Cytochrome P450 1A1
CYP1A1 Msp1 T>C & A>G Ile462Val
The 1000 Genomes Project Database and the genome Aggregation Database (gnomAD) reports global frequencies of 29.3% and 16.82% respectively for the variant C-allele (NIH).
The 1000 Genomes Project Database and the genome Aggregation Database (gnomAD) reports global frequencies of 13.3% and 5.0% respectively for the variant G-allele (NIH).
CYP1A1 Gene Detail
Cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) is a member of the larger CYP1 family: key enzymes in the metabolism of many endogenous substrates and exogenous carcinogens.
Research supports an association between the CYP1A1 Msp1 polymorphism (C-allele) and Ile462Val polymorphism (G-allele) and increased overall cancer risk. The mechanism behind increased cancer susceptibility has mainly been described as CYP1A1’s role in activating environmental pro-carcinogens and in catalysing the oxidative metabolites of oestrogen i.e. catechols and oestrogen quinones. Since certain compounds are more likely to influence cancer risk by the formation of harmful DNA adducts in the presence of a CYP1A1 polymorphism, it is recommended to avoid contact with environmental pro-carcinogens such as polycyclic aromatic hydrocarbons (PAH), aromatic amines, nitrates and smoking of any kind as a preventative strategy.
Some findings regarding these polymorphisms and cancer risk remains contradictory, which indicates that polymorphisms of CYP1A1 might exert different effects in different types of cancers. The effects of genetic polymorphisms on cancer risk also seem to be affected by ethnic background.
A meta-analysis from Wu et al. (2013) has revealed an increase in the risk of particularly lung and cervical cancer, and in terms of ethnicity, an increased cancer risk in the Asian population. Other meta-analyses respectively reported increased susceptibility in C-allele carriers for sporadic prostate cancer, renal cell carcinoma, cancers of the head and neck such as laryngeal cancer and once more, cervical and lung cancer.
An increased risk for particularly lung cancer, leukemia, esophageal carcinoma and prostate cancer has been observed in the large meta-analysis by Wu et al. (2013) for both Asian and Caucasian populations. Other studies have reported increased susceptibility in G-allele (or Val-allele) carriers for prostate, cervical, colorectal, laryngeal, lung, oral cancer, and renal cell carcinoma in smokers. Findings regarding breast cancer is contradicting.
CYP1A1 Msp T>C and A>G Ile462Val
Cytochromes P450 are heme-containing enzymes critical to phase I-dependent metabolism (such as C-, N- and S-oxidation and dealkylation) of drugs and other xenobiotics. The larger family of CYP enzymes has been implicated in cellular functions such as the metabolism of eicosanoids, the biosynthesis of cholesterol and bile acids, synthesis and metabolism of steroids and vitamin D3, synthesis and degradation of biogenic amines, and the hydroxylation of retinoic acid and presumably other morphogens. Many polymorphisms have been described in the CYP genes and these are thought to play an important role in determining individual cancer susceptibility.
The CYP1A1 gene is present on chromosome 15q24.1 and consists of 7 exons. It encodes for the enzyme aryl hydrocarbon hydroxylase (AHH) which is mainly expressed extra-hepatically, especially in epithelial tissues. This enzyme is considered important for the metabolism of many endogenous substrates and exogenous carcinogens such as polycyclic aromatic hydrocarbons (PAH), heterocyclic amines, dibenzofurans, biphenyls, aflatoxin B1 and oestrogen.
The expression of CYP1A1 is regulated by a ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR), which is part of phase I reactions in drug metabolism. Under normal physiologic conditions, CYP1A1 expression is induced by PAHs via activation of the AhR. The AhR complex then translocates to the nucleus and binds to its partner protein, aryl hydrocarbon receptor nuclear translocator (ARNT). The AhR/ARNT heterodimer binds to specific DNA recognition sites termed xenobiotic responsive elements (XREs) located upstream of the transcription start site and initiates CYP1A1 transcription. Previous studies have shown that the expression level of CYP1A1 is frequently upregulated in several human tissues due to hypomethylation of XRE sites.
