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Prostate cancer (CaP) is the most commonly diagnosed nonskin cancer and the second leading cause of cancer death in American men. Its etiology is not fully understood. Ethnicity/race and family history are associated with it, and incidence increases with age. As with other solid tumors, accumulation of mutations and decline in DNA repair during aging may lead to CaP. However, we believe that conducting a large population screening for every cancer susceptibility gene (e.g. DNA repair) is only meaningful, if we can predict to what extent genetic variants contribute to DNA-repair functional phenotype and CaP risk. This review focuses on the association between CaP and nucleotide excision repair (NER), because some of the DNA adducts generated by CaP-related carcinogens are removed by the NER pathway, and our previous data showed a significant association between lower NER capacity (NERC) and CaP risk. Many laboratories, including ours, have employed a variety of approaches to evaluate the functional significance of DNA-repair single-nucleotide polymorphisms (SNPs) in human cancer risk assessment. Genetic profiling and computational modeling that can predict NERC may have great potential for CaP-risk assessment, because the current NERC assay is quite labor intensive, costly, and therefore not suitable for population-based screening.

The ADP-ribosyltransferase (ADPRT) gene encodes the poly(ADP-ribose)polymerase-1 (PARP-1) enzyme, which plays critical roles in DNA-damage signaling and repair, cell death, maintenance of genomic stability, and carcinogenesis. It may also serve as a potential target for cancer therapy. In this review, we evaluate findings from animal model systems and molecular epidemiological studies to demonstrate the potential role of ADPRT/PARP-1 in aging and carcinogenesis. With increasing interest in associating human cancer risk with single nucleotide polymorphisms (SNPs) and/or dysfunction of ADPRT/PARP-1, several important technical challenges will need to be overcome. These challenges include developing specific functional assays, selecting SNPs with potential functional impact, and exploring statistical methods for gene-gene and gene-environmental interactions. Therefore, this review also highlights strategies to evaluate the functional significance of ADPRT/PARP-1 SNPs in human cancer risk assessment. In summary, dysfunction of PARP-1 may play a critical role in abnormal cellular functions; its molecular mechanism in aging and cancer susceptibility is an issue which needs urgently to be elucidated.

The ADP-ribosyltransferase (ADPRT) gene encodes a zinc-finger DNA-binding protein, poly(ADP-ribose) polymerase-1 (PARP-1), that modifies various nuclear proteins by poly(ADP-ribosyl)ation and functions as a key enzyme in the base excision repair pathway. We have conducted two studies to test whether an amino acid substitution variant, ADPRT V762A (T2444C), is associated with prostate cancer (CaP) risk and decreased enzyme function. The first study used genomic DNA samples from an ongoing, clinic-based case-control study (488 cases and 524 controls) to show that a higher percentage of the CaP cases carried the ADPRT 762 AA genotype than controls (4% versus 2%). In Caucasians, the AA genotype was significantly associated with increased CaP risk [odds ratio (OR), 2.65; 95% confidence interval (CI), 1.08–6.49], and the VA genotype was associated with a slight but not significantly increased CaP risk (OR, 1.18; 95% CI, 0.85–1.64) using VV as the referent group after adjustment for age, benign prostatic hyperplasia, and family history. Furthermore, this association was stronger in younger (

To evaluate whether deficient DNA repair contributes to elevated DNA damage and breast carcinogenesis, we used the comet assay (single-cell alkaline gel electrophoresis) to measure the levels of DNA damage in peripheral lymphocytes from 70 breast cancer cases and 70 controls. DNA damage, measured as the comet tail moment, was not influenced by age, family history (FH), age at menarche, age at first birth or parity. The results showed that cancer cases had significantly higher DNA damage compared with controls; the comet tail moments (mean +/- SD) for cases and controls were: 10.78 +/- 3.63 and 6.86 +/- 2.76 (P < 0.001) for DNA damage at baseline (DB), 21.24 +/- 4.88 and 14.97 +/- 4.18 (P < 0.001) for DNA damage after exposure to 6 Gy of ionizing radiation (DIR), and 14.76 +/- 5.35 and 9.75 +/- 3.35 (P < 0.001) for DNA damage remaining after 10 min repair following exposure to 6 Gy of IR (DRP), respectively. Body mass index (BMI) affected DNA damage differently for cases and controls. Damage decreased with increasing BMI for controls, while damage increased with increasing BMI for cases. Above-median DNA damage was significantly associated with breast cancer risk; the age-adjusted odds ratio (OR) = 13.44 [95% confidence interval (CI) = 5.97-30.24] for DB, 13.65 (6.07-30.71) for DIR and 6.54 (3.11-13.79) for DRP, respectively. This association was stronger in women with above-median BMI. Our results, although based on a relatively small group of subjects, indicate that elevated DNA damage is significantly associated with breast cancer risk and warrant larger studies to further define the molecular mechanisms of DNA damage/repair in breast cancer susceptibility.

Mammalian cells are constantly exposed to a wide variety of genotoxic agents from both endogenous and exogenous sources. Genetic variability in DNA repair may contribute to human cancer risk. We used a case-control study design (162 cases and 302 controls) to test the association between three amino acid substitution variants of DNA repair genes ( XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XRCC3 Thr241Met) and breast cancer susceptibility. We found a weak association between the XRCC1 194Trp allele and breast cancer risk (adjusted odds ratio (OR)=1.98; 95% confidence interval (CI)=0.85–4.63). We also found a potential gene-gene interaction between the XRCC1 194Trp allele and XRCC3 241Met allele and breast cancer risk (adjusted OR=8.74; 95% CI=1.13–67.53). Although larger studies are needed to validate the study results, our data suggest that amino acid substitution variants of XRCC1 and XRCC3 genes may contribute to breast cancer susceptibility.

Genetic variability in DNA repair may contribute to hypersensitivity to ionizing radiation (IR) and susceptibility to breast cancer. We used samples collected from a clinic-based breast cancer case-control study to test the working hypothesis that amino acid substitution variants of DNA repair genes may contribute to prolonged cell-cycle delay following IR and breast cancer risk. Fluorescence-activated cell sorter (FACS) analysis was used to measure cell-cycle delay. PCR-restriction fragment length polymorphism (RFLP) assays were used to determine four genotypes of three DNA repair genes: XRCC1, 194 Arg/Trp and 399 Arg/Gln; XRCC3, 241 Thr/Met; and APE1, 148 Asp/Glu. The data showed that breast cancer patients had a significantly higher delay index than that of controls (P < 0.001); the means +/- SD for cases and controls were 36.0 +/- 13.1 (n = 118) and 31.4 +/- 11.5 (n = 225), respectively. There was a significant dose-response relationship between delay index, categorized into quartiles, and an increasing risk of breast cancer (crude odds ratios: 1.00, 1.00, 1.27, and 2.46, respectively; P(trend) = 0.002). In controls, prolonged cell-cycle delay was significantly associated with the number of variant alleles in APE1 Asp148Glu and XRCC1 Arg399Gln genotypes (P(trend) = 0.001). Although larger studies are needed to validate the results, our data suggest that an inherited hypersensitivity to IR may contribute to human breast carcinogenesis.

