Cancer Epidemiology Term Paper

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HuGE Cancer Epidemiology

HuGE Study

Masson, L. Sharp, S.C. Cotton and J. Little. Cytochrome P-450 1A1 Gene Polymorphisms and Risk of Breast Cancer: A HuGE Review. Am. J. Epidemiol. (15 May 2005) 161 (10): 901-915.

Category of HuGE Information

The types of information available from the article:

Prevalence of gene variant

Gene-disease association

Gene-environment interaction

Gene-gene interaction

Cytochrome P-450 (CYP) 1A1 plays a key role in phase I metabolism of polycyclic aromatic hydrocarbons and in estrogen metabolism. It is expressed predominantly in extrahepatic tissues, including the breast. Four CYP1A1 gene polymorphisms (3801T-C, Ile462Val, 3205T-C, and Thr461Asp) have been studied in relation to breast cancer. The 3801C variant is more common than the Val variant. Both variants occur more frequently in Asians than in White populations. The 3205T-C polymorphism has been observed in African-Americans only. Little data are available on the geographic/ethnic distribution of the Thr461Asp polymorphism. The functional significance of the polymorphisms is unclear. In 17 studies, no consistent association between breast cancer and CYP1A1 genotype was found. Meta-analysis found no significant risk for the genotypes 1) 3801C/C (relative risk (RR) = 0.97, 95% confidence interval (CI): 0.52, 1.80) or 3801T/C (RR = 0.91, 95% CI: 0.70, 1.19) versus 3801T/T, 2) Val/Val (RR = 1.04, 95% CI: 0.63, 1.74) or Ile/Val (RR = 0.92, 95% CI: 0.76, 1.10) versus Ile/Ile, or 3) Asp/Asp (RR = 0.95, 95% CI: 0.20, 4.49) or Thr/Asp (RR = 1.12, 95% CI: 0.87, 1.43) versus Thr/Thr. Future studies should explore possible interactions between CYP1A1 and sources of polycyclic aromatic hydrocarbons, markers of estrogen exposure, other lifestyle factors influencing hormonal levels, and other genes involved in polycyclic aromatic hydrocarbon metabolism or hormonal biosynthesis.

Gene:

Gene Name, Chromosome location, and gene product/function:

Cytochrome P-450 (CYP) 1A1 is a key enzyme in phase I bioactivation of xenobiotics. It contributes to aryl hydrocarbon hydroxylase activity, catalyzing the first step in the metabolism of a number of polycyclic aromatic hydrocarbons (PAHs), such as the tobacco carcinogen benzo[a]pyrene, to their ultimate DNA-binding forms. It is also involved in estrogen metabolism, catalyzing the hydroxylation of 17?-estradiol at the C-2 position.

The CYP1A1 gene, located at 15q22-q24, comprises seven exons and six introns and spans 5,810 base pairs. In humans, CYP1A1 is under the regulatory control of the aryl hydrocarbon receptor, a transcription factor that regulates gene expression.

CYP1A1 expression occurs predominantly in extrahepatic tissue. CYP1A1 messenger RNA has been detected in normal and cancerous breast tissue and can be induced in human-breast-derived cell lines.

Alleles: CYP1 family:

CYP1A1; CYP1A2; CYP1B1; CYP2 family: CYP2A6; CYP2A13; CYP2B6; CYP2C8; CYP2C9; CYP2C19; CYP2D6; CYP2E1; CYP2F1; CYP2J2; CYP2R1; CYP2S1; CYP2W1

CYP3 family:

CYP3A4; CYP3A5; CYP3A7; CYP3A43

CYP4 family:

CYP4A11; CYP4A22; CYP4B1; CYP4F2

CYP>4 families:

CYP5A1

CYP8A1

CYP19A1

CYP21A2

CYP26A1

OMIM #: 108330

Environmental Factors:

1. PAHs (polyaromatic hydrocarbons)

2. Tobacco smoke

3. Estrogen

4. Fried foods

5. Alcohol

6. PCBs (polychlorinated biphenols)

Health Outcomes:

1. Incidence of breast cancer risk in association with C-P450 mutations

2. Determine variants of C-P450 polymorphisms in specific ethnic populations

3. Determine gene-gene and gene-environment interactions for CP450 alleles and breast cancer.

Study design

This is a descriptive, cross-sectional study.

Assessment of environmental factors:

Environmental factor: Smoking

Exposure assessment and definition: genotype-smoking interactions light smokers (

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Eligible studies presented frequencies for each genotype separately in nondiseased persons. Studies that did not include controls for breast cancer patients were excluded if there were fewer than 200 subjects in each ethnic group, which would limit precision of the estimates of the genotype frequencies. If there appeared to be an overlap in subjects between studies, only the largest study was reported. Hardy-Weinberg equilibrium was assessed by using the Pearson ?2 test.