CYP1A1 drives the first step in the metabolism of PAHs, reactive electrophilic metabolites that are formed during the incomplete combustion of coal, oil, gas and other organic substances like tobacco, thus it may contribute to the formation of highly reactive intermediates when these compounds bind to DNA to create PAH-DNA adducts. Should these adducts be left unrepaired, it can instigate or accelerate carcinogenesis Tobacco smoking has also been described as one supposed mechanism affecting XRE methylation status of CYP1A1.
Literature explains that the CYP1A1 polymorphisms may be risk factors for several malignancies as alterations in structure and function may influence its role in the detoxification of environmental carcinogens and metabolic activation of dietary compounds that would normally protect against cancer. Polymorphisms of the CYP1A1 enzymes may contribute to the variable susceptibility to carcinogenesis by altering the level of gene expression or messenger RNA stability, resulting in highly inducible activity of the enzyme.
The Msp1 T>C polymorphism (rs4646903, T6235C / T3801C, 2A or m1) is described as a functional, non-synonymous polymorphism occurring in the non-coding 3’-flanking region of the CYP1A1 gene. The T-to-C mutation results in the creation of a new Msp1 restriction site.
A large meta-analysis of 139 publications with 148 case-controlled studies for Msp1 found that the CC genotype was associated with increased risk of cancers, especially lung and cervical cancer among Asians and mixed population (composed of different ethnic groups). To support these findings, a meta-analysis within a Chinese-only population (22 studies comprising 3016 cases and 3932 controls) found strong evidence of a significant association between the Msp1 polymorphism and lung cancer risk.
Although small, a cross-sectional study in an Iranian population group also detected a significant positive association between the presence of the C-allele and lung cancer risk. It has been demonstrated that following high exposure to inducible PAHs, individuals carrying the C-allele could display enhanced regulation of transcription, or heightened enzymatic activity, although the precise mechanism underling this relation has not been determined.
Among both Asian and Caucasian C-allele carriers, a significantly increased risk for cervical cancer was also reported in a more recent meta-analysis, which considered 13 studies with 2148 cases and 2252 controls. This is consistent with previous findings from Sergentanis et al. (2012) in a European population, although recent findings also support the association in Asian C-allele carriers.
An older article from Mitrunen (2001) discussed the potential role of CYP1A1 polymorphism in modulating individual susceptibility to breast cancer as it plays a role in the conversion of the oestrogen metabolites and their by-products. The authors stated that evidence supports a role for oxidative metabolites, particularly catechol oestrogens, in the initiation of breast cancer. Enhanced cell proliferation, induced either by endogenous or exogenous oestrogens, increases the number of cell divisions and thereby the possibility for mutation. Since, a meta-analysis published by Yao et al. (2010) provided strong evidence that the Msp1 polymorphism is not associated with breast cancer risk after investigating 25 087 subjects. Sergentanis et al. (2009) also failed to find Msp1 capable of modifying breast cancer risk after considering 32 studies (11 909 cases and 16 179 controls). Similarly, more recently, no association with breast cancer risk was found amongst Iranian women with the rs4646903 polymorphism. Gene-environment interactions should however also be considered when establishing risk.
A meta-analysis from Shaik et al. (2009), including 14 studies on sporadic prostate cancer (2573 patients and 2576 controls), revealed an increased risk associated with sporadic prostate cancer on a wide population basis for C-allele carriers. An updated meta-analysis conducted 3 years later by Li et al. (2012), after some eligible and new studies were found, has however found markedly contradicting evidence. Although Shaik et al. (2009) stated that the Msp1 polymorphism had considerable influence on the risk of prostate cancer in the overall analysis, the updated meta-analysis on Msp1 does not confirm this observation. The more recent data showed that the increased risk of prostate cancer appears only in heterozygous (CT) individuals of Asian descent. However, this relationship also disappeared in the Asian group after excluding the studies that deviated from the Hardy-Weinberg Equilibrium (HWE). A very recent 2019 meta-analysis was performed by Zhu et al. (2019) to establish certainty regarding the abovementioned conflicting results; 31 articles including 12 745 cases and 12 471 controls were analysed. Their findings support an increased prostate cancer risk in CT heterozygotes of Asian descent and in CC homozygotes in the Caucasian population; but no association with increased prostate cancer risk in the overall population.
