Recreational physical activity and risk of triple negative breast cancer in the California Teachers Study.

BACKGROUND: Evidence has accumulated showing that recreational physical activity reduces breast cancer risk. However, it is unclear whether risk reduction pertains to specific receptor-defined subtypes. Moreover, few studies have examined whether changes in the amount of recreational physical activity during adulthood influence breast cancer risk. METHODS: A total of 108,907 women, ages 22 to 79 years with no history of breast cancer when joining the California Teachers Study in 1995-1996, completed a baseline questionnaire and were eligible for the study. Through 2012, 5882 women were diagnosed with invasive breast cancer. Breast cancer subtypes were defined by the expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Multivariable Cox proportional hazards models provided adjusted hazard ratios (HRs) and 95 % confidence intervals (CIs) for breast cancer overall and ER/PR/HER2-defined subtypes associated with long-term (from high school through age 54 or age at cohort entry, whichever was younger) and baseline (during 3 years prior to baseline) recreational physical activity. Among women who also completed a follow-up questionnaire at 10 years after baseline in 2005-2008 (54,686 women, 1406 with invasive breast cancer), risk associated with changes in the amount of recreational physical activity from baseline to the 10-year follow-up (during 3 years prior to the 10-year follow-up) was determined. RESULTS: Both long-term and baseline strenuous recreational physical activity were inversely associated with risk of invasive breast cancer (P trend ≤0.03). The observed associations were mainly confined to women with triple negative breast cancer (TNBC, ER-/PR-/HER2-, P trend ≤0.02) or luminal A-like subtype (ER+ or PR+ plus HER2-) who were former users of menopausal hormone therapy at baseline (P trend = 0.02, P homogeneity of trends ≤0.03). Moreover, women who consistently engaged in the highest level (≥3.51 h/wk/y) of strenuous recreational physical activity between baseline and 10-year follow-up had the lowest risk of breast cancer (HR = 0.71, 95 % CI = 0.52-0.98) when compared to those who were consistently low (≤0.50 h/wk/y). CONCLUSIONS: Strenuous recreational physical activity is associated with lower breast cancer risk, especially TNBC. The benefit may be maximized by consistently engaging in high-intensity recreational physical activity during adulthood.

Novel polymorphisms in caspase-8 are associated with breast cancer risk in the California Teachers Study.

BACKGROUND: The ability of tamoxifen and raloxifene to decrease breast cancer risk varies among different breast cancer subtypes. It is important to determine one's subtype-specific breast cancer risk when considering chemoprevention. A number of single nucleotide polymorphisms (SNPs), including one in caspase-8 (CASP8), have been previously associated with risk of developing breast cancer. Because caspase-8 is an important protein involved in receptor-mediated apoptosis whose activity is affected by estrogen, we hypothesized that additional SNPs in CASP8 could be associated with breast cancer risk, perhaps in a subtype-specific manner. METHODS: Twelve tagging SNPs of CASP8 were analyzed in a nested case control study (1,353 cases and 1,384 controls) of non-Hispanic white women participating in the California Teachers Study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each SNP using all, estrogen receptor (ER)-positive, ER-negative, human epidermal growth factor receptor 2 (HER2)-positive, and HER2-negative breast cancers as separate outcomes. RESULTS: Several SNPs were associated with all, ER-positive, and HER2-positive breast cancers; however, after correcting for multiple comparisons (i.e., p < 0.0008), only rs2293554 was statistically significantly associated with HER2-positive breast cancer (OR = 1.98, 95% CI 1.34-2.92, uncorrected p = 0.0005). CONCLUSIONS: While our results for CASP8 SNPs should be validated in other cohorts with subtype-specific information, we conclude that some SNPs in CASP8 are associated with subtype-specific breast cancer risk. This study contributes to our understanding of CASP8 SNPs and breast cancer risk by subtype.

Physical activity and cancer.

