms in carcinogen-metabolizing genes, smoking, and pancreatic adenocarcinoma risk. J Natl Cancer Inst 2002;94:297-306.
Li Y, Millikan RC, Bell DA, Cui L, Tse CK, Newman B, et al
. Polychlorinated biphenyls, cytochrome P450 1A1 (CYP1A1
) polymorphisms, and breast cancer risk among African American women and white women in North Carolina: A population-based case-control study. Breast Cancer Res 2005;7:R12-8.
Tai J, Yang M, Ni X, Yu D, Fang J, Tan W, et al.
Genetic polymorphisms in cytochrome P450 genes are associated with an increased risk of squamous cell carcinoma of the larynx and hypopharynx in a Chinese population. Cancer Genet Cytogenet 2010;196:76-82.
Varzim G, Monteiro E, Silva RA, Fernandes J, Lopes C. CYP1A1 and XRCC1 gene polymorphisms in SCC of the larynx. Eur J Cancer Prev 2003;12:495-9.
Kao SY, Wu CH, Lin SC, Yap SK, Chang CS, Wong YK, et al
. Genetic polymorphism of cytochrome P4501A1 and susceptibility to oral squamous cell carcinoma and oral precancer lesions associated with smoking/betel use. J Oral Pathol Med 2002;31:505-11.
Cha IH, Park JY, Chung WY, Choi MA, Kim HJ, Park KK. Polymorphisms of CYP1A1 and GSTM1 genes and susceptibility to oral cancer. Yonsei Med J 2007;48:233-9.
Xie H, Hou L, Shields PG, Winn DM, Gridley G, Bravo-Otero E, et al.
Metabolic polymorphisms, smoking, and oral cancer in Puerto Rico. Oncol Res 2004;14:315-20.
Buch SC, Nazar-Stewart V, Weissfeld JL, Romkes M. Case-control study of oral and oropharyngeal cancer in whites and genetic variation in eight metabolic enzymes. Head Neck 2008;30:1139-47.
Losi-Guembarovski R, Colus IM, De Menezes RP, Poliseli F, Chaves VN, Kuasne H, et al.
Lack of association among polymorphic xenobiotic-metabolizing enzyme genotypes and the occurrence and progression of oral carcinoma in a Brazilian population. Anticancer Res 2008;28:1023-8.
Varela-Lema L, Taioli E, Ruano-Ravina A, Barros-Dios JM, Anantharaman D, Benhamou SA, et al
. Meta-analysis and pooled analysis of GSTM1 and CYP1A1 polymorphisms and oral and pharyngeal cancers: A HuGE-GSEC review. Genet Med 2008;10:369-84.
Gajecka M, Rydzanicz M, Jaskula-Sztul R, Kujawski M, Szyfter W, Szyfter K. CYP1A1, CYP2D6, CYP2E1, NAT2, GSTM1 and GSTT1 polymorphisms or their combinations are associated with the increased risk of the laryngeal squamous cell carcinoma. Mutat Res 2005;574:112-23.
Notani PN. Global variation in cancer incidence and mortality. Curr Sci 2001;81:465-74.
Sreelekha TT, Ramadas K, Pandey M, Thomas G, Nalinakumari KR, Pillai MR. Genetic polymorphism of CYP1A1, GSTM1 and GSTT1 genes in Indian oral cancer. Oral Oncol 2001;37:593-8.
Chatterjee S, Chakrabarti S, Sengupta B, Poddar S, Biswas D, Sengupta S, et al
. Prevalence of CYP1A1 and GST polymorphisms in the population of northeastern India and susceptibility of oral cancer. Oncol Res 2009;17:397-403.
Anantharaman D, Chaubal PM, Kannan S, Bhisey RA, Mahimkar MB. Susceptibility to oral cancer by genetic polymorphisms at CYP1A1, GSTM1 and GSTT1 loci among Indians: Tobacco exposure as a risk modulator. Carcinogenesis 2007;28:1455-62.
Zhuo W, Wang Y, Zhuo X, Zhu Y, Wang W, Zhu B, et al
. CYP1A1 and GSTM1 polymorphisms and oral cancer risk: Association studies via evidence-based meta-analyses. Cancer Invest 2009;27:86-95.
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108.
Hosgood HD 3rd
, Menashe I, Shen M, Yeager M, Yuenger J, Rajaraman P, et al
. Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway. Carcinogenesis 2008;29:1938-43.