The variant allele has also been significantly associated with an increased risk of renal cell carcinoma (RCC), particularly among smokers carrying the C-allele. The authors claimed this meta-analysis was the first to investigate the Msp1 polymorphism and RCC risk – 3 studies with 531 cases and 739 controls were included.
A meta-analysis from Liu et al. (2015) reported a significant susceptibility to oral cancer in association with the Msp1 C-allele. With a subgroup analysis by ethnicity, this risk was equally observed in the Asian population but not in Caucasians (including 50 articles). Zeng et al. (2016) reported a significant association between the C-allele and increased laryngeal cancer risk, while the stratified analysis by ethnicity also only showed association in the Asian but not Caucasian population (meta-analysis included 10 published studies comprising 748 cases and 1558 controls).
The A-to-G transition in exon 7 of the CYP1A1 gene results in the replacement of Isoleucine (Ile) with Valine (Val) at codon 462, which is described as a heme-binding site. This functional, non-synonymous polymorphism (rs1048943, A4889G / A2455G, 2C or m2) is said to potentially influence the balance between metabolic activation and detoxification of toxins by enhancing catalytic activity – this may ultimately lead to individual susceptibilities to cancer. It has also been reported that this variant significantly increases the catalytic activity for all hydroxylation sites toward substrates such as 17β-estradiol (E2) and estrone (E1), most significantly for 2-hydroxylation.
The meta-analysis from Wu et al. (2012) considered 126 publications with 134 case-controlled studies to conclude that the GG genotype was associated with an increased risk of lung cancer, leukemia, esophageal carcinoma, and prostate cancer among Caucasians and Asians, but not in Africans or in populations of mixed descent. These findings are conflicting with previous data as other researchers reported that the Ile462Val GG polymorphism is not associated with an increased risk of esophageal carcinoma and prostate cancer. Wu et al. (2012) noted that consequently large-scale, detailed and mechanistic studies are needed to confirm these relationships.
In support of Wu et al. (2012), but in contrast to an earlier meta-analysis from Shaik et al. (2009), an updated meta-analysis from Li et al. (2012) reported that the Ile462Val polymorphism of CYP1A1 results in a significantly increased susceptibility to prostate cancer in all genetic models. This finding is supported in the most recent 2019 meta-analysis from Zhu et al. (2019), which concluded that the Ile462Val polymorphism is significantly associated with prostate cancer susceptibility in the overall population, as well as the Asian populations, but not in Caucasian men.
Cervical cancer is described as a complex disease and is essentially considered an outcome of viral-induced carcinogenesis. The CYP1A1 enzyme is involved in the oxidation of oestrogen to catechols and oestrogen quinones that forms mutagenic stable and depurinating DNA adducts, facilitating Human Papilloma Virus (HPV) integration in the host genome. Cervical carcinogenesis is said to occur due to the synergistic effect of HPV infection and oestrogen metabolism.
A significant increase in cervical cancer risk was found amongst Caucasian G-allele (Val) carriers, consistent with previous findings from Sergentanis et al. (2012) The subgroup analysis based on ethnicity indicated that the CYP1A1 Ile462Val polymorphism played different roles in Asian and Caucasian populations. In the Caucasian population, people with Ile462Val G or Val-allele might have a higher risk of cervical cancer, whereas in Asians, no significant correlation had been found. They did mention, however, that only 2 studies were included for the Asian population, thus the interpretation of results should be done cautiously and further studies were needed to validate the results. A meta-analysis published in the same year, performed among Indian women, was not included in the Ding et al. (2018) analysis. Their findings, after analysing 29 genetic association studies regarding cervical cancer in India, revealed significant association of rs1048943 with cervical cancer.