Background: Post-surgery adjuvant radiotherapy (RT) for breast cancer significantly reduced the local recurrence rate. However, many patients develop early adverse skin reactions (EASRs) that impact quality of life. Methods: In a large prospective study of 1,000 breast cancer patients undergoing RT, we evaluated an inflammatory biomarker, C-reactive protein (CRP) in predicting RT-induced EASRs. In each patient, we measured pre- and post-RT plasma CRP levels using a highly-sensitive ELISA CRP assay. RT-induced EASRs were assessed using the Oncology Nursing Society Skin Toxicity Criteria. Association between EASRs and CRP were assessed using logistic regression models after adjusting for potential confounders. Results: The study population includes 405 non-Hispanic White, 280 African Americans, 218 Hispanic Whites, 52 Asians, and 45 others. RT-induced grade 3+ and 4+ skin toxicity at the end of RT were observed in 42% and 15% patients, respectively. CRP levels differ significantly by race/ethnicity at baseline and at the end of RT. RT-induced grade 4+ skin toxicity was significantly associated with: obesity and pre-RT CRP > 2mg/L (OR=3.27; 95%CI=1.88, 5.68), obesity and post-RT CRP > 2mg/L (OR=4.42; 95%CI=2.38, 8.23), or obesity and change of CRP > 1mg/L (OR=3.58; 95%CI=2.00, 6.39). Conclusion: The current data validate our previous findings that the inflammatory biomarker CRP is associated with RT-induced EASRs, particularly combined with obesity. Impact: Our current findings support the discovery and development of anti-inflammatory agents to protect normal tissue from RT-induced EASRs and improve quality of life in breast cancer patients undergoing RT. Citation Format: Jennifer J. Hu, Doug Case, Mark O. Lively, Eunkyung Lee, Cristiane Takita, James J. Urbanic, Glenn J. Lesser, Edward G. Shaw. C-Reactive protein and radiotherapy-induced skin toxicity in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1615. doi:10.1158/1538-7445.AM2017-1615

Triple negative breast cancer (TNBC) presents clinical challenges due to unknown etiology, lack of treatment targets, and poor prognosis. We examined combined genetic and nutritional risk models of TNBC in 354 breast cancer cases. We evaluated 18 DNA-repair nonsynonymous single nucleotide polymorphisms (nsSNPs) and dietary/nutritional intakes. Multivariate Adaptive Regression Splines models were used to select nutrients of interest and define cut-off values for logistic regression models. Our results suggest that TNBC was associated with 6 DNA-repair nsSNPs, ERCC4 R415Q (rs1800067), MSH3 R940Q (rs184967), MSH6 G39E (rs1042821), POLD1 R119H (rs1726801), XRCC1 R194W (rs1799782), and XPC A499V (rs2228000) and/or deficiencies in 3 micronutrients (zinc, folate, and β-carotene). Combined analyses of these 6 nsSNPs and 3 micronutrients showed significant association with TNBC: odds ratios = 2.77 (95% confidence interval = 1.01-7.64) and 10.89 (95% confidence interval = 3.50-33.89) for 2 and at least 3 risk factors, respectively. To the best of our knowledge, this is the first study to suggest that multiple genetic and nutritional factors are associated with TNBC, particularly in combination. Our findings, if validated in larger studies, will have important clinical implication that dietary modulations and/or micronutrient supplementations may prevent or reverse TNBC phenotype, so tumors can be treated with less toxic therapeutic strategies, particularly in genetically susceptible women.

Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in American women. Postsurgery adjuvant radiotherapy (RT) significantly reduced the local recurrence rate. However, many patients develop early adverse skin reactions (EASR) that impact quality of life and treatment outcomes.We evaluated an inflammatory biomarker, C-reactive protein (CRP), in predicting RT-induced EASRs in 159 patients with breast cancer undergoing RT. In each patient, we measured pre- and post-RT plasma CRP levels using a highly sensitive ELISA CRP assay. RT-induced EASRs were assessed at weeks 3 and 6 using the National Cancer Institute Common Toxicity Criteria (v3.0). Associations between EASRs and CRP levels were assessed using logistic regression models after adjusting for potential confounders.RT-induced grade 2+ EASRs were observed in 8 (5%) and 80 (50%) patients at weeks 3 and 6 (end of RT), respectively. At the end of RT, a significantly higher proportion of African Americans developed grade 3 EASRs (13.8% vs. 2.3% in others); grade 2+ EASRs were significantly associated with: change of CRP1 mg/L [odds ratio (OR), 2.51; 95% confidence interval (CI), 1.06-5.95; P = 0.04], obesity (OR, 2.08; 95% CI, 1.03-4.21; P = 0.04), or combined both factors (OR, 5.21; 95% CI, 1.77-15.38; P = 0.003).This is the first study to demonstrate that an inflammatory biomarker CRP is associated with RT-induced EASRs, particularly combined with obesity.Future larger studies are warranted to validate our findings and facilitate the discovery and development of anti-inflammatory agents to protect normal tissue from RT-induced adverse effects and improve quality of life in patients with breast cancer undergoing RT.

Genome-wide association studies have identified 73 breast cancer risk variants mainly in European populations. Given considerable differences in linkage disequilibrium structure between populations of European and African ancestry, the known risk variants may not be informative for risk in African ancestry populations. In a previous fine-mapping investigation of 19 breast cancer loci, we were able to identify SNPs in four regions that better captured risk associations in African American women. In this study of breast cancer in African American women (3016 cases, 2745 controls), we tested an additional 54 novel breast cancer risk variants. Thirty-eight variants (70%) were found to have an association with breast cancer in the same direction as previously reported, with eight (15%) replicating at P < 0.05. Through fine-mapping, in three regions (1q32, 3p24, 10q25), we identified variants that better captured associations with overall breast cancer or estrogen receptor positive disease. We also observed suggestive associations with variants (at P < 5 × 10(-6)) in three separate regions (6q25, 14q13, 22q12) that may represent novel risk variants. Directional consistency of association observed for ∼65-70% of currently known genetic variants for breast cancer in women of African ancestry implies a shared functional common variant at most loci. To validate and enhance the spectrum of alleles that define associations at the known breast cancer risk loci, as well as genome-wide, will require even larger collaborative efforts in women of African ancestry.

Background: Preclinical and clinical data support a key role for the PI3K pathway in resistance to endocrine therapy in patients with ER+ breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. Short-term preoperative window of opportunity (WOO) studies are a validated strategy for novel treatments to provide proof-of-concept and define the most appropriate patient population by directly assessing treatment effects in tumour tissue before and after treatment. This is the first WOO study with the PI3K inhibitor pictilisib (GDC-0941) in combination with anastrozole (ANA). Methods: 73 postmenopausal patients (pts) have been randomized (2:1 in favour of the combination) to receive 2-week preoperative treatment with ANA plus pictilisib (n=50, "ANA+PIC" arm) or ANA alone (n=23, "ANA" arm). Pts had newly diagnosed, operable, ER+, HER2-negative breast cancer of ≥1 cm size. Pts receiving HRT were excluded. Treatment effects and correlative studies were assessed using FFPE and frozen tumour biopsies taken before and after 14 days of study treatment. The primary endpoint was inhibition of tumour-cell proliferation, as measured by change in Ki67 expression, determined centrally by 2 investigators. Secondary endpoints include induction of apoptosis (Caspase3) and safety. Comprehensive biomarkers analyses include targeted NGS of a comprehensive cancer panel of >400 genes, copy number analyses, and pre- and post-treatment reverse-phase protein arrays (RPPA) and RNA profiling. Results: Baseline (BL) disease characteristics were similar between both study arms. PAM50 analysis showed that 53% and 47% of tumors were Luminal (Lum) A and B, respectively. 65% of tumors had >14% Ki67-positive cells. Observed treatment-emergent AEs were consistent with those previously described for single-agent pictilisib and anastrozole. Mean post-treatment percentage reduction of Ki67 was 84% (95% CI, 75%-89%) for ANA+PIC and 72% (54%-87%) for ANA. Ki67-response (≥50% drop in % of Ki67+ cells) was 86% for ANA+PIC and 60% for ANA. By using the definition that pts with a natural logarithm of %Ki67+ cells of ≤1 or 1-2 have a day 15 anti-proliferative response, 93% [ln(ki67): Preplanned subgroup analyses showed a significant interaction of response to ANA+PIC with molecular subtype and Ki67 levels. Patients with LumB tumors or high BL Ki67 (>14%) had a higher Ki67 response with ANA+PIC compared to ANA (LumB, 83% vs 38%; Ki67>14%, 94% vs 55%), whereas Ki67 response was similar for both treatments for LumA tumors (ANA, 75%; ANA+PIC, 73%) or tumors with low BL Ki67. Mean post-treatment % reduction of Ki67 in LumB tumors was 87% (95% CI, 49%-96%) for ANA+PIC and 56% (16%-77%) for ANA (p=0.03). Additional data on apoptosis and comprehensive pre- and post-treatment biomarkers analyses will be presented. Conclusions: This first report of a preoperative WOO study evaluating a PI3K inhibitor in early breast cancer demonstrated addition of pictilisib to ANA was associated with increased anti-proliferative response over single-agent ANA. Citation Format: Peter Schmid, Sarah E Pinder, Duncan Wheatley, Jane Macaskill, Charles Zammit, Jennifer Hu, Robert Price, Nigel Bundred, Sirwan Hadad, Alice Shia, Louise Lim, Shah-Jalal Sarker, Patrycja Gazinska, Natalie Woodman, Darren Korbie, Matt Trau, Paul Mainwaring, Peter Parker, Arnie Purushotham, Alastair M Thompson. Preoperative window of opportunity study of the PI3K inhibitor pictilisib (GDC-0941) plus anastrozole vs anastrozole alone in patients with ER+, HER2-negative operable breast cancer (OPPORTUNE study) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-03.