Yang XR, Wacholder S, Xu Z, Dean M, Clark V, Gold B, et al.
CYP1A1 and GSTM1 polymorphisms in relation to lung cancer risk in Chinese women. Cancer Lett 2004;214:197-204.
Wang BG, Chen SD, Zhou WP, Zeng M, Li ZB, Cai XL, et al
. A case control study on the impact of CYP450 MSPI and GST-M1 polymorphisms on the risk of lung cancer. Zhonghua Zhong Liu Za Zhi 2004;26:93-7.
Shi X, Zhou S, Wang Z, Zhou Z, Wang Z. CYP1A1 and GSTM1 polymorphisms and lung cancer risk in Chinese populations: A meta-analysis. Lung Cancer 2008;59:155-63.
Yang M, Choi Y, Hwangbo B, Lee JS. Combined effects of genetic polymorphisms in six selected genes on lung cancer susceptibility. Lung Cancer 2007;57:135-42.
Sreeja L, Syamala V, Hariharan S, Madhavan J, Devan SC, Ankathil R. Possible risk modification by CYP1A1, GSTM1 and GSTT1 gene polymorphisms in lung cancer susceptibility in a South Indian population. J Hum Genet 2005;50:618-27.
Le Marchand L, Guo C, Benhamou S, Bouchardy C, Cascorbi I, Clapper ML, et al
. Pooled analysis of the CYP1A1 exon 7 polymorphism and lung cancer (United States). Cancer Causes Control 2003;14:339-46.
Larsen JE, Colosimo ML, Yang IA, Bowman R, Zimmerman PV, Fong KM. Risk of non-small cell lung cancer and the cytochrome P4501A1 Ile462Val polymorphism. Cancer Causes Control 2005;16:579-85.
Ozturk O, Isbir T, Yaylim I, Kocaturk CI, Gurses A. GST M1 and CYP1A1 gene polymorphism and daily fruit consumption in Turkish patients with non-small cell lung carcinomas. In vivo
Gallegos-Arreola MP, Figuera-Villanueva LE, Troyo-Sanroman R, Morgan-Villela G, Puebla-Perez AM, Flores-Marquez MR, et al
. CYP1A1 * 2B and *4 polymorphisms are associated with lung cancer susceptibility in Mexican patients. Int J Biol Markers 2008;23:24-30.
Vineis P, Veglia F, Anttila S, Benhamou S, Clapper ML, Dolzan V, et al
. CYP1A1, GSTM1 and GSTT1 polymorphisms and lung cancer: A pooled analysis of gene-gene interactions. Biomarkers 2004;9:298-305.
Taioli E, Gaspari L, Benhamou S, Boffetta P, Brockmoller J, Butkiewicz D, et al
. Polymorphisms in CYP1A1, GSTM1, GSTT1 and lung cancer below the age of 45 years. Int J Epidemiol 2003;32:60-3.
Honma HN, De Capitani EM, Barbeiro Ade S, Costa DB, Morcillo A, Zambon L. Polymorphism of the CYP1A1*2 A gene and susceptibility to lung cancer in a Brazilian population. J Bras Pneumol 2009;35:767-72.
Cote ML, Wenzlaff AS, Bock CH, Land SJ, Santer SK, Schwartz DR, et al
. Combinations of cytochrome P-450 genotypes and risk of early-onset lung cancer in Caucasians and African Americans: A population-based study. Lung Cancer 2007;55:255-62.
Ng DP, Tan KW, Zhao B, Seow A. CYP1A1 polymorphisms and risk of lung cancer in non-smoking Chinese women: Influence of environmental tobacco smoke exposure and GSTM1/T1 genetic variation. Cancer Causes Control 2005;16:399-405.
Wu MT, Lee JM, Wu DC, Ho CK, Wang YT, Lee YC, et al
. Genetic polymorphisms of cytochrome P4501A1 and oesophageal squamous-cell carcinoma in Taiwan. Br J Cancer 2002;87:529-32.
Yang CX, Matsuo K, Wang ZM, Tajima K. Phase I/II enzyme gene polymorphisms and esophageal cancer risk: A meta-analysis of the literature. World J Gastroenterol 2005;11:2531-8.
Jain M, Kumar S, Ghoshal UC, Mittal B. CYP1A1 Msp1 T/C polymorphism in esophageal cancer: No association and risk modulation. Oncol Res 2007;16:437-43.