Breast cancer risk associated with the Ile462Val polymorphism has been investigated due to the involvement of CYP1A1 in oestrogen metabolism. A meta-analysis from Sergentanis et al. (2009), which examined the Ile462Val polymorphism and breast cancer risk, included separate analyses on Caucasian, Chinese, and African populations, as well as on premenopausal and postmenopausal women. A total of 29 studies comprising 12 257 cases and 20 379 controls were considered. The meta-analysis reported a significantly increased breast cancer risk only in Caucasian subjects homozygous for the Val-allele (GG genotype). No association with breast cancer risk in Chinese subjects, or specifically in premenopausal/postmenopausal women were found. This is in contrast with previous meta-analyses, which either reported no association with breast cancer risk (Masson et al. in 2005) or reported an association only in East-Asians and in pre-menopausal women (Chen et al. in 2007). The authors explained these disparities: fewer studies were previously included, also studies were grouped differently to compose East Asian versus Caucasian populations. However, given the larger sample of studies in the present meta-analysis, adapting the population groupings to match the previous meta-analysis still did not lead to any different results.
In contrast to the above findings and in support of Verde et al. (2016), a more recent case-control study (988 cases and 1021 controls) utilising resources from the Long Island Breast Cancer Study Project (LIBCSP), reported an inverse relationship between the G-allele (AG and GG genotypes) and breast cancer incidence relative to the AA genotype. Parada et al. (2017) explains that since the Ile462Val mutation results in increased enzymatic activity, this would suggest more efficient generation of reactive PAH intermediates, and thus increased breast cancer risk. However, CYP1A1 also catalyses the conversion of estradiol into noncarcinogenic 2-hydroxyestradiol in extra-hepatic tissues, which may explain the inverse association they observed in this study between the G-allele and breast cancer. Their findings are also consistent with at least one other case–control study of Japanese women in which the G-allele was found to be associated with reduced breast cancer incidence compared with the AA genotype.
After the consideration of 20 studies (8665 cases and 9953 controls), the meta-analysis from Zhu et al. (2016) reported a significantly increased risk for colorectal cancer (CRC) in G-allele carriers. However, contradictory results were observed in a previous meta-analysis (Chen et al., 2005) which failed to find any association with CRC risk. The authors speculated that this discrepancy mainly results from sample size as the previous study only included two studies with 238 cases and 280 controls. In addition, 90% of studies included in this more recent meta-analysis were reportedly of high-quality score while the authors also conducted sensitivity analyses and found no obvious influence of a single study.
Significant association of the CYP1A1 rs1048943 polymorphism and laryngeal cancer risk was demonstrated in G-allele carriers when compared with the homozygous wild type genotype (AA). In the stratified analysis by ethnicity, the significant risks were found among Asian G-allele carriers whereas no significant associations were found in the Caucasian population. This meta-analysis assessed 10 studies with 748 cases and 1558 controls.
Lung cancer risk was significantly elevated in Val-allele carriers in a general population, according to a meta-analysis from Ji et al. (2012) The authors explored the association for lung cancer risk, and performed a subgroup analysis stratified by ethnicity, histological types of lung cancer and smoking status of case and control populations (43 case-control studies comprising 19 228 subjects). Their results indicated a significant association between the Val-allele and lung cancer risk in Asians and Caucasians with no significant association in mixed populations. The Val-allele was also associated with a 1.4-fold increase in the risk for lung squamous cell carcinoma (SCC) with no significant association found for lung adenocarcinoma (AC) and small cell lung cancer (SCLC). Additionally, a significant association was found in the smoker population and not in non-smoker populations.
A meta-analysis from Liu et al. (2015), including 50 studies, showed an increased risk for oral cancer in Asians, only after a subgroup analysis for ethnicity was performed.