Radiation therapy-induced acute and late effects, particularly skin toxicities, have significant impact on cancer patients’ quality of life and long-term survival. To date, no effective topical agents have been routinely used in the clinical setting to prevent skin toxicity. Using SKH-hr1 hairless mice, we investigated two complementary and alternative medicine in their effects on inflammation and ionizing radiation (IR)-induced skin toxicity: Calendula officinalis (CO) and Ching Wan Hung (CWH). They were applied immediately following each IR dosing of 10 Gy/day for 4 days. Skin toxicity and inflammatory factors were evaluated at multiple time points up to 15 days post-radiation. Serum interleukin (IL)-1α, monocyte chemotactic protein-1 (MCP1), keratinocyte-derived chemokine (KC), and granulocyte colony-stimulating factor (G-CSF) were significantly induced by radiation. Both CO and CWH significantly inhibited IR-induced MCP1 (p < 0.01), KC (p < 0.05), and G-CSF (p < 0.001). IR-induced erythema and blood vessel dilation were significantly reduced by CWH (p < 0.001) but not by CO at day 10 post-IR. Both agents inhibited IR-induced IL-1α (p < 0.01), MCP1 (p < 0.05), and vascular endothelial growth factor (p < 0.05). There were continuous inhibitory effects of CWH on IR-induced skin toxicities and inflammation. In contrast, CO treatment resulted in skin reactions compared to IR alone. Our results suggest that both CO and CWH reduce IR-induced inflammation and CWH reduced IR-induced erythema. In summary, CWH showed promising effects in reducing IR-related inflammation and skin toxicities, and future proof-of-principal testing in humans will be critical in evaluating its potential application in preventing IR-induced skin toxicities.

UV irradiation is known to cause cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), and plays a large role in the development of cancer. Tumor suppression, through DNA repair and proper cell cycle regulation, is an integral factor in maintaining healthy cells and preventing development of cancer. Transcriptional regulation of the genes involved in the various tumor suppression pathways is essential for them to be expressed when needed and to function properly. BRG1, an ATPase catalytic subunit of the SWI/SNF chromatin remodeling complex, has been identified as a tumor suppressor protein, as it has been shown to play a role in Nucleotide Excision Repair (NER) of CPDs, suppress apoptosis, and restore checkpoint deficiency, in response to UV exposure. Although BRG1 has been shown to regulate transcription of some genes that are instrumental in proper DNA damage repair and cell cycle maintenance in response to UV, its role in transcriptional regulation of the whole genome in response to UV has not yet been elucidated. With whole genome expression profiling in SW13 cells, we show that upon UV induction, BRG1 regulates transcriptional expression of many genes involved in cell stress response. Additionally, our results also highlight BRG1's general role as a master regulator of the genome, as it transcriptionally regulates approximately 4.8% of the human genome, including expression of genes involved in many pathways. RT-PCR and ChIP were used to validate our genome expression analysis. Importantly, our study identifies several novel transcriptional targets of BRG1, such as ATF3. Thus, BRG1 has a larger impact on human genome expression than previously thought, and our studies will provide inroads for future analysis of BRG1's role in gene regulation.

African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10(-8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.

Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.

Pain related to cancer or treatments is a critical quality of life (QOL) issue for breast cancer survivors. This study aimed to evaluate the association between the polymorphisms in DNA-repair genes and radiation therapy (RT)-associated pain among breast cancer patients receiving adjuvant RT. Pain score was assessed at pre- and post-RT as the mean of four pain severity items (i.e., pain at its worst, least, average, and now) from the Brief Pain Inventory with 11-point numeric rating scale (0-10) and RT-associated clinically relevant pain was considered present when pain score increased from Citation Format: Eunkyung Lee, Jean L. Wright, Cristiane Takita, Eden Martin, Susan Slifer, Jennifer J. Hu. Polymorphisms in DNA-repair genes and its association with pain among breast cancer patients receiving adjuvant radiation therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 807.

Radiotherapy-induced skin toxicity is one of the critical quality of life issues in breast cancer patients receiving adjuvant radiation therapy (RT). Finding a biomarker which can predict the development of acute RT-induced toxicity prior to RT is critical to improve precision medicine in radiation oncology. This study evaluated the association of single nucleotide polymorphisms (SNPs) in DNA-repair genes in 268 breast cancer undergoing adjuvant RT. We analyzed 3,747 polymorphisms in 119 DNA repair-related genes; 15 genes in base excision repair (BER), 11 in mismatch repair (MMR), 26 in nucleotide excision repair (NER), 15 in homologous recombination, 5 in non-homologous end-joining (NHEJ), 15 in DNA polymerases, and 47 in other DNA repair-related pathways. Skin toxicity was assessed at post-RT using the modified NCI's Common Toxicity Criteria for Adverse Events (CTCAE) and multiple logistic regression analyses were conducted to assess the associations between SNPs and grade ≥ 4 skin toxicity n = 115). After controlling for covariates, 221 SNPs were significant at p Citation Format: Sung Yong Eum, Eunkyung Lee, Jean L. Wright, Christiane Takita, Eden R, Martin, Susan Slifer, Jennifer J. Hu. Polymorphisms of DNA-repair pathways and its association with radiotherapy-induced acute skin toxicity among tri-racial breast cancer populations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3920.

