Associations between polycyclic aromatic hydrocarbon-related exposures and p53 mutations in breast tumors.

BACKGROUND: Previous studies have suggested that polycyclic aromatic hydrocarbons (PAHs) may be associated with breast cancer. However, the carcinogenicity of PAHs on the human breast remains unclear. Certain carcinogens may be associated with specific mutation patterns in the p53 tumor suppressor gene, thereby contributing information about disease etiology. OBJECTIVES: We hypothesized that associations of PAH-related exposures with breast cancer would differ according to tumor p53 mutation status, effect, type, and number. METHODS: We examined this possibility in a population-based case-control study using polytomous logistic regression. As previously reported, 151 p53 mutations among 859 tumors were identified using Surveyor nuclease and confirmed by sequencing. RESULTS: We found that participants with p53 mutations were less likely to be exposed to PAHs (assessed by smoking status in 859 cases and 1,556 controls, grilled/smoked meat intake in 822 cases and 1,475 controls, and PAH-DNA adducts in peripheral mononuclear cells in 487 cases and 941 controls) than participants without p53 mutations. For example, active and passive smoking was associated with p53 mutation-negative [odds ratio (OR) = 1.55; 95% confidence interval (CI), 1.11-2.15] but not p53 mutation-positive (OR = 0.77; 95% CI, 0.43-1.38) cancer (ratio of the ORs = 0.50, p < 0.05). However, frameshift mutations, mutation number, G:C-->A:T transitions at CpG sites, and insertions/deletions were consistently elevated among exposed subjects. CONCLUSIONS: These findings suggest that PAHs may be associated with specific breast tumor p53 mutation subgroups rather than with overall p53 mutations and may also be related to breast cancer through mechanisms other than p53 mutation.

Common genetic variations in the LEP and LEPR genes, obesity and breast cancer incidence and survival.

Obesity is a strong risk factor for breast cancer in postmenopausal women and adverse prognostic indicator regardless of menopausal status. Leptin is an important regulator of adipose tissue mass and has been associated with tumor cell growth. Leptin exerts its effects through interaction with the leptin receptor (LEPR). We investigated whether genetic variations in the leptin (LEP) and LEPR genes are associated with risk of breast cancer, or once diagnosed, with survival. The polymorphisms LEP G-2548A and LEPR Q223R were characterized in population-based study consisting of mostly European-American women. The study examined 1,065 women diagnosed with first, primary invasive breast cancer between 1996 and 1997. Controls were 1,108 women frequency matched to the cases by 5-year age group. A modest increase in risk of developing breast cancer was associated with the LEP -2548AA genotype when compared to the LEP -2548GG genotype (age-adjusted OR = 1.30; 95% CI = 1.01-1.66). This association was stronger among postmenopausal women who were obese (OR = 1.86; 95% CI = 0.95-3.64) although the interaction was of borderline statistical significance (P = 0.07). We found no evidence of an association with polymorphisms of either LEP or LEPR in relation to all-cause or breast cancer-specific mortality among women with breast cancer (mean follow-up time = 66.7 months). The effects of these genotypes on breast cancer risk and mortality did not vary significantly when stratified by menopausal status. In summary, our results show that a common variant in LEP may be associated with the risk of developing breast cancer supporting the hypothesis that leptin is involved in breast carcinogenesis.

Mutations in p53, p53 protein overexpression and breast cancer survival.

