Aggressive mammary carcinoma progression in Nrf2 knockout mice treated with 7,12-dimethylbenz[a]anthracene

<p>Abstract</p> <p>Background</p> <p>Activation of nuclear factor erythroid 2-related factor (Nrf2), which belongs to the basic leucine zipper transcription factor family, is a strategy for cancer chemopreventive phytochemicals. It is an important regulator of genes induced by oxidative stress, such as glutathione S-transferases, heme oxygenase-1 and peroxiredoxin 1, by activating the antioxidant response element (ARE). We <it>hypothesized </it>that (1) the citrus coumarin auraptene may suppress premalignant mammary lesions via activation of Nrf2/ARE, and (2) that Nrf2 knockout (KO) mice would be more susceptible to mammary carcinogenesis.</p> <p>Methods</p> <p>Premalignant lesions and mammary carcinomas were induced by medroxyprogesterone acetate and 7,12-dimethylbenz[a]anthracene treatment. The 10-week pre-malignant study was performed in which 8 groups of 10 each female wild-type (WT) and KO mice were fed either control diet or diets containing auraptene (500 ppm). A carcinogenesis study was also conducted in KO vs. WT mice (n = 30-34). Comparisons between groups were evaluated using ANOVA and Kaplan-Meier Survival statistics, and the Mann-Whitney U-test.</p> <p>Results</p> <p>All mice treated with carcinogen exhibited premalignant lesions but there were no differences by genotype or diet. In the KO mice, there was a dramatic increase in mammary carcinoma growth rate, size, and weight. Although there was no difference in overall survival, the KO mice had significantly lower mammary tumor-free survival. Also, in the KO mammary carcinomas, the active forms of NF-κB and β-catenin were increased ~2-fold whereas no differences in oxidized proteins were observed. Many other tumors were observed, including lymphomas. Interestingly, the incidences of lung adenomas in the KO mice were significantly higher than in the WT mice.</p> <p>Conclusions</p> <p>We report, for the first time, that there was no apparent difference in the formation of premalignant lesions, but rather, the KO mice exhibited rapid, aggressive mammary carcinoma progression.</p

The tumor mutational landscape of BRCA2-deficient primary and metastatic prostate cancer

Abstract Carriers of germline BRCA2 pathogenic sequence variants have elevated aggressive prostate cancer risk and are candidates for precision oncology treatments. We examined whether BRCA2-deficient (BRCA2 d ) prostate tumors have distinct genomic alterations compared with BRCA2-intact (BRCA2 i ) tumors. Among 2536 primary and 899 metastatic prostate tumors from the ICGC, GENIE, and TCGA databases, we identified 138 primary and 85 metastatic BRCA2 d tumors. Total tumor mutation burden (TMB) was higher among primary BRCA2 d tumors, although pathogenic TMB did not differ by tumor BRCA2 status. Pathogenic and total single nucleotide variant (SNV) frequencies at KMT2D were higher in BRCA2 d primary tumors, as was the total SNV frequency at KMT2D in BRCA2 d metastatic tumors. Homozygous deletions at NEK3, RB1, and APC were enriched in BRCA2 d primary tumors, and RB1 deletions in metastatic BRCA2 d tumors as well. TMPRSS2-ETV1 fusions were more common in BRCA2 d tumors. These results identify somatic alterations that hallmark etiological and prognostic differences between BRCA2 d and BRCA2 i prostate tumors

EZH2 protein expression in normal breast epithelium and risk of breast cancer: results from the Nurses’ Health Studies

Background: Enhancer of zeste homolog 2 (EZH2) is a polycomb-group protein that is involved in stem cell renewal and carcinogenesis. In breast cancer, increased EZH2 expression is associated with aggressiveness and has been suggested to identify normal breast epithelium at increased risk of breast cancer development. However, the association between EZH2 expression in benign breast tissue and breast cancer risk has not previously been evaluated in a large prospective cohort. Methods: We examined the association between EZH2 protein expression and subsequent breast cancer risk using logistic regression in a nested case-control study of benign breast disease (BBD) and breast cancer within the Nurses’ Health Studies. EZH2 immunohistochemical expression in normal breast epithelium and stroma was evaluated by computational image analysis and its association with breast cancer risk was analyzed after adjusting for matching factors between cases and controls, the concomitant BBD diagnosis, and the Ki67 proliferation index. Results: Women with a breast biopsy in which more than 20% of normal epithelial cells expressed EZH2 had a significantly increased risk of developing breast cancer (odds ratio (OR) 2.95, 95% confidence interval (CI) 1.11–7.84) compared to women with less than 10% EZH2 epithelial expression. The risk of developing breast cancer increased for each 5% increase in EZH2 expression (OR 1.22, 95% CI 1.02–1.46, p value 0.026). Additionally, women with high EZH2 expression and low estrogen receptor (ER) expression had a 4-fold higher risk of breast cancer compared to women with low EZH2 and low ER expression (OR 4.02, 95% CI 1.29–12.59). Conclusions: These results provide further evidence that EZH2 expression in the normal breast epithelium is independently associated with breast cancer risk and might be used to assist in risk stratification for women with benign breast biopsies. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0817-6) contains supplementary material, which is available to authorized users

Discovering novel driver mutations from pan-cancer analysis of mutational and gene expression profiles.