Introduction: Accumulating evidence suggest that obesity is associated with breast cancer diagnosis, recurrence, and mortality. Obese subjects with genetic predisposition may need more aggressive weight loss management, such as bariatric surgery. Therefore, the primary aim of this study was to assess the racial/ethnic disparities in obesity and the prevalence of breast cancer study participants who may be eligible for bariatric surgery. Methods: In three clinic-based studies conducted at University of Miami during 2008 to 2015, we evaluated 462 healthy controls and 975 breast cancer patients. Genotyping data of two obesity-related genes (FTO and MC4R) were also evaluated. Race/ethnicity and obesity-related comorbidities were self- reported. Body Mass Index (BMI) was calculated as kg/m2. The classification of BMI was: (1) < 18.5, underweight; (2) 18.5-24.9, normal weight; (3) 25.0-29.9, overweight; (4) 30.0-34.9, class I obesity; (5) 35.0-39.9, class II obesity; and (6) ≥ 40.0, class III obesity. The NIH eligibility for bariatric surgery was for class II obese subjects with obesity-related comorbidities and class III obese subjects. Results: The study consists of 70.0% Hispanic whites (HW), 21.7% black or African American (AA), and 6.4% non-Hispanic whites (NHW). Mean and SD of age was 54.1± 9.9 years and mean BMI was 29.0±6.1 kg/m2. Overall, about 11.1% of study participants met criteria for bariatric surgery and there were significant racial/ethnic disparities (19.7% AA, 8.5% HW, 8.8% NHW, and 17.2% others; p Conclusion: In addition to cancer risk, obesity is a major risk factor for cancer treatment-related side effects and worse survival. Our results suggest that at least 11% of breast cancer patients may be eligible for bariatric surgery. Considering some other beneficial effects of bariatric surgery on physical quality of life, metabolic syndrome, diabetes, and microbiome, future studies will consider weight loss and bariatric surgery programs in breast cancer patients, particularly in underserved minorities with higher obesity rate and worse survival. Citation Format: Carolina Puyana Barcha, Eunkyung Lee, Cristiane Takita, Jean L. Wright, Wei Zhao, Isildinha M. Reis, Jennifer J. Hu. Racial/ethnic disparities of obesity in a breast clinic population: Consideration for weight loss program in improving clinical outcomes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1767.

The ERCC1 protein (excision repair cross-complementing rodent repair deficiency, complementation group 1) forms a heterodimer with the Xeroderma pigmentosum group F (XPF) endonuclease (also known as ERCC4), and the heterodimeric endonuclease catalyzes the 5′ incision in the process of excising the DNA lesion. The ERCC1–XPF heterodimer has an important role in genome maintenance. While most of the DNA repair proteins function only in a specific repair pathway, ERCC1–XPF is involved in multiple DNA repair pathways and telomere maintenance, making this heterodimer not only an attractive therapeutic target, but also a biomarker to predict treatment outcome (Fig. 2.3).

Background: Head and neck squamous cell carcinoma (HNSCC) is a debilitating and deadly disease largely due to late stage diagnosis. Prior work indicates that soluble CD44 (solCD44) and total protein may be useful diagnostic markers for HNSCC. In this study we combine the markers solCD44, IL-8, HA, and total protein with demographic and risk factor data to derive a multivariate logistic model that improves HNSCC detection as compared to our previous data using biomarkers alone. Methods: We performed the solCD44, IL-8, HA, and total protein assays on oral rinses from 40 HNSCC patients and 39 controls using ELISA assays. Controls had benign diseases of the upper aerodigestive tract and a history of tobacco or alcohol use. All subjects completed a questionnaire including demographic and risk factor data. Results: Depending on cancer subsite, differences between cases and controls were found for all markers. A multivariate logistic model including solCD44, total protein and variables related to smoking, oral health and education offered a significant improvement over the univariate models with an AUC of 0.853. Sensitivity ranged from 75-82.5% and specificity from 69.2- 82.1% depending on predictive probability cut points. Conclusion: A multivariate model, including simple and inexpensive molecular tests in combination with risk factors, results in a promising tool for distinguishing HNSCC patients from controls. Impact: In this case-control study, the resulting observations led to an unprecedented multivariate model that distinguished HNSCC cases from controls with better accuracy than the current gold standard which includes oral examination followed by tissue biopsy. Since the components are simple, noninvasive, and inexpensive to obtain, this model combining biomarkers, risk factor and demographic data serves as a promising prototype for future cancer detection tests.

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

The 26S proteasome, a multicatalytic enzyme complex, is the main intracellular proteolytic system involved in the degradation of ubiquitinated proteins. The ability of proteasome inhibitors to induce apoptosis has been exploited in the recent development of chemotherapeutic agents. Here, we show that inhibition of proteasome by MG132 blocks DNA damage-induced apoptosis. Blockage of apoptosis by MG132 correlates with p53 stabilization and upregulation of p21/WAF1, a p53 transcriptional target. Surprisingly, in the absence of MG132, robust apoptosis induced by a high dose of UV irradiation correlate with rapid p53 degradation. This is in sharp contrast to p53 stabilization when cells were exposed to lower levels of UV irradiation. Our findings highlight a scenario in which severe UV damage can induce rapid p53 degradation by the proteasome. Importantly, these data suggest that the 26S proteasome plays a key role in promoting apoptosis induced by high doses of UV irradiation.

Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P value

Background In this study, we pilot tested an in vitro assay of cancer killing activity (CKA) in circulating leukocytes of 22 cancer cases and 25 healthy controls. Methods Using a human cervical cancer cell line, HeLa, as target cells, we compared the CKA in circulating leukocytes, as effector cells, of cancer cases and controls. The CKA was normalized as percentages of total target cells during selected periods of incubation time and at selected effector/target cell ratios in comparison to no-effector-cell controls. Results Our results showed that CKA similar to that of our previous study of SR/CR mice was present in human circulating leukocytes but at profoundly different levels in individuals. Overall, males have a significantly higher CKA than females. The CKA levels in cancer cases were lower than that in healthy controls (mean ± SD: 36.97 ± 21.39 vs. 46.28 ± 27.22). Below-median CKA was significantly associated with case status (odds ratio = 4.36; 95% Confidence Interval = 1.06, 17.88) after adjustment of gender and race. Conclusions In freshly isolated human leukocytes, we were able to detect an apparent CKA in a similar manner to that of cancer-resistant SR/CR mice. The finding of CKA at lower levels in cancer patients suggests the possibility that it may be of a consequence of genetic, physiological, or pathological conditions, pending future studies with larger sample size.

Defective DNA repair may contribute to early age and late stage at time of diagnosis and mutations in critical tumor suppressor genes, such as TP53 in breast cancer. Using DNA samples from 436 breast cancer cases (374 Caucasians and 62 African-Americans), we tested these associations with 18 non-synonymous single-nucleotide polymorphisms (nsSNPs) in four DNA repair pathways: (i) base excision repair: ADPRT V762A, APE1 D148E, XRCC1 R194W/R280H/R399Q and POLD1 R119H; (ii) double-strand break repair: NBS1 E185Q and XRCC3 T241M; (iii) mismatch repair: MLH1 I219V, MSH3 R940Q/T1036A and MSH6 G39E and (iv) nucleotide excision repair: ERCC2 D312N/K751Q, ERCC4 R415Q, ERCC5 D1104H and XPC A499V/K939Q. Younger age at diagnosis (

BACKGROUND: Most studies exploring ethnic/racial disparities in nonsmall cell lung cancer (NSCLC) compare black patients with whites. Currently, the effect of Hispanic ethnicity on the overall survival of NSCLC is poorly understood. Therefore, the authors carried out a large-scale, population-based analysis using the Surveillance, Epidemiology, and End Results (SEER) data base to determine the impact of Hispanic ethnicity the survival of patients with NSCLC. METHODS: The authors identified 172,398 adult patients with pathologically confirmed NSCLC from the SEER data base who were diagnosed between 1988 and 2007. A multivariate Cox proportional hazards regression analysis was used to determine the impact of race/ethnicity on overall survival. Pair-wise comparisons were used to determine whether Hispanic ethnicity influenced NSCLC histology or stage at diagnosis. RESULTS: Compared with non-Hispanic white patients, Hispanic white patients had a statistically significant better overall survival (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.83-0.87), and black patients had worse survival (HR, 1.091; 95% CI, 1.072-1.109). Within the bronchioalveolar carcinoma (BAC) subtype, Hispanic-white patients tend to be over represented (8.1% Hispanic whites vs 5.5% non-Hispanic whites vs 3.7% blacks; P < .001). CONCLUSIONS: The current study demonstrated that Hispanic-white patients with NSCLC had a decreased risk for overall mortality compared with non-Hispanic whites and blacks. Moreover, Hispanic patients were over represented within the BAC histologic subtype. Thus, the overall survival advantage of Hispanic NSCLC patients may be because of their predilection toward developing certain histologic subtypes of NSCLC. Further studies are warranted to determine the etiologies of such predilections and may reveal certain genetic, environmental, and/or epigenetic factors associated with Hispanic ethnicity. Cancer 2012. © 2012 American Cancer Society.

