Biomarkers Of Cancer Risk Research Articles

Association between vitamin D and calcium intakes, breast microcalcifications, breast tissue age-related lobular involution and breast density.

To demystify the potential role of vitamin D and calcium intakes in breast carcinogenesis, we explored the association between these two nutrients and three biomarkers of breast cancer risk: the presence of microcalcifications, age-related lobular involution and breast density. A total of 82 premenopausal and 79 postmenopausal women diagnosed with breast cancer completed a food frequency questionnaire to assess their total vitamin D and calcium intakes. Presence of microcalcifications was determined by reviewing pathology reports. Age-related lobular involution was assessed in nontumoral breast tissue on hematoxylin-eosin-stained slides and percent breast density was assessed by a computer-assisted method. Multivariate generalized linear models were used to evaluate associations between quartiles of vitamin D and calcium intakes and the biomarkers of breast cancer risk. Increasing quartiles of vitamin D intake were inversely associated with the presence of microcalcifications (fourth quartile [Q4] prevalence ratio [PR] = 0.55; Ptrend = 0.021) and breast density (Q4-Q1 = -7.7%; Ptrend = 0.023) in postmenopausal women, and positively associated with age-related lobular involution in women with microcalcifications (Q4 PR = 1.62; Ptrend = 0.036). Increasing quartiles of calcium intake were inversely associated with microcalcifications among all (Q4 PR = 0.44), premenopausal (Q4 PR = 0.37) and postmenopausal women (Q4 PR = 0.38; Ptrend < 0.014 for all). It was also inversely associated with breast density in women without microcalcification (Q4-Q1 = -8.3%; Ptrend = 0.047), but positively associated with breast density in women with microcalcifications (Q4-Q1 = 10.0%; Ptrend = 0.032). Results suggest that the association between vitamin D and calcium intakes and breast cancer risk factors could be influenced by the presence of microcalcifications.

Aspirin, Risk of Colorectal Cancer, & Genetic Risk-Reply.

We appreciated the letter by Koulaouzidis and colleagues, which highlights the need for further studies to understand the mechanistic basis for aspirin's effect on colorectal cancer. Alongside their summary of our work (1) in the context of prior studies, they suggest that the effect of aspirin on gut microbiota should be examined. We agree that this is a high priority. As a rationale, they highlight research that shows aspirin appears to alter the gut microbiome to promote bacteria that are anti-inflammatory, thereby reducing colorectal cancer risk (2). We would further add that preclinical studies identify specific microbes that promote a proinflammatory environment, leading to induction of the enzymes that synthesize oncogenic prostaglandins which are inhibited by aspirin. Our group has also demonstrated that aspirin significantly inhibits tumorigenesis in ApcMin/+ mice inoculated with F. nucleatum and adenomas in aspirin users have significantly less Fusobacterium compared with nonaspirin users (3–5). These results are further supported by recent findings that aspirin treatment raises aspirin plasma concentrations and lowers tumor burden in microbiota-depleted mouse colorectal cancer models (ApcMin/+ and AOM/DSS), compared with microbiome-intact models and causes shifts in fecal metagenomic profiles of microbiome-intact mice that modulate aspirin bioavailability (6). Finally, a small randomized trial showed that aspirin alters the relative abundance of gut bacteria associated with colorectal cancer (7).Beyond playing a role in the development progression of colorectal cancer (8), the gut microbiome is being exploited to develop fecal microbial markers as a possible biomarker of colorectal cancer risk (9). If these studies are successful, gut microbiome risk markers could be leveraged alongside other risk measures including diet, age, and polygenic risk score to help identify patients who may have a more optimal risk-benefit profile for aspirin prevention.See the original Letter to the Editor, p. 701A.T. Chan reports personal fees from Bayer Pharma AG, Boehringer Ingelheim; grants and personal fees from Pfizer Inc.; and grants from Zoe, Ltd. outside the submitted work. No disclosures were reported by the other author.

Quantification of Plasma 8-Isoprostane by High-Performance Liquid Chromatography with Tandem Mass Spectrometry in a Case-Control Study of Lung Cancer.