p53 is an important tumour suppressor gene that encodes p53 protein, a molecule involved in cell cycle regulation and has been inconsistently linked to breast cancer survival. Using archived tumour tissue from a population-based sample of 859 women diagnosed with breast cancer between 1996 and 1997, we determined p53 mutations in exons 5-8 and p53 protein overexpression. We examined the association of p53 mutations with overexpression and selected tumour clinical parameters. We assessed whether either p53 marker was associated with survival through 2002, adjusting for other tumour markers and prognostic factors. The prevalence of protein overexpression in the tumour was 36% (307/859) and of any p53 mutation was 15% (128/859). p53 overexpression was positively associated with the presence of any p53 mutation (odds ratio [OR]= 2.2, 95% confidence interval [CI]= 1.5-3.2), particularly missense mutations (ER = 7.0, 95% CI = 3.6-13.7). Negative oestrogen and progesterone receptor (ER/PR) status was positively associated with both p53 protein overexpression (= 2.6, 95% CI = 1.7-4.0) and p53 mutation (OR = 3.9, 95% CI = 2.4-6.5). Any p53 mutation and missense mutations, but not p53 protein overexpression, were associated with breast cancer-specific mortality (hazard ratio [HR]= 1.7, 95% CI = 1.0-2.8; HR = 2.0, 95% CI = 1.1-3.6, respectively) and all-cause mortality (HR = 1.5, 95% CI = 1.0-2.4; HR = 2.0, 95% CI = 1.2-3.4, respectively); nonsense mutations were associated only with breast cancer-specific mortality (HR = 3.0, 95% CI = 1.1-8.1). These associations however did not remain after adjusting for ER/PR status. Thus, in this population-based cohort of women with breast cancer, although p53 protein overexpression and p53 mutations were associated with each other, neither independently impacted breast cancer-specific or all-causing mortality, after considering ER/PR status.

A CYP19 (aromatase) polymorphism is associated with increased premenopausal breast cancer risk.

Due to the established association between estrogen levels and breast cancer risk, polymorphic variation in genes regulating estrogen levels is thought to be related to breast cancer risk. Aromatase, the protein product of the CYP19 gene, is involved in the production of endogenous estrogens via androgen conversion. We examined whether polymorphic variation in CYP19 associated with increased breast cancer risk in a population based case-control study. We examined two single nucleotide polymorphisms (SNP), rs1008805 (A/G) and rs730154 (C/T), which have been shown to tag SNPs within two different haplotype blocks in CYP19. Among premenopausal women, the presence of at least one G allele at rs1008805 was significantly associated with an increase in the risk of breast cancer (OR = 1.72 [95% CI, 1.20-2.49]), especially with estrogen and progesterone receptor negative breast cancer (OR = 3.89 [1.74-8.70] and OR = 2.52 [1.26-5.05], respectively). No association was observed among postmenopausal women (OR = 1.06 [0.82-1.36]). There was no significant association between rs730154 and breast cancer, regardless of menopausal status. Our results suggest that premenopausal women carrying the G allele at CYP19 rs1008805 have increased risk of breast cancer. The finding supports the potential role of variation in estrogen biosynthesis genes in premenopausal breast cancer risk.

Polymorphisms in nucleotide excision repair genes, polycyclic aromatic hydrocarbon-DNA adducts, and breast cancer risk.

Genes involved in the nucleotide excision repair (NER) pathway, which removes bulky DNA adducts, are potential low-penetrance cancer susceptibility genes. We recently reported an association between detectable polycyclic aromatic hydrocarbon (PAH)-DNA adducts and breast cancer risk. Using a population-based breast cancer case-control study on Long Island, New York, we examined whether polymorphisms in NER genes modified the association between PAH-DNA adducts and breast cancer risk. We examined polymorphisms in ERCC1 (3'-untranslated region 8092C/A), XPA (5'-untranslated region -4G/A), XPD (Asp(312)Asn in exon 10), XPF (Arg(415)Gln in exon 8), and XPG (Asp(1104)His in exon 15) in 1,053 breast cancer cases and 1,102 population-based controls. The presence of at least one variant allele in XPD was associated with a 25% increase in the odds ratio [OR, 1.25; 95% confidence interval (95% CI), 1.04-1.50] for breast cancer. The increase associated with homozygosity of the variant alleles for XPD and ERCC1 was stronger among those with detectable PAH-DNA adduct levels (OR, 1.83; 95% CI, 1.22-2.76 and OR, 1.92; 95% CI, 1.14-3.25 for detectable versus nondetectable adducts and homozygous wild-type genotype for XPD and ERCC1, respectively). We found no association between XPA, XPF, and XPG genotypes, PAH-DNA adducts, and breast cancer risk. When we combined genotypes for these NER pathway genes, there was a significant trend for increasing breast cancer risk with increasing number of putative high-risk alleles. Overall, this study suggests that the risk of breast cancer may be elevated among women with polymorphisms in NER pathway genes and detectable PAH-DNA adducts.