Background: Genome-wide association studies (GWAS) have identified numerous prostate cancer susceptibility alleles, but these loci have been identified primarily in men of European descent. There is limited information about the role of these loci in men of African descent. Methods: We identified 7,788 prostate cancer cases and controls with genotype data for 47 GWAS-identified loci. Results: We identified significant associations for SNP rs10486567 at JAZF1, rs10993994 at MSMB, rs12418451 and rs7931342 at 11q13, and rs5945572 and rs5945619 at NUDT10/11. These associations were in the same direction and of similar magnitude as those reported in men of European descent. Significance was attained at all reported prostate cancer susceptibility regions at chromosome 8q24, including associations reaching genome-wide significance in region 2. Conclusion: We have validated in men of African descent the associations at some, but not all, prostate cancer susceptibility loci originally identified in European descent populations. This may be due to the heterogeneity in genetic etiology or in the pattern of genetic variation across populations. Impact: The genetic etiology of prostate cancer in men of African descent differs from that of men of European descent. Cancer Epidemiol Biomarkers Prev; 20(1); 23–32. ©2011 AACR.

Tocopherols are lipophilic antioxidants found in vegetable oils. Here, we examined the growth inhibitory effect of a gamma-tocopherol-enriched tocopherol mixture (gammaTmT) against CL13 murine lung cancer cells grown in culture and as subcutaneous tumors in A/J mice. We found gammaTmT had no effect after 2 days and weakly inhibited the growth of CL13 in culture after 5 days (28% growth inhibition at 80 microM). Dietary treatment with 0.1 and 0.3% gammaTmT for 50 days inhibited the growth of CL13 tumors in A/J mice by 53.9 and 80.5%, respectively. Histopathological analysis revealed an increase in tumor necrosis compared to control tumors (80 and 240% increase by 0.1 and 0.3% gammaTmT, respectively). Dietary treatment with gammaTmT dose-dependently increased gamma- (10.0-37.6-fold) and delta-tocopherol (8.9-26.7-fold) in the tumors of treated mice compared to controls. Dietary treatment with gammaTmT also increased plasma gamma- (5.4-6.7-fold) and delta-tocopherol (5.5-7-fold). Whereas others have demonstrated the cancer preventive activity of gammaTmT against mammary and colon cancer, this is the first report of growth inhibitory activity against lung cancer. Further studies are needed to determine the underlying mechanisms for this anticancer activity, and to determine if such activity occurs in other models of cancer.

Four genome-wide association studies, all in populations of European descent, have identified 20 independent single nucleotide polymorphisms (SNP) in 20 regions that are associated with prostate cancer risk. We evaluated these 20 SNPs in a combined African American (AA) study, with 868 prostate cancer patients and 878 control subjects. For 17 of these 20 SNPs, implicated risk-associated alleles were found to be more common in these AA cases than controls, significantly more than expected under the null hypothesis (P = 0.03). Two of these 17 SNPs, located at 3p12, and region 2 at 8q24, were significantly associated with prostate cancer risk (P < 0.05), and only SNP rs16901979 at region 2 of 8q24 remained significant after accounting for 20 tests. A multivariate analysis of additional SNPs across the broader 8q24 region revealed three independent prostate cancer risk-associated SNPs, including rs16901979, rs13254738, and rs10086908. The first two SNPs were ∼20 kb apart and the last SNP, a novel finding from this study, was ∼100 kb centromeric to the first two SNPs. These results suggest that a systematic evaluation of regions harboring known prostate cancer risk SNPs implicated in other races is an efficient approach to identify risk alleles for AA. However, studies with larger numbers of AA subjects are needed, and this will likely require a major collaborative effort to combine multiple AA study populations. (Cancer Epidemiol Biomarkers Prev 2009;18(7):2145–9)

Plant foods and associated nutrients may impact prostate cancer (PC) risk and survival. Therefore, we compared dietary intake, mainly plant food groups among 382 controls and 478 PC cases (373 incident and 105 prevalent cases). Caucasian controls had significantly higher daily servings of vegetables (3.4 vs. 2.5, P= 0.002) and fruits and/or fruit juices (1.6 vs. 1.3, P = 0.02) compared to African American controls. In Caucasians, incident cases reported lower intake of fiber, vitamin C, vitamin A, alpha -carotene, beta -carotene, cryptoxanthin, folate, genistein, daidzein, and fruits and/or fruit juice than controls and/or prevalent cases. In African Americans, incident cases had lower intake of alpha -carotene compared to controls and prevalent cases. Reduced PC risk was associated with the highest tertile of cryptoxanthin (OR = 0.51; 95% CI = 0.35-0.75), fiber (OR = 0.56; 95% CI = 0.35-0.89), vitamin C (OR = 0.60; 95% CI = 0.41-0.88), and fruits and/or fruit juices (OR = 0.46; 95% CI = 0.31-0.68), with significant linear trends. Increased risk of PC was associated with the highest tertile of protein (OR = 1.99; 95% CI = 1.05-3.79) and daily servings of grains (OR = 1.99; 95% CI = 1.23-3.22) with significant linear trends. In summary, we demonstrate racial/ethnic differences in dietary intake of plant foods. The significantly higher consumption of protective dietary constituents among prevalent cases compared to incident cases suggests that PC survivors may be amenable to dietary change.

Genetic variations in DNA repair may impact repair functions, DNA damage and breast cancer risk. Using data/samples collected from the first 752 Caucasians and 141 African-Americans in an ongoing case-control study, we examined the association between breast cancer risk and 18 non-synonymous single-nucleotide polymorphisms (nsSNPs) in four DNA repair pathways-(i) base excision repair: ADPRT V762A, APE1 D148E, XRCC1 R194W/R280H/R399Q and POLD1 R119H; (ii) nucleotide excision repair: ERCC2 D312N/K751Q, ERCC4 R415Q, ERCC5 D1104H and XPC A499V/K939Q; (iii) mismatch repair: MLH1 I219V, MSH3 R940Q/T1036A and MSH6 G39E and (iv) double-strand break repair: NBS1 E185Q and XRCC3 T241M. In Caucasians, breast cancer risk was significantly associated with ADPRT 762VV [odds ratio (OR) = 1.45; 95% confidence interval (CI) = 1.03, 2.03], APE1 148DD (OR = 1.44; 95% CI = 1.03, 2.00), MLH1 219II/IV (OR = 1.87; 95% CI = 1.11, 3.16) and ERCC4 415QQ (OR = 8.64; 95% CI = 1.04, 72.02) genotypes. With a limited sample size, we did not observe any significant association in African-Americans. However, there were significant trends in breast cancer risk with increasing numbers of risk genotypes for ADPRT 762VV, APE1 148DD, ERCC4 415RQ/QQ and MLH1 219II/IV (P(trend)0.001) in Caucasians and ADPRT 762VA, ERCC2 751KQ/QQ and NBS1 185EQ/QQ in African-Americans (P(trend) = 0.006), respectively. Our results suggest that combined nsSNPs in multiple DNA repair pathways may contribute to breast cancer risk and larger studies are warranted to further evaluate polygenic models of DNA repair in breast cancer risk.