Epidemiological evidence continues to accumulate on the benefits of physical activity in relation to cancer risk, progression and mortality. Recent studies suggest that sedentary behavior may independently affect cancer risk; they also focus on factors that may explain associations with physical activity, including cancer risk factors and whether associations exist for precancerous lesions. Despite enormous efforts to examine associations between physical activity and cancer, the literature is hindered by inconsistent assessment of physical activity across studies, and incomplete consideration of variation of effects across population subgroups (for example, defined by body size, age or sex) or tumors subgroups (organ location, receptor status, or molecular subtype), and whether other factors explain study results. Clearly, public health recommendations for appropriate changes in activity levels are needed; unfortunately, at this time, we have no exact physical activity prescription to give to the public.

The future workforce in cancer prevention: advancing discovery, research, and technology.

As part of a 2-day conference on October 15 and 16, 2009, a nine-member task force composed of scientists, clinicians, educators, administrators, and students from across the USA was formed to discuss research, discovery, and technology obstacles to progress in cancer prevention and control, specifically those related to the cancer prevention workforce. This article summarizes the task force's findings on the current state of the cancer prevention workforce in this area and its needs for the future. The task force identified two types of barriers impeding the current cancer prevention workforce in research, discovery, and technology from reaching its fullest potential: (1) limited cross-disciplinary research opportunities with underutilization of some disciplines is hampering discovery and research in cancer prevention, and (2) new research avenues are not being investigated because technology development and implementation are lagging. Examples of impediments and desired outcomes are provided in each of these areas. Recommended solutions to these problems are based on the goals of enhancing the current cancer prevention workforce and accelerating the pace of discovery and clinical translation.

Genetic variations in microRNA-related genes are associated with survival and recurrence in patients with renal cell carcinoma.

We took a polygenic approach to evaluate the effects of 41 potentially functional single-nucleotide polymorphisms (SNPs) in microRNAs (miRNAs)-related genes on survival and recurrence among renal cell carcinoma (RCC) patients. During a median follow-up of 21.8 months, among 316 RCC patients, 64 died and 56 developed recurrence. In single-SNP analysis, we identified seven SNPs significantly associated with RCC survival and five SNPs with recurrence. The most significant associations were SNPs in GEMIN4 with the variant alleles of both rs7813 and rs910925 associated with 1.74-fold [95% confidence interval (CI) = 1.15-2.62] increased risk of death, whereas the variant allele of rs3744741 conferred a decreased risk of death [hazard ratio (HR) = 0.39; 95% CI = 0.19-0.77]. Several SNPs belonging to the pre-miRNA and were identified to be significantly associated with RCC recurrence. Haplotypes of DICER and DROSHA were also associated with altered patient survival and recurrence. More importantly, we observed cumulative effects of multiple SNPs on RCC survival. Compared with subjects carrying zero to two unfavorable genotypes, those carrying three to five and six and more unfavorable genotypes had an increased risk of death with a HR of 2.49 (95% CI = 1.24-5.00) and 6.66 (95% CI = 2.49-17.86), respectively, with significant dose-response trend (P for trend<0.001). As the first study of miRNA-related genetic polymorphisms on RCC clinical outcome, our results strongly suggested that miRNA-related SNPs may impact the recurrence and survival in RCC patients. Future investigation in larger populations and functional characterizations are necessary to validate these results.

Genetic variation in MicroRNA genes and risk of oral premalignant lesions.

MicroRNAs (miRNAs) have been reported to play a key role in oncogenesis and, recently, studies have examined the role miRNAs might play in the risk of premalignant lesions. To our knowledge, no study has investigated the association between miRNA polymorphisms and risk of oral premalignant lesions (OPLs). We genotyped 31 single nucleotide polymorphisms (SNPs) among 21 miRNA-related genes in a case-control study including 136 OPL patients and 136 matched controls. Patients with at least one variant allele of mir26a-1:rs7372209 had a significantly increased risk of OPL (OR, 2.09; 95% CI, 1.23-3.56). Likewise, patients with at least one variant allele of DICER:rs3742330 had a significantly increased risk of OPL (OR, 2.09; 95% CI, 1.03-4.24). To assess the cumulative effects, we performed a combined unfavorable genotype analysis that included all SNPs showing at least a borderline statistical significance. A significant trend of increased risk of OPL with increasing number of unfavorable genotypes was observed (P for trend <0.0001). This study presents the first epidemiologic evidence supporting that individual as well as combined genotypes of miRNA-related variants may be used to predict the risk of OPL, and may be useful for identifying patients with OPL at high risk for progression to oral cancer.