Wang LD, Zheng S, Liu B, Zhou JX, Li YJ, Li JX. CYP1A1, GSTs and mEH polymorphisms and susceptibility to esophageal carcinoma: Study of population from a high- incidence area in north China. World J Gastroenterol 2003;9:1394-7.
Wang AH, Sun CS, Li LS, Huang JY, Chen QS. Relationship of tobacco smoking CYP1A1 GSTM1 gene polymorphism and esophageal cancer in Xi'an. World J Gastroenterol 2002;8:49-53.
Wang AH, Sun CS, Li LS, Huang JY, Chen QS, Xu DZ. Genetic susceptibility and environmental factors of esophageal cancer in Xi'an. World J Gastroenterol 2004;10:940-4.
Wideroff L, Vaughan TL, Farin FM, Gammon MD, Risch H, Stanford JL, et al
. GST, NAT1, CYP1A1 polymorphisms and risk of esophageal and gastric adenocarcinomas. Cancer Detect Prev 2007;31:233-6.
Malik MA, Upadhyay R, Mittal RD, Zargar SA, Modi DR, Mittal B. Role of xenobiotic-metabolizing enzyme gene polymorphisms and interactions with environmental factors in susceptibility to gastric cancer in Kashmir Valley. J Gastrointest Cancer 2009;40:26-32.
Gonzalez A, Ramirez V, Cuenca P, Sierra R. Polymorphisms in detoxification genes CYP1A1, CYP2E1, GSTT1 and GSTM1 in gastric cancer susceptibility. Rev Biol Trop 2004;52:591-600.
Ma JX, Zhang KL, Liu X, Ma YL, Pei LN, Zhu YF, et al
. Concurrent expression of aryl hydrocarbon receptor and CYP1A1 but not CYP1A1 MspI polymorphism is correlated with gastric cancers raised in Dalian, China. Cancer Lett 2006;240:253-60.
Agudo A, Sala N, Pera G, Capella G, Berenguer A, Garcia N, et al
. Polymorphisms in metabolic genes related to tobacco smoke and the risk of gastric cancer in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev 2006;15:2427-34.
Roth MJ, Abnet CC, Johnson LL, Mark SD, Dong ZW, Taylor PR, et al
. Polymorphic variation of Cyp1A1 is associated with the risk of gastric cardia cancer: A prospective case-cohort study of cytochrome P-450 1A1 and GST enzymes. Cancer Causes Control 2004;15:1077-83.
Darazy M, Balbaa M, Mugharbil A, Saeed H, Sidani H, Abdel-Razzak Z. CYP1A1, CYP2E1, and GSTM1 gene polymorphisms and susceptibility to colorectal and gastric cancer among Lebanese. Genet Test Mol Biomarkers 2011;15:423-9.
Sachse C, Smith G, Wilkie MJ, Barrett JH, Waxman R, Sullivan F, et al
.; Colorectal Cancer Study Group. A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer. Carcinogenesis 2002;23:1839-49.
Pereira Serafim PV, Cotrim Guerreiro da Silva ID, Manoukias Forones N. Relationship between genetic polymorphism of CYP1A1 at codon 462 (Ile462Val) in colorectal cancer. Int J Biol Markers 2008;23:18-23.
Little J, Sharp L, Masson, Brockton NT, Cotton SC, Haites NE, et al
. Colorectal cancer and genetic polymorphisms of CYP1A1, GSTM1 and GSTT1: A case-control study in the Grampian region of Scotland. Int J Cancer 2006;119:2155-64.
Yoshida K, Osawa K, Kasahara M, Miyaishi A, Nakanishi K, Hayamizu S, et al
. Association of CYP1A1, CYP1A2, GSTM1 and NAT2 gene polymorphisms with colorectal cancer and smoking. Asian Pac J Cancer Prev 2007;8:438-44.
Pande M, Amos CI, Osterwisch DR, Chen J, Lynch PM, Broaddus R, et al
. Genetic variation in genes for the xenobiotic-metabolizing enzymes CYP1A1, EPHX1, GSTM1, GSTT1, and GSTP1and susceptibility to colorectal cancer in Lynch syndrome. Cancer Epidemiol Biomarkers Prev 2008;17:2393-401.
Nisa H, Kono S, Yin G, Toyomura K, Nagano J, Mibu R, et al.