Polymorphisms in the cytochrome P450 1B1 (CYP1B1) and glutathione S-transferase (GST) drug metabolic enzymes, which are responsible for metabolic activation/detoxification of estrogen and environmental carcinogens, were analyzed for their association with breast cancer risk in 541 cases and 635 controls from a North Carolina population. Each polymorphism, altering the catalytic function of their respective enzymes, was analyzed in Caucasian and African-American women. As reported in previous studies, individual polymorphisms did not significantly impact breast cancer risk in either Caucasian or African-American women. However, African-American women exhibited a trend towards a protective effect when they had at least one CYP1B1 119S allele (OR=0.53; 95% CI=0.20-1.40) and increased risk for those women harboring at least one CYP1B1 432V allele (OR=5.52; 95% CI=0.50-61.37). Stratified analyses demonstrated significant interactions in younger (age < or =60) Caucasian women with the CYP1B1 119SS genotype (OR=3.09; 95% CI=1.22-7.84) and younger African-American women with the GSTT1 null genotype (OR=4.07; 95% CI=1.12-14.80). A notable trend was also found in Caucasian women with a history of smoking and at least one valine allele at GSTP1 114 (OR=2.12; 95% CI=1.02-4.41). In Caucasian women, the combined GSTP1 105IV/VV and CYP1B1 119AA genotypes resulted in a near 2-fold increase in risk (OR=1.96; 95% CI=1.04-3.72) and the three way combination of GSTP1 105IV/VV, CYP1B1 119AS/SS and GSTT1 null genotypes resulted in an almost 4-fold increase in risk (OR=3.97; 95% CI=1.27-12.40). These results suggest the importance of estrogen/carcinogen metabolic enzymes in the etiology of breast cancer, especially in women before the age of 60, as well as preventative measures such as smoking cessation.

Polymorphisms in the cytochrome P450 1B1 (CYP1B1) and glutathione S-transferase (GST) drug metabolic enzymes, which are responsible for metabolic activation/detoxification of estrogen and environmental carcinogens, were analyzed for their association with breast cancer risk in 541 cases and 635 controls from a North Carolina population. Each polymorphism, altering the catalytic function of their respective enzymes, was analyzed in Caucasian and African-American women. As reported in previous studies, individual polymorphisms did not significantly impact breast cancer risk in either Caucasian or African-American women. However, African-American women exhibited a trend towards a protective effect when they had at least one CYP1B1 119S allele (OR=0.53; 95% CI=0.20-1.40) and increased risk for those women harboring at least one CYP1B1 432V allele (OR=5.52; 95% CI=0.50-61.37). Stratified analyses demonstrated significant interactions in younger (ageor =60) Caucasian women with the CYP1B1 119SS genotype (OR=3.09; 95% CI=1.22-7.84) and younger African-American women with the GSTT1 null genotype (OR=4.07; 95% CI=1.12-14.80). A notable trend was also found in Caucasian women with a history of smoking and at least one valine allele at GSTP1 114 (OR=2.12; 95% CI=1.02-4.41). In Caucasian women, the combined GSTP1 105IV/VV and CYP1B1 119AA genotypes resulted in a near 2-fold increase in risk (OR=1.96; 95% CI=1.04-3.72) and the three way combination of GSTP1 105IV/VV, CYP1B1 119AS/SS and GSTT1 null genotypes resulted in an almost 4-fold increase in risk (OR=3.97; 95% CI=1.27-12.40). These results suggest the importance of estrogen/carcinogen metabolic enzymes in the etiology of breast cancer, especially in women before the age of 60, as well as preventative measures such as smoking cessation.

Prostate cancer (CaP) is the second leading cause of cancer death in American men. Chronic inflammation has been one of several factors associated with the development of CaP. Single-nucleotide polymorphisms (SNPs) in cytokine genes have been associated with increased inflammation, increased cytokine production and possibly increased CaP risk. However, the effects of cytokine SNPs on CaP susceptibility have not been consistent. Using the genomic DNA collected in a CaP case-control study (557 cases and 547 controls), we pilot tested the interactions of nine functionally characterized SNPs of three cytokine genes in CaP risk using the multivariate adaptive regression splines (MARS)-logit models. African-Americans with the IL10-819TT genotype had a lower CaP risk [odds ratio (OR) = 0.27, 95% confidence interval (CI) = 0.07-1.01], but subjects with the genotype combination of IL1B-511CT/TT and IL10-592CC had a higher CaP risk (OR = 2.56, 95% CI = 1.09-6.02). In Caucasians, higher CaP risk was associated with the IL10-1082AG/GG genotype (OR = 3.62, 95% CI = 1.42-9.28), the genotype combination of IL10-1082AA plus IL1B-31TT/TC (OR = 2.92, 95% CI = 1.13-7.55) and the genotype combination of TNF-238GG plus IL10-592AA (OR = 2.14, 95% CI = 1.05-4.38). Our results highlight the importance of cytokine SNPs and their interactions in CaP risk.

Black Americans are adversely affected by many types of malignancies.We reviewed data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program to evaluate racial disparities in head and neck cancer incidence, mortality, and survival.Head and neck cancer incidence is greater in the black population and peaks at a younger age. The incidence disparity is decreasing over time and is less for cancers of the oral cavity/pharynx (OCP) than for cancers of the larynx. The disparity in survival after diagnosis is substantial for both sites and is increasing over time because of improvement in survival for the white population, but not for the black population. Some, but not all, of the survival disparity is due to more advanced stage at the time of diagnosis within the black population. The age-adjusted mortality rate for black men is approximately twice the rate for white men.Black Americans clearly bear a greater burden from head and neck cancer. The underlying causes are largely unknown, but are most likely due to a complex interplay of differences in access to health care, quality of medical care, biologic/genetic factors, incidence of comorbid conditions, exposure to carcinogens, diet, and cultural beliefs. Prospective studies are needed to define the relative importance of these factors and to inform intervention strategies.

Polymorphisms in phase I and phase II enzymes may enhance the occurrence of mutations at critical tumor suppressor genes, such as p53, and increase breast cancer risk by either increasing the activation or detoxification of carcinogens and/or endogenous estrogens. We analyzed polymorphisms in CYP1B1, GSTM1, GSTT1, and GSTP1 and p53 mutations in 323 breast tumor samples. Approximately 11% of patients exhibited mutations in p53. Women with mutations had a significantly younger age of diagnosis (P = 0.01) and a greater incidence of tumors classified as stage II or higher (P = 0.002). More women with mutations had a history of smoking (55%) compared to women without mutations (39%). Although none of the genotypes alone were associated with p53 mutations, positive smoking history was associated with p53 mutations in women with the GSTM1 null allele [OR = 3.54; 95% CI = 0.97-12.90 P = 0.06] compared to women with the wild-type genotype and smoking history [OR = 0.62, 95% CI = 0.19-2.07], although this association did not reach statistical significance. To test for gene-gene interactions, our exploratory analysis in the Caucasian cases suggested that individuals with the combined GSTP1 105 VV, CYP1B1 432 LV/VV, and GSTM1 positive genotype were more likely to harbor mutations in p53 [OR = 4.94; 95% CI = 1.11-22.06]. Our results suggest that gene-smoking and gene-gene interactions may impact the prevalence of p53 mutations in breast tumors. Elucidating the etiology of breast cancer as a consequence of common genetic polymorphisms and the genotoxic effects of smoking will enable us to improve the design of prevention strategies, such as lifestyle modifications, in genetically susceptible subpopulations.