The D2 dopamine receptor gene and nicotine dependence among bladder cancer patients and controls.

Multiple twin, family, and genetic studies have rendered substantial evidence supporting an association between hereditary factors and smoking initiation and maintenance. To investigate further the relationships between the DRD2 genotypes, cigarette use and nicotine dependence, we examined the prevalence of polymorphisms in the TaqIA (A1 and A2) and the TaqIB (B1 and B2) alleles among a series of 608 non-Hispanic White bladder cancer patients and 608 matched controls. Among ever-smoking controls, A1 and B1 genotypes exhibited a greater smoking intensity and were significantly younger at the age of initiation than A2A2 or B2B2 genotypes (two-sided P < 0.05). Among former smoking cases, persons with the A1 genotypes exhibited significantly higher mean pack-years and years of smoking, and were younger at the age of initiation than were persons with the A2A2 genotype (two-sided P < 0.05). Additionally, current smokers with the A1 genotypes reported fewer quit attempts than those with the A2A2 genotype (two-sided P < 0.01). The present study suggests that the DRD2 alleles A1 and B1 confer greater vulnerability to tobacco use.

Sensitivity to NNKOAc is associated with renal cancer risk.

Cigarette smoking has been investigated as a major risk factor for renal cell carcinoma (RCC). 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most abundant carcinogenic N-nitrosamines present in cigarette smoke. However, the association between repair capacity of NNK-induced DNA damage and RCC risk remains unknown. We used the comet assay to assess whether sensitivity to a NNK precursor 4-[(acetoxymethyl) nitrosamino]-1-(3-pyridyl)-1-butanone (NNKOAc) induced DNA damage, which partly reflects host sensitivity to NNK, was associated with increased risk of RCC in a population-based case-control study. The study included 95 RCC cases and 188 matched controls. Epidemiologic data were collected via in-person interview. Baseline and NNK-induced DNA damage in peripheral blood lymphocytes were measured using the comet assay and quantified by the Olive tail moment. The NNKOAc-induced median Olive tail moments were significantly higher in cases than in controls (2.27 versus 1.76, P = 0.002). Using the 75th percentile Olive tail moments of the controls as the cutoff point, we found that higher levels of NNKOAc-induced DNA damage were associated with a significantly increased risk of RCC [odds ratio, 2.06; 95% confidence interval, 1.17-3.61]. In quartile analysis, there was a dose-response association between NNKOAc-induced damage and risk of RCC (P for trend, 0.006). Our data strongly suggest that higher levels of NNKOAc-induced damage are associated with higher risks of RCC. Future studies with larger sample sizes are warranted to further investigate whether repair of NNKOAc-induced damage, as quantified by the comet assay, could be used as a predictive marker for RCC risk.

Family history and risk of renal cell carcinoma: results from a case-control study and systematic meta-analysis.

We conducted a case-control analysis, a family-based population analysis, and a meta-analysis to assess the role of family history of cancer and kidney cancer in association with the risk of renal cell carcinoma (RCC). A total of 325 cases and 329 controls were identified from an ongoing case-control study of RCC. Study variables were assessed through 45-minute structured face-to-face interviews. In the case-control analysis, a family history of any cancer (in first-degree relatives) was associated with a nonsignificant 1.2-fold increase in RCC risk [95% confidence interval (95% CI), 0.8-1.6]. The risk increased to 1.7 and became significant when the relative was a sibling (95% CI, 1.1-2.5). A family history of kidney cancer (kidney cancer in first-degree relatives) was associated with a 4.3-fold significantly increased risk of RCC (95% CI, 1.6-11.9). The cases reported a total of 2,536 first-degree relatives of which 21 (0.8%) had kidney cancer, and the controls reported a total of 2,333 first-degree relatives of which 5 (0.2%) had kidney cancer (P=0.003). In the family-based population analysis, a family history of kidney cancer was associated with a 2.8-fold increased risk of RCC (95% CI, 1.0-7.8). The meta-analysis further confirmed this significant association with a 2.2-fold increased risk of RCC (95% CI, 1.6-2.9). To our knowledge, this is the first study to use three analytic strategies to investigate the association between a family history of kidney cancer and risk of RCC, and the first systematic evaluation of the relative risk for developing RCC associated with family history.