Cigarette smoking, genetic polymorphisms and colorectal cancer risk: The Fukuoka Colorectal Cancer Study. BMC Cancer 2010;10:274.
Hou L, Chatterjee N, Huang WY, Baccarelli A, Yadavalli S, Yeager M, et al.
CYP1A1 Val462 and NQO1 Ser187 polymorphisms, cigarette use, and risk for colorectal adenoma. Carcinogenesis 2005;26:1122-8.
Park SK, Andreotti G, Sakoda LC, Gao YT, Rashid A, Chen J, et al.
Variants in hormone-related genes and the risk of biliary tract cancers and stones: A population-based study in China. Carcinogenesis 2009;30:606-14.
Kimura A, Tsuchiya Y, Lang I, Zoltan S, Nakadaira H, Ajioka Y, et al.
Effect of genetic predisposition on the risk of gallbladder cancer in Hungary. Asian Pac J Cancer Prev 2008;9:391-6.
Tsuchiya Y, Kiyohara C, Sato T, Nakamura K, Kimura A, Yamamoto M. Polymorphisms of cytochrome P450 1A1, glutathione S-transferase class mu, and tumour protein p53 genes and the risk of developing gallbladder cancer in Japanese. Clin Biochem 2007;40:881-6.
Pandey SN, Choudhuri G, Mittal B. Association of CYP1A1 Msp1 polymorphism with tobacco-related risk of gallbladder cancer in a north Indian population. Eur J Cancer Prev 2008;17:77-81.
Yu L, Sun L, Jiang YF, Lu BL, Sun DR, Zhu LY. Interactions between CYP1A1 polymorphisms and cigarette smoking are associated with the risk of hepatocellular carcinoma: Evidence from epidemiological studies. Mol Biol Rep 2012;39:6641-6.
Souhami R, Tobias J. Cancer and its management. 5th
ed. Oxford (UK): Blackwell Publishers; 2005.
Smits KM, Schouten LJ, van Dijk BA, van Houwelingen K, Hulsbergen-van de Kaa CA, Kiemeney LA, et al
. Polymorphisms in genes related to activation or detoxification of carcinogens might interact with smoking to increase renal cancer risk: Results from The Netherlands Cohort Study on diet and cancer. World J Urol 2008;26:103-10.
Grando JP, Kuasne H, Losi-Guembarovski R, Sant'ana Rodrigues I, Matsuda HM, Fuganti PE, et al.
Association between polymorphisms in the biometabolism genes CYP1A1, GSTM1, GSTT1 and GSTP1 in bladder cancer. Clin Exp Med 2009;9:21-8.
Ozturk T, Kahraman OT, Toptaş B, Kisakesen HI, Cakalir C, Verim L, et al.
The effect of CYP1A1 and GSTM1 gene polymorphisms in bladder cancer development in a Turkish population. In Vivo
Srivastava DS, Mandhani A, Mittal RD. Genetic polymorphisms of cytochrome P450 CYP1A1 (*2 A) and microsomal epoxide hydrolase gene, interactions with tobacco-users, and susceptibility to bladder cancer: A study from North India. Arch Toxicol 2008;82:633-9.
Vijayalakshmi K, Vettriselvi V, Krishnan M, Shroff S, Jayanth VR, Paul SF. Cytochrome p4501A1 gene variants as susceptibility marker for prostate cancer. Cancer Biomark 2005;1:251-8.
Silig Y, Pinarbasi H, Gunes S, Ayan S, Bagci H, Cetinkaya O. Polymorphisms of CYP1A1, GSTM1, GSTT1, and prostate cancer risk in Turkish population. Cancer Invest 2006;24:41-5.
Guan TY, Li M, Na YQ. Polymorphism of metabolic gene and genetic susceptibility to prostate cancer. Zhonghua Wai Ke Za Zhi 2005;43:1467-70.
Suzuki K, Matsui H, Nakazato H, Koike H, Okugi H, Hasumi M, et al
. Association of the genetic polymorphism in cytochrome P450 (CYP) 1A1 with risk of familial prostate cancer in a Japanese population: A case-control study. Cancer Lett 2003;195:177-83.
Gao JP, Huang YD, Yang GZ, Yang YQ. Relationship between genetic polymorphisms of metabolizing enzymes and prostate cancer. Zhonghua Nan Ke Xue 2003;9:32-5.