Deficient repair activity for 8-hydroxy-2′-deoxyguanine (8-oxoguanine), a premutagenic oxidative DNA damage, has been observed in affected tissues in neurodegenerative diseases of aging, such as Alzheimer's disease, and in ischemia/reperfusion injury, type 2 diabetes mellitus, and cancer. These conditions have in common the accumulation of oxidative DNA damage, which is believed to play a role in disease progression, and loss of intracellular calcium regulation. These observations suggest that oxidative DNA damage repair capacity may be influenced by fluctuations in cellular calcium. We have identified human 8-oxoguanine-DNA glycosylase 1 (OGG1), the major 8-oxoguanine repair activity, as a specific target of the Ca 2+ -dependent protease Calpain I. Protein sequencing of a truncated partially calpain-digested OGG1 revealed that calpain recognizes OGG1 for degradation at a putative PEST (proline, glutamic acid, serine, threonine) sequence in the C-terminus of the enzyme. Co-immunoprecipitation experiments showed that OGG1 and Calpain I are associated in human cells. Exposure of HeLa cells to hydrogen peroxide or cisplatin resulted in the degradation of OGG1. Pretreatment of cells with the calpain inhibitor calpeptin resulted in inhibition of OGG1 proteolysis and suggests that OGG1 is a target for calpain-mediated degradation in vivo during oxidative stress- and cisplatin-induced apoptosis. Polymorphic OGG1 S326C was comparatively resistant to calpain digestion in vitro , yet was also degraded by a calpain-dependent pathway in vivo following DNA damaging agent exposure. The degradation of OGG1 by calpain may contribute to decreased 8-oxoguanine repair activity and elevated levels of 8-oxoguanine reported in tissues undergoing chronic oxidative stress, ischemia/reperfusion, and other cellular stressors known to produce perturbations of intracellular calcium homeostasis which activate calpain.

patients with higher education levels and longer travel distance for treatment. Overall, this is consistent with dissemination of data from the invasive breast cancer paradigm, and recognition of similar efficacy and improved convenience of HF-WBI relative to standard fractionation. Author Disclosure: Y. An: None. C.E. Rutter: Employee; Connecticut Children’s Medical Center. H.S. Park: Employee; Yale-New Haven Hospital. C.D. Corso: None. B.R. Mancini: Employee; The Connecticut Hospice, Inc. N.H. Lester-Coll: None. D.N. Yeboa: None. S.B. Evans: None.

Purpose: Pain is one of the multiple quality of life issues in breast cancer survivors. We sought to determine whether race/ethnic disparity exists in radiotherapy (RT)-induced pain and to assess associated risk factors. Methods and Materials: Consecutive 375 female patients undergoing adjuvant RT after breast-conserving surgery during 2009-2014 were evaluated. Pain score was assessed as mean of the four pain severity items (pain at its worst, least, average, and now) using 11-point numeric rating scale (0-10) at pre-RT and post-RT. Pain scores of 4 to 10 were regarded as clinically relevant pain. Pain presence and RT-induced change were examined. In multivariable logistic regression analysis, we evaluated risk factors for pre-RT, post-RT, and RT-induced pain. Results: A total of 15.5% participants self-identified as non-Hispanic white (NHW), 20.8% African American (AA), and 63.7% as Hispanic white (HW). AA patients were more likely to be obese, to report comorbidities, and to have advanced diseases. Pain prevalence was 15.9% at pre-RT and 31.3% at post-RT while 19.7% of patients experienced RT-induced pain. Post-RT pain severity and pain presence were associated with race/ethnicity, age, BMI, number of comorbidity, tumor stage, HER2 status, axillary surgery, fractionation, RT dose, breast volume, and hotspot volume (V105). Multivariable analyses identified HW and obese as independently associated with pre-RT pain while AA, HW, younger age ( Conclusions: This prospective study demonstrates AA and younger women are more susceptible to RT-induced pain. In addition, the management of comorbidity conditions, such as diabetes, hypertension, and thyroid disease, deserves attention to prevent RT-induced pain in breast cancer patients. Citation Format: Eunkyung Lee, Cristiane Takita, Jean L. Wright, Isildinha M. Reis, Wei Zhao, Jennifer J. Hu. A prospective study of racial/ethnic disparities in pain experience among breast cancer patients undergoing radiotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3703. doi:10.1158/1538-7445.AM2015-3703

Head and neck squamous cell carcinoma (HNSCC) is a devastating illness with racial/ethnic disparities in survival. Using a retrospective study design, we evaluated 210 somatic mutation sties of 10 cancer genes (i.e., CDKN2A, EGFR, FGFR3, HRAS, KRAS, MET, NOTCH1, PIK3CA, STK11, and TP53) in 214 HNSCC patients: 98 Non-Hispanic Whites (NHW; 46%), 72 Hispanic Whites (HW; 34%), and 44 African Americans (AA; 20%). HW and AA had significantly higher mutation rates for EGFR, HRAS, KRAS, and TP53 compared to that in NHW. Significantly higher proportions of HW (30%) and AA (18%) had at least 3 mutations compared to that in NHW (p Citation Format: Omar L. Nelson, Evan S. Wu, Jong Y. Park, Joseph Zeitouni, Carmen R. Gomez, Isildinha M. Reis, Wei Zhao, Eunkyung Lee, Hui-Yi Lin, Elizabeth J. Franzman, Jason Savell, Thomas V. McCaffrey, W. Jarrard Goodwin, Jennifer J. Hu. Actionable somatic mutations in head and neck cancer prognosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3876. doi:10.1158/1538-7445.AM2015-3876

Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer death in American women. Clinical guidelines recommend that when breast-conserving surgery is provided as a primary therapy for early-stage breast cancer, RT should follow to improve clinical outcome. Although well tolerated by most patients, even with improved RT technology, breast cancer patients experience moist desquamation as early adverse skin reactions. To elucidate the molecular mechanisms involved in RT-related normal tissure toxicity, global metabolomic profiles were determined in urine samples comparing across paired pre-RT and post-RT samples from 60 breast cancer patients exhibiting low (n = 30) or high (n = 30) skin toxicity in response to RT. The extracted samples were split into equal parts for analysis on the GC/MS and LC/MS platforms. The dataset comprises a total of 478 compounds of known identity. Preliminary data suggest that pre-RT glucose and a variety of derivatives linked to the pentose phosphate pathway, such as ribulose, or the consumption of pyruvate in the mitochondrial tricarboxylic acid cycle, including citrate and succinate, were significantly elevated in the high toxicity group. Multiple metabolites derived from the oxidation of aromatic compounds such as amino acids and dietary polyphenolics - vanillate, 3-hydromandelate, tyramine, 3-methoxy-4-hydroxyphenylglycol, and 2-hydroxyphenylacetate - were elevated in a trending or significant fashion at the pre-RT baseline in the high toxicity relative to the low toxicity group. Pre-RT ascorbate depletion and accumulation of tobacco metabolites were associated with radiation sensitivity. Ascorbate was significantly decreased at baseline in the high toxicity group and its pre-RT levels were negatively correlated with post-RT skin toxicity. Nicotine derivatives were only detected in 12% of the pre- and post-RT samples but their presence seemed to be a risk factor that could predispose smokers to unfavorable outcomes during radiation therapy. Histamine breakdown markers provided an indication of a heightened inflammatory activity in individuals who experienced toxicity as suggested that anti-histamines might be useful to prevent sensitivity. Our preliminary data suggest the potential application of metabolomics in predicting and monitoring RT-related normal tissue toxicities; future larger studies are warranted to confirm out promising findings and identify targeted metabolic pathways for effective intervention. Citation Format: Jennifer J. Hu, Eunkyung Lee, Cristiane Takita, Jean L. Wright, Omar L. Nelson. Metabolomics: Potential molecular mechanisms of radiotherapy (RT)-related normal tissue toxicities in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3327. doi:10.1158/1538-7445.AM2015-3327

6593 Background: RT-related early adverse skin reactions (EASR) are common in BC patients. EASR occur during/within 2 months post-RT. Predictive biomarkers for EASR are under active investigation. ...

