Fang Fang Zhang

Relationship between urinary 15-F2t-isoprostane and 8-oxodeoxyguanosine levels and breast cancer risk

To evaluate the role of oxidative stress in breast cancer, we measured urinary levels of 15-F2t-isoprostane (15-F2t-IsoP) and 8-oxodeoxyguanosine (8-oxodG) in 400 cases and 401 controls, participants of the Long Island Breast Cancer Study Project. We also analyzed the effect of different factors that are associated with oxidative stress and might influence 15-F2t-IsoP and 8-oxodG levels. We observed a statistically significant trend in breast cancer risk with increasing quartiles of 15-F2t-IsoP levels [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 0.81-1.94; OR, 1.53; 95% CI, 0.99-2.35; OR, 1.88; 95% CI, 1.23-2.88, for the 2nd, 3rd, and 4th quartile relative to the lowest quartile, respectively; Ptrend = 0.002]. Although it is possible that increased levels may reflect the stress associated with recent treatment, the positive association was also observed when the analyses were restricted to case women for whom chemotherapy and radiation therapy had not yet been initiated at the time of the urine collection. The association with the highest quartile compared with lowest quartile of 15-F2t-IsoP was similar across strata of age, physical activity, fruit and vegetable intake, alcohol intake, cigarette smoking, body mass index, and menopausal status. We did not observe any association of breast cancer risk with 8-oxodG levels, but when cases with radiation treatment were removed from the analysis, a significant inverse trend (P = 0.04) was observed. Among controls, levels of 15-F2t-IsoP were higher among current cigarette smokers but did not differ by the amount of physical activity, fruit and vegetable intake, alcohol intake, body mass index, and menopausal status. Among controls, levels of 8-oxodG were higher among postmenopausal women and current and former cigarette smokers but did not differ by the other factors. In summary, our results suggest that urinary markers of lipid peroxidation and oxidative DNA damage may be associated with breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(4):639-44)

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 (Asp312Asn in exon 10), XPF (Arg415Gln in exon 8), and XPG (Asp1104His 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. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2033–41)

OGG1 polymorphisms and breast cancer risk

The role of oxidative stress in breast cancer risk is still unclear. OGG1 encodes an 8-oxoguanine DNA glycosylase/AP lyase that catalyzes the removal of 8-oxodeoxyguanosine from DNA. 8-Oxodeoxyguanosine, the most abundant lesion generated by oxidative stress, is highly mutagenic. Environmental sources of oxidative stress, such as alcohol consumption, cigarette smoking, high body mass index (BMI), and low fruits and vegetables intake, may modify the association of genetic polymorphisms with breast cancer risk. We investigated the association between three genetic polymorphisms in OGG1 (Ser326Cys, 7143A/G, and 11657A/G) and breast cancer risk among 1,058 cases and 1,102 controls participating in the Long Island Breast Cancer Study Project. No associations were observed between individual OGG1 polymorphisms, haplotypes, or diplotypes and breast cancer. The association between having at least one variant allele and breast cancer risk was stronger among moderate alcohol drinkers for Ser326Cys [odds ratio (OR), 1.82; 95% confidence interval (95% CI), 1.06-3.10] relative to nondrinkers with the wild-type genotype and among those with higher BMI for 7143A/G (OR, 1.47; 95% CI, 1.10-1.96) and for 11657A/G (OR, 1.41; 95% CI, 1.05-1.88), relative to women with BMI < 25 kg/m2 and the wild-type genotype. However, the patterns were not seen for all three single nucleotide polymorphisms (SNP) nor were there any clear allele dose associations; only one interaction was statistically significant, assuming a multiplicative model (11657A/G, Pinteraction = 0.04). In summary, although we found some differences between the three OGG1 SNPs and breast cancer risk among moderate alcohol drinkers and women with higher BMI, replication of these results is needed to rule out spurious findings. In addition, data on functionality of these polymorphisms are crucial to understand if these modest differences are important. (Cancer Epidemiol Biomarkers Prev 2006;15(4):811–5)