Chang BL, Zheng SL, Isaacs SD, Turner A, Hawkins GA, Wiley KE, et al
. Polymorphisms in the CYP1A1 gene are associated with prostate cancer risk. Int J Cancer 2003;106:375-8.
Kristiansen W, Haugen TB, Witczak O, Andersen JM, Fossa SD, Aschim EL. CYP1A1, CYP3A5 and CYP3A7 polymorphisms and testicular cancer susceptibility. Int J Androl 2011;34:77-83.
Goodman MT, McDuffie K, Kolonel LN, Terada K, Donlon TA, Wilkens LR, et al.
Case-control study of ovarian cancer and polymorphisms in genes involved in catecholestrogen formation and metabolism. Cancer Epidemiol Biomarkers Prev 2001;10:209-16.
Terry KL, Titus-Ernstoff L, Garner EO, Vitonis AF, Cramer DW. Interaction between CYP1A1 polymorphic variants and dietary exposures influencing ovarian cancer risk. Cancer Epidemiol Biomarkers Prev 2003;12:187-90.
Huang M, Chen Q, Xiao J, Zhao X, Liu C. CYP1A1 Ile462Val is a risk factor for ovarian cancer development. Cytokine 2012;58:73-8.
Esinler I, Aktas D, Alikasifoglu M, Tuncbilek E, Ayhan A. CYP1A1 gene polymorphism and risk of endometrial hyperplasia and endometrial carcinoma. Int J Gynecol Cancer 2006;16:1407-11.
Gulyaeva LF, Mikhailova ON, PustyInyak VO, Kim IV 4th
, Gerasimov AV, Krasilnikov SE, et al
. Comparative analysis of SNP in estrogen-metabolizing enzymes for ovarian, endometrial, and breast cancers in Novosibirsk, Russia. Adv Exp Med Biol 2008;617:359-66.
McGrath M, Hankinson SE, De Vivo I. Cytochrome P450 1A1, cigarette smoking, and risk of endometrial cancer (United States). Cancer Causes Control 2007;18:1123-30.
Sugawara T, Nomura E, Sagawa T, Sakuragi N, Fujimoto S. CYP1A1 polymorphism and risk of gynecological malignancy in Japan. Int J Gynecol Cancer 2003;13:785-90.
Holt SK, Rossing MA, Malone KE, Schwartz SM, Weiss NS, Chen C. Ovarian cancer risk and polymorphisms involved in estrogen catabolism. Cancer Epidemiol Biomarkers Prev 2007;16:481-9.
US Department of Health and Human Services, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, United States Public Health Service, Office of the Surgeon General. Smoking and Health: A national status report. A report to Congress Atlanta, GA: Centers for Disease Control and Prevention; 1990.
Doherty JA, Weiss NS, Freeman RJ, Dightman DA, Thornton PJ, Houck JR, et al
. Genetic factors in catechol estrogen metabolism in relation to the risk of endometrial cancer. Cancer Epidemiol Biomarkers Prev 2005;14:357-66.
Hirata H, Hinoda Y, Okayama N, Suehiro Y, Kawamoto K, Kikuno N, et al
. CYP1A1, SULT1A1, and SULT1E1 polymorphisms are risk factors for endometrial cancer susceptibility. Cancer 2008;112:1964-73.
Sergentanis TN, Economopoulos KP, Choussein S, Vlahos NF. Cytochrome P450 1A1 gene polymorphisms and endometrial cancer risk: A meta-analysis. Int J Gynecol Cancer 2011;21:323-31.
Joseph T, Chacko P, Wesley R, Jayaprakash PG, James FV, Pillai MR. Germline genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes in Indian cervical cancer: Associations with tumor progression, age and human papillomavirus infection. Gynecol Oncol 2006;101:411-7.
Juarez-Cedillo T, Vallejo M, Fragoso JM, Hernandez-Hernandez DM, Rodriguez-Perez JM, Sanchez-Garcia S, et al
. The risk of developing cervical cancer in Mexican women is associated to CYP1A1 MspI polymorphism. Eur J Cancer 2007;43:1590-5.
Taskiran C, Aktas D, Yigit-Celik N, Alikasifoglu M, Yuce K, Tunçbilek E, et al
. CYP1A1 gene polymorphism as a risk factor for cervical intraepithelial neoplasia and invasive cervical cancer. Gynecol Oncol 2006;101:503-6.