TPS5619 Background: Despite platinum based chemoradiation (C-XRT), 40-50% of women with locally advanced cervical cancer will die from their disease. Nelfinavir (NFV), a protease inhibitor, has bee...

This study used the alkaline Comet assay to evaluate whether basal or H2O2-induced DNA damage is associated with prostate cancer (CaP) risk. Using lymphocyte samples from 158 CaP cases and 128 controls, collected in an ongoing case-control study, our results showed that basal DNA damage did not differ between cases and controls. However, the H2O2-induced DNA damage level was significantly higher in incident cases (mean +/- SD; 6.61 +/- 4.43, n = 102) than controls (5.30 +/- 3.60, n = 128) or prevalent cases (4.47 +/- 3.19; n = 56). Incident cases with a positive smoking history had significantly higher H2O2-induced DNA damage than never-smokers (7.57 +/- 4.82 versus 4.52 +/- 2.40; P0.001). Above-median H2O2-induced DNA damage was associated with a 1.61-fold increase in CaP risk [95% confidence interval (CI) = 0.92-2.81], after adjustment for age, race, benign prostatic hyperplasia (BPH), smoking history and family history (FH). Using the lowest quartile of H2O2-induced DNA damage as the referent group, the adjusted ORs for the 25th, 50th and 75th quartiles were 0.90 (95% CI = 0.39-2.05), 1.06 (95% CI = 0.48-2.35) and 2.05 (95% CI = 0.96-4.37), respectively (P = 0.046, test for linear trend). The association between CaP and DNA damage was modified by age, smoking history, family history and body mass index. Our results suggest that DNA damage may be associated with CaP risk. However, larger case-control and follow-up studies are warranted to further evaluate the potential application of the alkaline Comet assay in CaP risk assessment and prevention.

Objectives To report a prospective trial of lycopene supplementation in biochemically relapsed prostate cancer. Methods A total of 36 men with biochemically relapsed prostate cancer were enrolled in a dose-escalating, Phase I-II trial of lycopene supplementation. Six consecutive cohorts of 6 patients each received daily supplementation with 15, 30, 45, 60, 90, and 120 mg/day for 1 year. The serum levels of prostate-specific antigen (PSA) and plasma levels of lycopene were measured at baseline and every 3 months. The primary endpoints were PSA response (defined as a 50% decrease in serum PSA from baseline), pharmacokinetics, and the toxicity/tolerability of this regimen. Results A total of 36 patients were enrolled. The median age was 74 years (range 56 to 83), with a median serum PSA at entry of 4.4 ng/mL (range 0.8 to 24.9). No serum PSA responses were observed, and 37% of patients had PSA progression. The median time to progression was not reached. Toxicity was mild, with 1 patient discontinuing therapy because of diarrhea. Significant elevations of plasma lycopene were noted at 3 months and then appeared to plateau for all six dose levels. The plasma levels for doses between 15 and 90 mg/day were similar, with additional elevation only at 120 mg/day. Conclusions Lycopene supplementation in men with biochemically relapsed prostate cancer is safe and well tolerated. The plasma levels of lycopene were similar for a wide dose range (15 to 90 mg/day) and plateaued by 3 months. Lycopene supplementation at the doses used in this study did not result in any discernible response in serum PSA.

Cigarette smoke is a risk factor for colon cancer, but the importance of dose and interaction with genetic susceptibility remain poorly understood. We used data from a population-based case control study, to examine the association between cigarette smoking and colon cancer in African Americans and whites, and colon cancer and polymorphisms in GSTM1 and GSTT1. A total of 554 cases of primary colon cancer and 874 controls were included in this analysis. We found no association between cigarette smoking (ever versus never) and colon cancer in African Americans (odds ratio (OR)=0.93, 95% confidence interval (CI)=0.65–1.33). In contrast, there was an increased risk of cigarette smoking in whites (OR=1.43, CI=1.05–1.94). There was a small increased risk of colon cancer for individuals with GSTM1 null (African Americans, OR=1.43, CI, 0.98–2.09; whites, OR=1.19, CI, 0.90–1.58) and a decreased risk of colon cancer for individuals with GSTT1 null (African Americans, OR=0.59, CI: 0.40–0.86; whites, OR=0.72, CI: 0.53–1.00). There were weak interactions between GSTT1 null and cigarette smoking in whites, and GSTM1 null genotype and cigarette smoking in African Americans. GSTT1 and GSTM1 polymorphisms may be weakly related to colon cancer risk and there may be racial differences in gene-smoking interactions.

Prostate cancer (CaP) is the most commonly diagnosed non-skin cancer and the second leading cause of cancer death in American men. The etiology of CaP is not fully understood. Because most of the DNA adducts generated by some CaP-related carcinogens, including polycyclic aromatic hydrocarbons, heterocyclic amines, and pesticides, are removed by the nucleotide excision repair (NER) pathway, we pilot tested the hypothesis that CaP is associated with deficient NER capacity (NERC), measured by a plasmid-based host reactivation assay. Using cryopreserved lymphocytes collected in an ongoing, clinic-based case-control study, our results showed that the mean NERC was significantly lower (P = 0.03) in 140 cases (mean ± SD, 8.06 ± 5.17) than in 96 controls (9.64 ± 5.49). There was a significant association between below-median NERC and CaP risk: odds ratio (OR), 2.14; 95% confidence interval (CI), 1.19–3.86, after adjustment for age, race/ethnicity, smoking history, benign prostatic hyperplasia, and family history. This association was stronger in younger (

Mammalian cells are constantly exposed to genotoxic agents from both endogenous and exogenous sources. Genetic variability in DNA repair contributes to deficient repair and breast cancer risk. Using samples collected in an ongoing, clinic-based, case-control study (253 cases and 268 controls), we tested whether breast cancer risk is associated with four amino acid substitution variants in three DNA repair genes, including XRCC1 Arg194Trp and XRCC1 Arg399Gln in base excision repair, XRCC3 Thr241Met in homologous recombination repair, and ERCC4/XPF Arg415Gln in nucleotide excision repair. Carriers of at least one variant allele of XRCC1 Arg194Trp [Arg/Trp and Trp/Trp versus Arg/Arg, odds ratio (OR) = 1.60, 95% confidence interval (CI) = 0.89-2.87] or two variant alleles of XRCC3 241Met/Metmay have an increased risk of breast cancer (Met/Met versus Thr/Thr and Thr/Met, OR = 1.54, 95% CI = 0.94-2.52). No association between XRCC1 Arg399Gln Dgenotype and breast cancer risk was observed. The genotype distribution of ERCC4/XPF Arg415Gln differed significantly between cases and controls (P = 0.02), and the ERCC4/XPF 415Gln/Gln genotype was found in only seven cases (3%) but not in controls. In addition, breast cancer risk was significantly associated with an increasing number of combined variant alleles of XRCC1 Arg194Trp, XRCC3 Thr241Met, and ERCC4/XPF Arg415Gln in a four-level model (P(trend) = 0.04): OR = 1.0 for those without a variant allele (referent group); OR = 1.04 (95% CI = 0.67-1.61) for those with one variant allele; OR = 1.38 (95% CI = 0.83-2.29) for those with two variant alleles; and age-adjusted OR = 2.60 (95% CI = 1.03-6.59) for those with three or more variant alleles after adjustment for age, family history, age at menarche, age at first live birth, and body mass index. We provide evidence that variants of XRCC1, XRCC3, and ERCC4/XPF genes, particularly in combination, contribute to breast cancer susceptibility.