Menopausal hormone therapy and lung cancer-specific mortality following diagnosis: the California Teachers Study.

Previous results from research on menopausal hormone therapy (MHT) and lung cancer survival have been mixed and most have not studied women who used estrogen therapy (ET) exclusively. We examined the associations between MHT use reported at baseline and lung cancer-specific mortality in the prospective California Teachers Study cohort. Among 727 postmenopausal women diagnosed with lung cancer from 1995 through 2007, 441 women died before January 1, 2008. Hazard Ratios (HR) and 95% Confidence Intervals (CI) for lung-cancer-specific mortality were obtained by fitting multivariable Cox proportional hazards regression models using age in days as the timescale. Among women who used ET exclusively, decreases in lung cancer mortality were observed (HR, 0.69; 95% CI, 0.52-0.93). No association was observed for estrogen plus progestin therapy use. Among former users, shorter duration (<5 years) of exclusive ET use was associated with a decreased risk of lung cancer mortality (HR, 0.56; 95% CI, 0.35-0.89), whereas among recent users, longer duration (>15 years) was associated with a decreased risk (HR, 0.60; 95% CI, 0.38-0.95). Smoking status modified the associations with deceases in lung cancer mortality observed only among current smokers. Exclusive ET use was associated with decreased lung cancer mortality.

Prevalence and type of BRCA mutations in Hispanics undergoing genetic cancer risk assessment in the southwestern United States: a report from the Clinical Cancer Genetics Community Research Network.

PURPOSE: To determine the prevalence and type of BRCA1 and BRCA2 (BRCA) mutations among Hispanics in the Southwestern United States and their potential impact on genetic cancer risk assessment (GCRA). PATIENTS AND METHODS: Hispanics (n = 746) with a personal or family history of breast and/or ovarian cancer were enrolled in an institutional review board-approved registry and received GCRA and BRCA testing within a consortium of 14 clinics. Population-based Hispanic breast cancer cases (n = 492) enrolled in the Northern California Breast Cancer Family Registry, negative by sequencing for BRCA mutations, were analyzed for the presence of the BRCA1 ex9-12del large rearrangement. RESULTS: Deleterious BRCA mutations were detected in 189 (25%) of 746 familial clinic patients (124 BRCA1, 65 BRCA2); 21 (11%) of 189 were large rearrangement mutations, of which 62% (13 of 21) were BRCA1 ex9-12del. Nine recurrent mutations accounted for 53% of the total. Among these, BRCA1 ex9-12del seems to be a Mexican founder mutation and represents 10% to 12% of all BRCA1 mutations in clinic- and population-based cohorts in the United States. CONCLUSION: BRCA mutations were prevalent in the largest study of Hispanic breast and/or ovarian cancer families in the United States to date, and a significant proportion were large rearrangement mutations. The high frequency of large rearrangement mutations warrants screening in every case. We document the first Mexican founder mutation (BRCA1 ex9-12del), which, along with other recurrent mutations, suggests the potential for a cost-effective panel approach to ancestry-informed GCRA.

RAD51C germline mutations in breast and ovarian cancer cases from high-risk families.