Agorastos T, Papadopoulos N, Lambropoulos AF, Chrisafi S, Mikos T, Goulis DG, et al
. Glutathione-S-transferase M1 and T1 and cytochrome P1A1 genetic polymorphisms and susceptibility to cervical intraepithelial neoplasia in Greek women. Eur J Cancer Prev 2007;16:498-504.
Gutman G, Morad T, Peleg B, Peretz C, Bar-Am A, Safra T, et al.
CYP1A1 and CYP2D6 gene polymorphisms in Israeli Jewish women with cervical cancer. Int J Gynecol Cancer 2009;19:1300-2.
Sergentanis TN, Economopoulos KP, Choussein S, Vlahos NF. Cytochrome P450 1A1 (CYP1A1) gene polymorphisms and cervical cancer risk: A meta-analysis. Mol Biol Rep 2012;39:6647-54.
Krajinovic M, Ghadirian P, Richer C, Sinnett H, Gandini S, Perret C, et al
. Genetic susceptibility to breast cancer in French-Canadians: Role of carcinogen-metabolizing enzymes and gene-environment interactions. Int J Cancer 2001;92:220-5.
Yao L, Yu X, Yu L. Lack of significant association between CYP1A1 T3801C polymorphism and breast cancer risk: A meta-analysis involving 25,087 subjects. Breast Cancer Res Treat 2010;122:503-7.
Syamala VS, Syamala V, Sheeja VR, Kuttan R, Balakrishnan R, Ankathil R. Possible risk modification by polymorphisms of estrogen metabolizing genes in familial breast cancer susceptibility in an Indian population. Cancer Invest 2010;28:304-11.
Long JR, Cai Q, Shu XO, Cai H, Gao YT, Zheng W. Genetic polymorphisms in estrogen- metabolizing genes and breast cancer survival. Pharmacogenet Genomics 2007;17:331-8.
Sillanpaa P, Heikinheimo L, Kataja V, Eskelinen M, Kosma VM, Uusitupa M, et al
. CYP1A1 and CYP1B1 genetic polymorphisms, smoking and breast cancer risk in a Finnish Caucasian population. Breast Cancer Res Treat 2007;104:287-97.
Sergentanis TN, Economopoulos KP. Four polymorphisms in cytochrome P450 1A1 (CYP1A1) gene and breast cancer risk: A meta-analysis. Breast Cancer Res Treat 2010;122:459-69.
Singh N, Mitra AK, Garg VK, Agarwal A, Sharma M, Chaturvedi R, et al
. Association of CYP1A1 polymorphisms with breast cancer in North Indian women. Oncol Res 2007;16:587-97.
Boyapati SM, Shu XO, Gao YT, Cai Q, Jin F, Zheng W. Polymorphisms in CYP1A1 and breast carcinoma risk in a population-based case-control study of Chinese women. Cancer 2005;103:2228-35.
Okobia M, Bunker C, Zmuda J, Kammerer C, Vogel V, Uche E, et al
. Cytochrome P4501A1 genetic polymorphisms and breast cancer risk in Nigerian women. Breast Cancer Res Treat 2005;94:285-93.
Miyoshi Y, Takahasi Y, Egawa C, Noguchi S. Breast cancer risk associated with CYP1A1 genetic polymorphisms in Japanese women. Breast J 2002;8:209-15.
Chen C, Huang Y, Li Y, Mao Y, Xie Y. Cytochrome P450 1A1 (CYP1A1) T3801C and A2455G polymorphisms in breast cancer risk: A meta-analysis. J Hum Genet 2007;52:423-35.
Shin A, Kang D, Choi JY, Lee KM, Park SK, Noh DY, et al
. Cytochrome P450 1A1 (CYP1A1) polymorphisms and breast cancer risk in Korean women. Exp Mol Med 2007;39:361-6.
Swinney RM, Beuten J, Collier AB 3rd
, Chen TT, Winick NJ, Pollock BH, et al.
Polymorphisms in CYP1A1 and ethnic-specific susceptibility to acute lymphoblastic leukemia in children. Cancer Epidemiol Biomarkers Prev 2011;20:1537-42.
Joseph T, Kusumakumari P, Chacko P, Abraham A, Radhakrishna Pillai M. Genetic polymorphism of CYP1A1, CYP2D6, GSTM1 and GSTT1 and susceptibility to acute lymphoblastic leukemia in Indian children. Pediatr Blood Cancer 2004;43:560-7.