As the genomic profile across cancers varies from person to person, patient prognosis and treatment may differ based on the mutational signature of each tumour. Thus, it is critical to understand genomic drivers of cancer and identify potential mutational commonalities across tumors originating at diverse anatomical sites. Large-scale cancer genomics initiatives, such as TCGA, ICGC and GENIE have enabled the analysis of thousands of tumour genomes. Our goal was to identify new cancer-causing mutations that may be common across tumour sites using mutational and gene expression profiles. Genomic and transcriptomic data from breast, ovarian, and prostate cancers were aggregated and analysed using differential gene expression methods to identify the effect of specific mutations on the expression of multiple genes. Mutated genes associated with the most differentially expressed genes were considered to be novel candidates for driver mutations, and were validated through literature mining, pathway analysis and clinical data investigation. Our driver selection method successfully identified 116 probable novel cancer-causing genes, with 4 discovered in patients having no alterations in any known driver genes: MXRA5, OBSCN, RYR1, and TG. The candidate genes previously not officially classified as cancer-causing showed enrichment in cancer pathways and in cancer diseases. They also matched expectations pertaining to properties of cancer genes, for instance, showing larger gene and protein lengths, and having mutation patterns suggesting oncogenic or tumor suppressor properties. Our approach allows for the identification of novel putative driver genes that are common across cancer sites using an unbiased approach without any a priori knowledge on pathways or gene interactions and is therefore an agnostic approach to the identification of putative common driver genes acting at multiple cancer sites

Racial and Ethnic Variation in PSA Testing and Prostate Cancer Incidence Following the 2012 USPSTF Recommendation

Abstract Background The 2012 US Preventive Services Task Force recommendation against routine prostate-specific antigen (PSA) testing led to a decrease in prostate cancer screening, but the heterogeneity of its impact by race and ethnicity remains unclear. Methods The proportion of 40- to 74-year-old men who self-reported receiving a routine PSA test in the past year was estimated in the Behavioral Risk Factor Surveillance System (2012-2018). Odds ratios (ORs) of undergoing screening by race and ethnicity were estimated, adjusting for healthcare–related factors. Prostate cancer incidence rates and rate ratios (IRRs) by race and ethnicity were estimated using Surveillance, Epidemiology, and End Results registry data (2004-2017). Results PSA testing frequencies were 32.3% (95% confidence interval [CI] = 31.7% to 32.8%) among non-Hispanic White (NHW), 30.3% (95% CI = 28.3% to 32.3%) among non-Hispanic Black (NHB), 21.8% (95% CI = 19.9% to 23.7%) among Hispanic, and 17.7% (95% CI = 14.1% to 21.3%) among Asian and Pacific Islander men in 2012. The absolute screening frequency declined by 9.5% from 2012 to 2018, with a larger decline among NHB (11.6%) than NHW men (9.3%). The relative annual decrease was greater among NHB (OR = 0.86, 95% CI = 0.84 to 0.88) than NHW men (OR = 0.89, 95% CI = 0.89 to 0.90; Pheterogeneity = .005), driven by a larger decline among NHB men ages 40-54 years. The NHB to NHW IRR for total prostate cancer increased from 1.73 (95% CI = 1.69 to 1.76) in 2011 to 1.87 (95% CI = 1.83 to 1.92) in 2012 and has remained elevated, driven by differences in localized tumor incidence. Metastatic disease incidence is rising across all racial and ethnic groups. Conclusions The frequency of prostate cancer screening varies by race and ethnicity, and there was a modestly steeper decline in PSA testing among younger NHB men relative to NHW men since 2012. The NHB to NHW IRR for localized prostate cancer modestly increased following 2012