Aim: 8-iso-prostaglandin F2α is a biomarker of lipid peroxidation, and one of the most commonly used measures of oxidative stress. It is an established biomarker of lung cancer risk. It is commonly measured by enzyme-linked immunosorbent assay. Given its importance, we developed a stable isotope dilution UPLC-tandem mass spectrometric method for the rapid determination of 8-isoprostane in blood. Methods: We tested the discriminatory capability of the method in 49 lung cancer patients, 55 benign lung nodule patients detected by chest X-ray, and 41 patients with chronic obstructive pulmonary disease (COPD) or asthma. Results: Significant differences were found in mean 8-isoprostane levels between the three groups (p = 0.027), and post-hoc tests found higher levels in the lung cancer patients than in patients with benign nodules (p = 0.032) and COPD/asthma (p = 0.014). The receiving operating characteristic area under the curve (AUC) was 0.69 for differentiating the lung cancer group from the benign nodule group, and 0.7 for differentiating from the COPD/asthma group. Conclusions: The UPLC-MS/MS-based method is an efficient analytical tool for measuring 8-isoprostane plasma concentrations. The results suggest exploring its utility as a marker for early lung cancer screening.

New Moms Wellness Study: the randomized controlled trial study protocol for an intervention study to increase fruit and vegetable intake and lower breast cancer risk through weekly counseling and supplemental fruit and vegetable box delivery in breastfeeding women

BackgroundLaboratory studies indicate that chemicals in fruits and vegetables have anti-carcinogenic and anti-inflammatory activities that can lower breast cancer risk. However, epidemiologic studies of the association between fruit and vegetable intake and breast cancer risk have produced mixed results. Measurement error, confounding, and an emphasis on diet in later adulthood may contribute to weak associations. This paper describes a randomized controlled diet intervention trial in breastfeeding women to examine the effect of high fruit and vegetable intake on breast cancer risk factors, including weight, DNA methylation and inflammatory markers.MethodsEligible breastfeeding women who reside within a 35-mile radius of Amherst, MA are enrolled at five to six weeks postpartum and randomly assigned to a Fruit and Vegetable Intervention Arm (target n = 200) or to a USDA MyPlate Control Arm (target n = 200). The Fruit and Vegetable Intervention group receives weekly telephone or video-based counseling to encourage intake of at least eight to ten daily servings of fruits and vegetables and a weekly delivery of a supplemental box of fruits and vegetables for 20 weeks, and less intensive counseling for up to one year. Breastmilk and infant fecal specimens are collected at baseline, 10 and 20 weeks. Anthropometric measurements are obtained at these timepoints and at the 1-year follow-up. The primary outcomes are change in DNA methylation in breast epithelial cells and change in inflammatory markers in breastmilk from randomization to 20 weeks; and change in weight, waist circumference, and fruit and vegetable intake for the period from randomization to 20 weeks and 1 year.DiscussionThis 1-year randomized diet intervention trial in breastfeeding women will assess whether intake of at least eight to ten daily servings of fruits and vegetables per day improves biomarkers of breast cancer risk directly in the breast (i.e., DNA methylation and inflammatory markers) and helps women maintain a healthy weight.Trial registration: ClinicalTrials.gov Identifier: NCT04374747. Registered May 5, 2020. https://www.clinicaltrials.gov/ct2/show/NCT04374747.

SDC4-rs1981429 and ATM-rs228590 may provide early biomarkers of breast cancer risk

In Australia, 13% of women are diagnosed with breast cancer (BC) in their lifetime with approximately 20,000 women diagnosed with the disease in 2021. BC is characterised by complex histological and genomic influences with recent advances in cancer biology improving early diagnosis and personalised treatment interventions. The Phosphatidyl-inositol-3-kinase/Protein kinase B (PI3K/AKT) pathway is essential in apoptosis resistance, cell survival, activation of cellular responses to DNA damage and DNA repair. Heparan sulfate proteoglycans (HSPGs) are ubiquitous molecules found on the cell surface and in the extracellular matrix with essential functions in regulating cell survival, growth, adhesion and as mediators of cell differentiation and migration. HSPGs, particularly the syndecans (SDCs), have been linked to cancers, making them an exciting target for anticancer treatments. In the PI3K/AKT pathway, syndecan-4 (SDC4) has been shown to downregulate AKT Serine/Threonine Kinase (AKT1) gene expression, while the ATM Serine/Threonine Kinase (ATM) gene has been found to inhibit this pathway upstream of AKT. We investigated single-nucleotide polymorphisms (SNPs) in HSPG and related genes SDC4, AKT1 and ATM and their influence on the prevalence of BC. SNPs were genotyped in the Australian Caucasian Genomics Research Centre Breast Cancer (GRC-BC) population and in the Griffith University–Cancer Council Queensland Breast Cancer Biobank (GU-CCQ BB) population. We identified that SDC4-rs1981429 and ATM-rs228590 may influence the development and progression of BC, having the potential to become biomarkers in early BC diagnosis and personalised treatment.