Vijayakrishnan J, Houlston RS. Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: A systematic review and meta-analysis. Haematologica 2010;95:1405-14.
Gallegos- Arreola MP, Gonzalez-Garcia JR, Figuera LE, Puebla-Perez AM, Delgado-Lamas JL, Zuniga-Gonzalez GM. Distribution of CYP1A1*2 A
polymorphism in adult patients with acute lymphoblastic leukemia in a Mexican population. Blood Cells Mol Dis 2008;41:91-4.
Taspinar M, Aydos SE, Comez O, Elhan AH, Karabulut HG, Sunguroglu A. CYP1A1, GST gene polymorphisms and risk of chronic myeloid leukemia. Swiss Med Wkly 2008;138:12-7.
Kang SH, Kim TY, Kim HY, Yoon JH, Cho HI, Yoon SS, et al
. Protective role of CYP1A1*2 A in the development of multiple myeloma. Acta Haematol 2008;119:60-4.
Siraj AK, Ibrahim M, Al-Rasheed M, Abubaker J, Bu R, Siddiqui SU, et al
. Polymorphisms of selected xenobiotic genes contribute to the development of papillary thyroid cancer susceptibility in Middle Eastern population. BMC Med Genet 2008;9:61.
Pearce CL, Near AM, Van Den Berg DJ, Ramus SJ, Gentry-Maharaj A, Menon U, et al
. Validating genetic risk associations for ovarian cancer through the international ovarian cancer association consortium. Br J Cancer 2009;100:412-20.
Alexandrie AK, Nyberg F, Warholm M, Rannug A. Influence of CYP1A1, GSTM1, GSTT1, and NQO1 genotypes and cumulative smoking dose on lung cancer risk in a Swedish population. Cancer Epidemiol Biomarkers Prev 2004;13:908-14.
Belogubova EV, Ulibina YM, Suvorova IK, Kulligina ESh, Karpova MB, Shutkin VA, et al
. Combined CYP1A1/GSTM1 at-risk genotypes are overrepresented in squamous cell lung carcinoma patients but underrepresented in elderly tumor-free subjects. J Cancer Res Clin Oncol 2006;132:327-31.
Raimondi S, Boffetta P, Anttila S, Brockmoller J, Butkiewicz D, Cascorbi I, et al
. Metabolic gene polymorphisms and lung cancer risk in non-smokers. An update of the GSEC study. Mutat Res 2005;592:45-57.
Gattas GJ, de Carvalho MB, Siraque MS, Curioni OA, Kohler P, Eluf-Neto J, et al
. Genetic polymorphisms of CYP1A1, CYP2E1, GSTM1, and GSTT1 associated with head and neck cancer. Head Neck 2006;28:819-26.
Torresan C, Oliveira MM, Torrezan GT, de Oliveira SF, Abuazar CS, Losi-Guembarovski R, et al
. Genetic polymorphisms in oestrogen metabolic pathway and breast cancer: A positive association with combined CYP/GST genotypes. Clin Exp Med 2008;8:65-71.
Firozi PF, Bondy ML, Sahin AA, Chang P, Lukmanji F, Singletary ES, et al
. Aromatic DNA adducts and polymorphisms of CYP1A1, NAT2, and GSTM1 in breast cancer. Carcinogenesis 2002;23:301-6.
Rebbeck TR, Troxel AB, Walker AH, Panossian S, Gallagher S, Shatalova EG, et al
. Pairwise combinations of estrogen metabolism genotypes in postmenopausal breast cancer etiology. Cancer Epidemiol Biomarkers Prev 2007;16:444-50.
Quinones LA, Irarrazabal CE, Rojas CR, Orellana CE, Acevedo C, Huidobro C, et al
. Joint effect among p53, CYP1A1, GSTM1 polymorphism combinations and smoking on prostate cancer risk: An exploratory genotype-environment interaction study. Asian J Androl 2006;8:349-55.
Acevedo C, Opazo JL, Huidobro C, Cabezas J, Iturrieta J, Quinones SL. Positive correlation between single or combined genotypes of CYP1A1 and GSTM1 in relation to prostate cancer in Chilean people. Prostate 2003;57:111-7.
Lira MG, Provezza L, Malerba G, Naldi L, Remuzzi G, Boschiero L, et al
. Glutathione S-transferase and CYP1A1 gene polymorphisms and non-melanoma skin cancer risk in Italian transplanted patients. Exp Dermatol 2006;15:958-65.