Plasma protein carbonyl levels and breast cancer risk

To study the role of oxidative stress in breast cancer risk, we analysed plasma levels of protein carbonyls in 1050 cases and 1107 controls. We found a statistically significant trend in breast cancer risk in relation to increasing quartiles of plasma protein carbonyl levels (OR = 1.2, 95% CI = 0.9–1.5; OR = 1.5, 95% CI = 1.2–2.0; OR = 1.6, 95% CI = 1.2–2.1, for the 2nd, 3rd and 4th quartile relative to the lowest quartile, respectively, P for trend = 0.0001). The increase in risk was similar for younger (<50 years) and older women, more pronounced among women with higher physical activity levels (0.7 hrs/week for 4th quartile versus lowest quartile OR = 2.0, 95% CI = 1.4–3.0), higher alcohol consumption (≥15 grams/day for 4th quartile versus lowest quartile OR = 2.3, 95% CI = 1.1–4.7), and hormone replacement therapy use (HRT, OR = 2.6, 95% CI = 1.6–4.4 for 4th quartile versus lowest quartile). The multiplicative interaction terms were statistically significant only for physical activity and HRT. The positive association between plasma protein carbonyl levels and breast cancer risk was also observed when the analysis was restricted to women who had not received chemotherapy or radiation therapy prior to blood collection. Among controls, oxidized protein levels significantly increased with cigarette smoking and higher fruit and vegetable consumption, and decreased with alcohol consumption >30 grams per day. Women with higher levels of plasma protein carbonyl and urinary 15F2t‐isoprostane had an 80% increase in breast cancer risk (OR = 1.8, 95% CI = 1.2–2.6) compared to women with levels below the median for both markers of oxidative stress. In summary, our results suggest that increased plasma protein carbonyl levels may be associated with breast cancer risk.

Genetic Polymorphisms in Folate Metabolism and the Risk of Stomach Cancer

Folate deficiency has been implicated in the etiology of stomach cancer through abnormal DNA methylation and disrupted DNA synthesis and repair. Enzyme-coding genes involved in folate metabolism are often polymorphic. In a population-based study of 305 cases and 427 controls in Warsaw, Poland, we evaluated the risk of stomach cancer in relation to polymorphisms in folate-metabolizing genes, including MTHFR (Ex5+79C>T and Ex8−62A>C), MTR (Ex26−20A>G), and MTRR (Ex2−64A>G, Ex5+123C>T, Ex15+572C>T, Ex15−405A>T, Ex9−85C>T, Ex15−526G>A, and Ex14+14C>T). Polymorphisms in the MTHFR gene were not associated with stomach cancer risk. No notable effect was found for polymorphisms in MTR or MTRR either, although MTR Ex26−20 A>G and MTRR Ex5+123C>T polymorphisms were associated with a borderline increased risk of stomach cancer (MTR Ex26−20A>G, AG/GG versus AA: odds ratio, 1.35; 95% confidence interval, 0.96-1.90; MTRR Ex5+123C>T, CT/TT versus CC: odds ratio, 1.30; 95% confidence interval, 0.93-1.82). We did not find significant interactions between polymorphisms in MTHFR, MTR, and MTRR genes and dietary folate and alcohol consumption. Our study did not identify strong genetic determinants in the folate metabolism pathway for stomach cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(1):115–21)

An International Case Control Study of Adult Diet and Brain Tumor Risk: A Histology-Specific Analysis by Food Group

PURPOSE Existing studies of diet and adult brain tumors have been limited by small numbers in histology-specific subgroups. Dietary data from an international collaborative case-control study on adult brain tumors were used to evaluate associations between histology-specific risk and consumption of specific food groups. METHODS The study included 1548 cases diagnosed between 1984 and 1991 and 2486 control subjects from 8 study centers in 6 countries. Of the 1548 cases, 1185 were gliomas, 332 were meningiomas, and 31 were other tumor types. Dietary consumption was measured as average grams per day. RESULTS We found inverse associations between some vegetable groups and glioma risk, the strongest for yellow-orange vegetables (odds ratio [OR], 0.7, 95% confidence interval [CI], 0.5-0.9 for the 4th vs. 1st quartile of consumption, p for trend<0.001), and the association was limited to specific glioma subtypes. There was no association with cured meat. Non-cured meat was associated with a modest increase in glioma risk (OR, 1.3; 95% CI, 1.0-1.7 for 4th quartile vs. 1st quartile, p for trend=0.01). We also found positive associations between egg, grain, and citrus fruit consumption and glioma but not meningioma risk. CONCLUSIONS Our study suggests that selected dietary food groups may be associated with adult gliomas and its subtypes but not meningiomas.