The subjects in most studies are volunteers (with the sampling frame unspecified) or hospital or clinic patients. It is unclear whether genotype frequencies in such series will reflect those in the general population. Considerable data are available from Japanese, western European, and White American populations. Data are limited, or not available, for other populations. Information is also lacking on genotype frequencies in different age groups. Most studies consider only the 3801T-C and/or Ile462Val polymorphisms, which has the potential to result in misclassification. When individual polymorphisms are assessed, those persons who do not carry the specific variant may not be true wild-type homozygotes; a proportion may carry another variant. Moreover, the presence of the Thr461Asp polymorphism may interfere with detection of the Ile462Val polymorphism, resulting in overestimation of the Val allele if the polymerase chain reaction product has not been digested with BsrD1 (13). Genotype frequencies were in Hardy-Weinberg equilibrium, except in two studies of the 3801T-C polymorphism (63, 65) and nine studies of the Ile462Val polymorphism (19, 41, 53, 64, 67, 70, 76, 78, 82).

3801T-C (CYP1A1*2A, CYP1A1*2B).

The 3801C variant is most prevalent in Asian populations, where the frequency of the C/C genotype is 2 -- 18% and that of the T/C genotype is 32 -- 55%. In European and White American series, 0 -- 5% are C/C and 9 -- 28% are T/C. Frequencies in African-Americans are intermediate between White and Asian populations (4 -- 6% C/C, 35 -- 39% T/C).

In their pooled analysis, the C/C genotype frequency was 13% (95% confidence interval (CI): 12.0, 14.0) in Asians, 1% (95% CI: 0.9, 1.4) in Whites, and 6% (95% CI: 3.7, 8.1) in African-Americans. The heterozygote frequency was 44% (95% CI: 42.6, 45.6) in Asians, 17% (95% CI: 16.5, 18.0) in Whites, and 36% (95% CI: 31.7, 40.6) in African-Americans.

Ile462Val (CYP1A1*2B, CYP1A1*2C).

In all ethnic groups, the Val variant occurs less frequently than the 3801C variant. Similar to the 3801C variant, it is most common among Asians, where 1 -- 8% are Val/Val and 15 -- 46% are Ile/Val. In Europeans and U.S. Whites, at most 3% are Val/Val and as many as 15% are Ile/Val. The Val variant is less common among African-Americans than Whites. In studies including African-Americans, no subjects had the Val/Val genotype, but up to 6% were Ile/Val.

Their pooled estimate of Val/Val genotype frequency was 5% (95% CI: 4.0, 5.0) in Asians, 0.7% (95% CI: 0.5, 0.8) in Whites, and 0% in African-Americans. The pooled estimate of Ile/Val genotype frequency was 31% (95% CI: 29.5, 31.7), 8% (95% CI: 7.8, 8.9), and 5% (95% CI: 3.2, 7.3), respectively.

3205T-C (CYP1A1*3).

The 3205C variant was originally thought to occur in African-Americans only. This view is supported by studies of Turkish, French, German, Polish, Russian, and U.S. White subjects in whom the 3205C variant was not found. In four African-American series, less than 1% had the C/C genotype, while 14 -- 24% were heterozygotes. In their pooled analysis, the C/C and T/C genotype frequencies were 0.1% (95% CI: 0.0, 0.8) and 15% (95% CI: 12.8, 18.3), respectively, in African-Americans.

Thr461Asp (CYP1A1*4).

Asp/Asp homozygotes are very rare (?1%). The Thr/Asp genotype frequency is 4 -- 12% in Turkish, European, and White North American populations. The pooled estimates of the Asp/Asp and Thr/Asp genotype frequencies in Whites were 0.2% (95% CI: 0.1, 0.4) and 8% (95% CI: 7.1, 8.8), respectively.

Associations between the CYP1A1 polymorphisms.

Studies of linkage between the polymorphisms are limited by the relative rarity of the variants. From the comparatively few studies carried out, the 3801T-C and Ile462Val polymorphisms appear to be closely linked in Asians, less closely linked in Europeans, and not linked in African-Americans. In 81 Africans and African-Americans carrying the 3205C variant, 23% also carried the 3801C variant, and no subjects carried the Val variant (18). The Thr461Asp and 3801T-C polymorphisms were not linked in Turkish, German, or Polish populations. No evidence for linkage.....

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