BRCA1 and BRCA2 are the most well-known breast cancer susceptibility genes. Additional genes involved in DNA repair have been identified as predisposing to breast cancer. One such gene, RAD51C, is essential for homologous recombination repair. Several likely pathogenic RAD51C mutations have been identified in BRCA1- and BRCA2-negative breast and ovarian cancer families. We performed complete sequencing of RAD51C in germline DNA of 286 female breast and/or ovarian cancer cases with a family history of breast and ovarian cancers, who had previously tested negative for mutations in BRCA1 and BRCA2. We screened 133 breast cancer cases, 119 ovarian cancer cases, and 34 with both breast and ovarian cancers. Fifteen DNA sequence variants were identified; including four intronic, one 5' UTR, one promoter, three synonymous, and six non-synonymous variants. None were truncating. The in-silico SIFT and Polyphen programs were used to predict possible pathogenicity of the six non-synonomous variants based on sequence conservation. G153D and T287A were predicted to be likely pathogenic. Two additional variants, A126T and R214C alter amino acids in important domains of the protein such that they could be pathogenic. Two-hybrid screening and immunoblot analyses were performed to assess the functionality of these four non-synonomous variants in yeast. The RAD51C-G153D protein displayed no detectable interaction with either XRCC3 or RAD51B, and RAD51C-R214C displayed significantly decreased interaction with both XRCC3 and RAD51B (p<0.001). Immunoblots of RAD51C-Gal4 activation domain fusion peptides showed protein levels of RAD51C-G153D and RAD51C-R214C that were 50% and 60% of the wild-type, respectively. Based on these data, the RAD51C-G153D variant is likely to be pathogenic, while the RAD51C- R214C variant is hypomorphic of uncertain pathogenicity. These results provide further support that RAD51C is a rare breast and ovarian cancer susceptibility gene.

Menopausal hormone therapy does not influence lung cancer risk: results from the California Teachers Study.

BACKGROUND: Results from studies examining the association between hormone therapy (HT) and lung cancer risk disagree. METHODS: We examined the associations between HT use and lung cancer risk among 60,592 postmenopausal women enrolled in the prospective California Teachers Study cohort. Between 1995 and 2007, a total of 727 women had a diagnosis of lung cancer. Multivariable Cox proportional hazards regression models were fit using age as the time metric. RESULTS: No measure of HT use was associated with lung cancer risk (all P(trend) values ≥0.4). In addition, no variations in risk by smoking status (never, ever, former, current), type of HT [estrogen (E)-alone, E + progestin (P) use], type of menopause, or lung cancer histology were observed. CONCLUSIONS: Our findings do not support an association between HT and lung cancer. IMPACT: This large-scale, prospective study, which capitalizes on the detailed hormone use, smoking history, and type of menopause information available within this unique cohort, was unable to find any association between intake of HT and lung cancer risk.

Genetic variations in the sonic hedgehog pathway affect clinical outcomes in non-muscle-invasive bladder cancer.

Sonic hedgehog (Shh) pathway genetic variations may affect bladder cancer risk and clinical outcomes. Therefore, we genotyped 177 single-nucleotide polymorphisms (SNP) in 11 Shh pathway genes in a study including 803 bladder cancer cases and 803 controls. We assessed SNP associations with cancer risk and clinical outcomes in 419 cases of non-muscle-invasive bladder cancer (NMIBC) and 318 cases of muscle-invasive and metastatic bladder cancer (MiMBC). Only three SNPs (GLI3 rs3823720, rs3735361, and rs10951671) reached nominal significance in association with risk (P ≤ 0.05), which became nonsignificant after adjusting for multiple comparisons. Nine SNPs reached a nominally significant individual association with recurrence of NMIBC in patients who received transurethral resection (TUR) only (P ≤ 0.05), of which two (SHH rs1233560 and GLI2 rs11685068) were replicated independently in 356 TUR-only NMIBC patients, with P values of 1.0 × 10(-3) (SHH rs1233560) and 1.3 × 10(-3) (GLI2 rs11685068). Nine SNPs also reached a nominally significant individual association with clinical outcome of NMIBC patients who received Bacillus Calmette-Guérin (BCG; P ≤ 0.05), of which two, the independent GLI3 variants rs6463089 and rs3801192, remained significant after adjusting for multiple comparisons (P = 2 × 10(-4) and 9 × 10(-4), respectively). The wild-type genotype of either of these SNPs was associated with a lower recurrence rate and longer recurrence-free survival (versus the variants). Although three SNPs (GLI2 rs735557, GLI2 rs4848632, and SHH rs208684) showed nominal significance in association with overall survival in MiMBC patients (P ≤ 0.05), none remained significant after multiple-comparison adjustments. Germ-line genetic variations in the Shh pathway predicted clinical outcomes of TUR and BCG for NMIBC patients.