No significant associations were found for the Ile462Val polymorphism and RCC risk, although smokers with the variant G-allele showed a significantly increased RCC risk.
Stop Smoking and/or Minimise Contact With Cigarette Smoke
Tobacco smoke contains many carcinogens and procarcinogens, such as benzopyrene and nitrosamine. These compounds are metabolized by the phase I enzymes, including CYP family enzymes, and converted to inactive metabolites by the phase II enzymes. Also present in tobacco smoke, PAH exposure may lead to PAH-DNA adduct formation and increased oncogenesis.
Smoking has been recognized as risk factor for lung cancer, breast cancer, renal cell carcinoma, oral cancer, cervical cancer, and colorectal cancer.
The Msp1 C-allele has showed a significant association with smoking for prostate cancer risk in various studies, although some results have been conflicting. A study from Mitsui et al. (2016) demonstrated that CYP1A1 is an important oncogene in prostate cancer as it is upregulated by DNA promoter hypomethylation. Tobacco smoking can cause a further reduction of methylation at the CYP1A1 distal enhancer that may lead to carcinogen activation through increased CYP1A1 expression. Altogether their findings demonstrate that tobacco smoking may contribute to the pathogenesis of prostate cancer and that inhibition of CYP1A1 may have therapeutic potential.
Smokers carrying the Msp1 C-allele has also been demonstrated to have an increased risk for renal cell carcinoma.
Many of the thousands of chemical compounds contained in tobacco smoke are considered mammary carcinogens. The activity of CYP1A1 may influence breast carcinogenesis via at least two distinct pathways, tobacco metabolites and oestrogen metabolism. A case-control study amongst 297 Spanish women supported the hypothesis that CYP1A1 Ile462Val, in association with long periods of active smoking, could be a breast cancer risk factor. When smokers were stratified by smoking duration however, researchers observed that only long-term smokers (≥ 20 years) with the Ile462Ile genotype (AA) was associated with increased risk of breast cancer. The authors speculated that their results support the main effect of CYP1A1 in estrogenic metabolism rather than in tobacco carcinogen activation in breast cancer. Smoking induces CYP1A1 and the effect of its polymorphisms in estrogenic metabolism is upregulated in a dose-dependent manner.
The Ji et al. (2012) meta-analysis results showed that a significantly increased lung cancer risk was associated with the Ile462Val polymorphism (G-allele) in smokers, with no significant association found among non-smokers.
Boost Flavonoid Intake
A case-control study in a Korean population (923 cases and 1846 controls) has revealed an inverse association between dietary flavonoid intake (particularly flavonols and flavan-3-ols) and CRC risk, which was stronger among CC homozygotes than among T allele carriers, particularly for rectal cancer association. A semi-quantitative food frequency questionnaire was used to assess the dietary intake of six flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols, anthocyanidins, and isoflavones), bioactive polyphenolic compounds that naturally occur in plant-based foods (e.g., fruits, vegetables, grains, and herbs) and drinks (e.g., tea, wine and juices). Several previous studies identified different associations based on the flavonoid subclass, consistent with the results of the present study.
The authors explain that CYP1A1 might interact with flavonoid compounds in several ways. First, flavonoids induce CYP expression and modulate their enzymatic activity. Some flavonoids alter CYP activity by binding to the AhR, as either AhR agonist or antagonist. Second, flavonoids are metabolized by CYP1A1, therefore, CYP1A1 genetic variants can alter flavonoid metabolism and subsequently modify the association between flavonoids and the risk of cancer. Variations in CYP1A1 activity in response to dietary flavonoids and genetic variations might affect carcinogen metabolism. As shown in the present study, the protective effect of flavonols is stronger among CYP1A1 rs4646903 CC homozygotes than among T-allele carriers.
Associations of CYP1 polymorphisms with risk of prostate cancer: an updated meta-analysis
Zhu et al, 2019.