Abstract 3509: Racial variation in molecularly-defined prostate cancer subtypes

Abstract Background: Socioeconomic, environmental, and healthcare utilization factors are likely drivers of the persistent prostate cancer disparities between African-American (AA) and European-American (EA) men. Tumor molecular heterogeneity may also contribute, and Eurocentric studies and initiatives have the potential to widen disparities through the development of prognostic signatures and targeted therapeutics that do not account for genetic diversity. Methods: The Decipher Genomics Resource Information Database (GRID) contains tumor mRNA expression and clinical data generated through use of the Decipher test to predict prostate cancer prognosis. We matched 426 AA and 426 EA patients with localized prostate cancer using a propensity score accounting for age and tumor clinicopathological factors. We then applied five validated prostate cancer molecular subtype classifiers by Alshalalfa et al (Neuroendocrine, Adenocarcinoma), Kamoun et al (S1-S3), Tomlins et al(ERG+, ETS+, SPINK1+, ERG-/ETS-/SPINK1-), You et al (PCS1-PCS3), and Zhang et al (Basal, Luminal) to assign tumor subtypes. Heterogeneity in subtype frequency by self-identified race (SIR) was evaluated using chi-squared tests. Differences in subtype prognostic value by SIR were evaluated in logistic regression models using a high Decipher tumor genomic risk score of ≥0.6 as a surrogate for higher risk of metastases. Results: AA men were more likely to have a Decipher score ≥0.6 than EA men (25.6% vs. 20.0%, p<0.001). Subtypes reflecting SPINK1 overexpression were more frequent among AA men, while subtypes reflecting the presence of ERG or ETS fusions were more common among EA men (all p<0.001). The distribution of Basal vs. Luminal tumors did not differ by SIR (p=0.19), nor did Neuroendocrine vs. Adenocarcinoma (p=0.14). Across SIR groups, the ERG+, Basal, PCS1, and Neuroendocrine tumors were the most likely to have high Decipher scores, while the S2 subtype was associated with a lower Decipher score. However, associations between subtypes and the Decipher score differed by SIR for three of five classifiers. The ERG+ subtype (relative to ERG-/ETS-/SPINK1-) was associated with a higher risk of metastases in AA men (OR=3.18 95% CI 1.59-6.37), but not in EA men (OR=0.69, 95% CI 0.39-1.24, p-het=0.002). A similar pattern was observed in the PCS3 subtype, which is also characterized by the presence of ERG or ETS fusions (p-het=0.003). The hypothesized low-risk S2 subtype was associated with lower risk of metastases (relative to S1) among EA men (OR=0.31, 95% CI 0.15-0.61), but not among AA men (OR=0.99, 95% CI 0.39-2.49, p-het=0.001). The Zhang (p-het=0.36) and Alshalalfa (p-het=0.85) classifiers did not show heterogeneous associations between subtype and Decipher score by SIR. Conclusions: Prostate cancer molecular subtype distributions differed by SIR, with AA men generally more likely to have aggressive subtypes across classification schemes. Furthermore, AA and EA had a heterogeneous risk of metastases (defined by Decipher genomic risk score) for several subtypes. Further research is needed to better define subtyping classifiers and the prognostic value thereof in AA men. Citation Format: Kevin H. Kensler, Mohamed Alshalalfa, Brandon A. Mahal, Yang Liu, Elai Davicioni, Shivanshu Awasthi, Kosj Yamoah, Timothy R. Rebbeck. Racial variation in molecularly-defined prostate cancer subtypes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3509

Sulforaphane-Mediated Reduction of Aflatoxin B1-N7-Guanine in Rat Liver DNA: Impacts of Strain and Sex

Aflatoxin B1 (AFB1) is a DNA-binding toxin that contributes to the burden of liver cancer in tropical areas. AFB1-DNA adducts are powerful biomarkers that discern individual and population risk from exposure to this carcinogen. The discovery of concordance between the metabolic pathways of the male Fischer rat and humans allowed data from rats to guide the development of chemoprevention strategies employed in clinical trials in high-risk regions. In this study, the variables of strain and sex are studied in the rat model, as a step toward understanding how ethnic differences and sex influence DNA adduct formation and the induction of enzymes by chemoprotective agents. Sulforaphane (SF), which induces phase II enzymes including glutathione S-transferases (GSTs), was evaluated for its ability to induce GST activity and reduce the AFB1-DNA adducts in livers of both sexes of two rat strains that differ in susceptibility to AFB1 hepatocarcinogenesis. A dose-dependent relationship was found for SF for both induction of GST and reduction in of AFB1-N7-guanine in both Fischer (sensitive to AFB1) and Sprague-Dawley rats (relatively resistant). Sprague-Dawley rats exhibited the greatest increase in GST levels and the largest reduction in AFB1-N7-guanine in liver DNA. Males and females of each strain were also compared to determine if the ability of SF to induce GST and reduce AFB1-N7-guanine correlated with gender differences in sensitivity to AFB1 carcinogenesis. No gender-specific responses to SF were observed. These results support the view that SF induction of liver GST activity may play a role in its chemoprotective activity