Chen HC, Hu WX, Liu QX, Li WK, Chen FZ, Rao ZZ, et al
. Genetic polymorphisms of metabolic enzymes CYP1A1, CYP2D6, GSTM1 and GSTT1 and leukemia susceptibility. Eur J Cancer Prev 2008;17:251-8.
D'Alo F, Voso MT, Guidi F, Massini G, Scardocci A, Sica S, et al
. Polymorphisms of CYP1A1 and glutathione S-transferase and susceptibility to adult acute myeloid leukemia. Haematologica 2004;89:664-70.
Krajinovic M, Labuda D, Mathonnet G, Labuda M, Moghrabi A, Champagne J, et al
. Polymorphisms in genes encoding drugs and xenobiotic metabolizing enzymes, DNA repair enzymes, and response to treatment of childhood acute lymphoblastic leukemia. Clin Cancer Res 2002;8:802-10.
Bolufer P, Collado M, Barragan E, Calasanz MJ, Colomer D, Tormo M, et al
. Profile of polymorphisms of drug-metabolising enzymes and the risk of therapy-related leukaemia. Br J Haematol 2007;136:590-6.
Heubner M, Wimberger P, Riemann K, Kasimir-Bauer S, Otterbach F, Kimmig R, et al
. The CYP1A1 Ile462Val polymorphism and platinum resistance of epithelial ovarian neoplasms. Oncol Res 2010;18:343-7.
Li X, Kamenecka TM, Cameron MD. P450-mediated bioactivation of the epidermal growth factor receptor inhibitor erlotinib to a reactive electrophile. Drug Metab Dispos 2010;38:1238-45.
McLeod HL, Goh BC. Pharmacogenomics. In: DeVita VT Jr., Hellman S, Rosenberg SA, editors. In: Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams and Wilkins; 2005. p. 327.
Garcia- Closas M, Malats N, Silverman D, Dosemeci M, Kogevinas M, Hein DW, et al
. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: Results from the Spanish Bladder Cancer Study and meta-analyses. Lancet 2005;366:649-59.
Holmes MV, Shah T, Vickery C, Smeeth L, Hingorani AD, Casas JP. Fulfilling the promise of personalized medicine? Systematic review and field synopsis of pharmacogenetic studies. PLoS One 2009;4:e7960.
Spitz MR, Bondy ML. The evolving discipline of molecular epidemiology of cancer. Carcinogenesis 2010;31:127-34.
Vineis P. The relationship between polymorphisms of xenobiotic metabolizing enzymes and susceptibility to cancer. Toxicology 2002;181-182:457-62.
Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science 1996;273:1516-7.
Boffetta P. Biomarkers in cancer epidemiology: An integrative approach. Carcinogenesis 2010;31:121-6.
|This article has been cited by|
||Assessment of the carcinogenic effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin using mouse embryonic stem cells to form teratoma in vivo
| ||Xiaoxi Yang,Tingting Ku,Zhendong Sun,Qian S. Liu,Nuoya Yin,Qunfang Zhou,Francesco Faiola,Chunyang Liao,Guibin Jiang |
| ||Toxicology Letters. 2019; 312: 139 |
|[Pubmed] | [DOI]|
||Bacterial mutagenicity of selected procarcinogens in the presence of recombinant human or rat cytochrome P4501A1
| ||Rebeca Santes-Palacios,Rafael Camacho-Carranza,Jesús Javier Espinosa-Aguirre |
| ||Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 2018; 835: 25 |
|[Pubmed] | [DOI]|
||Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin
| ||Cara Chang,Yichun Hu,Susan Hogan,Nickie Mercke,Madeleine Gomez,Cindy O’Bryant,Daniel Bowles,Blessy George,Xia Wen,Lauren Aleksunes,Melanie Joy |
| ||International Journal of Molecular Sciences. 2017; 18(7): 1333 |
|[Pubmed] | [DOI]|
||Genetic polymorphisms of human cytochrome P450 CYP1A1 in an Egyptian population and tobacco-induced lung cancer
| ||Nada Ezzeldin,Dalia El-Lebedy,Amira Darwish,Ahmed El-Bastawisy,Mirhane Hassan,Shereen Abd El-Aziz,Mohamed Abdel-Hamid,Amal Saad-Hussein |
| ||Genes and Environment. 2017; 39(1) |
|[Pubmed] | [DOI]|