Cigarette smoking, body mass index, gastro-esophageal reflux disease, and non-steroidal anti-inflammatory drug use and risk of subtypes of esophageal and gastric cancers by P53 overexpression.

A number of risk factors for esophageal and gastric cancers have emerged, yet little is known whether risk factors map to molecular tumor markers such as overexpression of the tumor suppressor TP53. Using a US multicenter, population-based case–control study (170 cases of esophageal adenocarcinomas, 147 gastric cardia adenocarcinomas, 220 non-cardia gastric adenocarcinomas, and 112 esophageal squamous cell carcinomas), we examined whether the risk associated with cigarette smoking, body mass index (BMI), gastroesophageal reflux disease (GERD), and non-steroidal anti-inflammatory drug (NSAID) use varied by P53 overexpression. We defined P53 overexpression through immunohistochemistry of paraffin-embedded tumor tissues, using cutpoints based on percent of cells positive. Polytomous logistic regression was used to assess differences between each case group (defined by tumor subtype and P53 expression) and the control group by risk factors. The proportion of cases overexpressing P53 by tumor subtype was 72% for esophageal adenocarcinoma, 69% for gastric cardia adenocarcinoma, 52% for non-cardia gastric adenocarcinoma, and 67% for esophageal squamous cell carcinoma. For most tumor subtypes, we found little difference in risk factors by tumor P53 overexpression. For non-cardia gastric cancer however, an association with cigarette smoking was suggested for tumors that do not overexpress P53, whereas larger BMI was related to adenocarcinomas that overexpress P53 versus no overexpression. Overall, this study did not find a clear relationship between P53 protein overexpression and the known risk factors for subtypes of esophageal and gastric cancers. Further research on these tumors is needed to identify molecular markers associated with variations in the risk factor profiles.

Abstract B132: Risk factors for uncommon histologically defined subgroups of breast cancer using the Breast Cancer Family Registry

Breast cancer is a heterogeneous disease; risk factors may differ for histologically‐defined subgroups. Because most breast cancers are of ductal or lobular histology, previous studies have been limited in their ability to evaluate risk factors in rarer histologies, such as medullary, mucinous, and tubular, due to small sample sizes. We evaluated risk factors for histologically‐defined breast cancer subgroups (ductal, lobular, tubular, medullary, or mucinous) using population‐based data from the Breast Cancer Family Registry. Data were available for 3260 incident breast cancer cases (including 92 cases of medullary, 90 cases of mucinous, and 86 cases of tubular histology) and 2997 unrelated controls. Several reproductive factors were associated with the risk of mucinous breast cancer, whereas cigarette smoking and body mass index (BMI) were associated with the risk of medullary breast cancer. For the mucinous subtype, we observed positive associations with nulliparity (OR=2.54, 95%CI 1.17–5.50) and age at first birth (OR=1.08, 95%CI=1.02–1.14, for each additional year of age), and an inverse association with age at menarche (≥13 vs. ≤11) (OR=0.52, 95%CI 0.29–0.94). These reproductive factors were not associated with other histologic subtypes. Mucinous cases were less likely than controls to have used oral contraceptives (OC use ≤ 5 years: OR=0.50, 95%CI 0.28–0.92; OC use > 5 years, OR=0.45, 95%CI 0.24–0.84), and these findings did not differ by menopausal status. Oral contraceptive use was also inversely associated with tubular histology among premenopausal women only (OC use > 5 years, OR=0.35, 95%CI 0.14–0.87), but was not associated with other histologic subtypes when compared with controls. Medullary histology was inversely associated with smoking status (former smoker vs. never smoker, OR=0.30, 95%CI 0.14–0.62), and positively associated with BMI (OR=1.05, 95%CI 1.01–1.09, for each one‐unit increase in BMI). Other known breast cancer risk factors, such as hormone‐replacement therapy (HRT), breastfeeding history, and alcohol use, were not associated with the any of the rarer subtypes. Family history of breast cancer was associated with increased risk of all histologic subtypes. If replicated, these findings suggest different patterns for selected breast cancer risk factors, such as parity, oral contraceptive use, and smoking, by tumor histology. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B132.