Somatic loss of the Y chromosome is associated with arsenic exposure among Bangladeshi men.

Arsenic exposure increases the risk of several cancers in humans and contributes to genomic instability. Somatic loss of the Y chromosome (LoY) is a potential biomarker of genomic instability and cancer risk. Smoking is associated with LoY, but few other carcinogens have been investigated. We tested the cross-sectional association between arsenic exposure and LoY in leukocytes among genotyped Bangladeshi men (age 20-70 years) from the Health Effects of Arsenic Longitudinal Study. We extracted the median of logR-ratios from probes on the Y chromosome (mLRR-chrY) from genotyping arrays (n = 1364) and estimated the percentage of cells with LoY (% LoY) from mLRR-chrY. We evaluated the association between arsenic exposure (measured in drinking water and urine) and LoY using multivariable linear and logistic regression models. The association between LoY and incident arsenic-induced skin lesions was also examined. Ten percent of genotyped men had LoY in at least 5% of cells and % LoY increased with age. Among men randomly selected for genotyping (n = 778), higher arsenic in drinking water, arsenic consumed and urinary arsenic were associated with increased % LoY (P = 0.006, P = 0.06 and P = 0.13, respectively). LoY was associated with increased risk of incident skin lesions (P = 0.008). Arsenic exposure was associated with increased LoY, providing additional evidence that arsenic contributes to genomic instability. LoY was associated with developing skin lesions, a risk factor for cancer, suggesting that LoY may be a biomarker of susceptibility in arsenic-exposed populations. The effect of arsenic on somatic events should be further explored in cancer-prone tissue types.

EP01.04-005 Quantitative Characteristics in Global CT Lung Cancer Screening Populations Using the ELIC Distributed Database and Computation Environment

High resolution CT lung scans contain large amounts of potentially relevant information to evaluate the prospective risk of developing lung cancer. Significant relationships between presence of emphysema and lung cancer risk have been observed, particularly when analyzing high-quality, high-resolution CT scans. A systematic quantitative analysis of lung structure, considering both the shape and density of lungs and lobes of screening detected lung cancer patients and lung cancer free screening participants has the potential to provide insight into promising quantitative lung cancer risk biomarkers.

Artichoke phytocomplex modulates serum microRNAs in patients exposed to asbestos: a first step of a phase II clinical trial

BackgroundMalignant pleural mesothelioma is a highly aggressive tumor associated with asbestos exposure. There are few effective treatment options for mesothelioma, and patients have a very poor prognosis. Mesothelioma has the potential to represent an appropriate disease to prevent because of its strong association with asbestos exposure and the long latency from exposure to the disease on-set.MethodsIn the present study, we tested biological activity and toxicity of an artichoke freeze-dried extract (AWPC) as potential complementary preventive/early stage treatment agent for mesothelioma. This phase II clinical study then was conducted in 18 male-patients with evidence of radiographic characteristics related to asbestos exposure such as asbestosis or benign pleural disease as surrogate disease for mesothelioma clinical model.ResultsWe investigate AWPC biological activity assessing its effect on mesothelin serum level, a glycoprotein with low expression in normal mesothelial cells and high expression in mesothelioma and asbestos related diseases. We also assess the AWPC effect on circulating miRNAs, as novel biomarkers of both cancer risk and response to therapeutic targets. While we found a small and not significant effect of AWPC on mesothelin serum levels, we observed that AWPC intake modulated 11 serum miRNAs related to gene-pathways connected to mesothelioma etiology and development. In terms of toxicity, we also did not observe any severe adverse effects associated to AWPC treatment, only gastro-intestinal symptoms were reported by five study participants.ConclusionsWe observed an interesting AWPC effect on miRNAs which targets modulate mesothelioma development. New and much larger clinical studies based on follow-up of workers exposed to asbestos are needed to corroborate the role of AWPC in prevention and early treatment of mesothelioma.Trial registrationClinicalTrials.gov, NCT02076672. Registered 03/03/2014.

The insulin sensitivity Mcauley index (MCAi) is associated with 40-year cancer mortality in a cohort of men and women free of diabetes at baseline

The association between insulin resistance and cancer-mortality is not fully explored. We investigated the association between several insulin sensitivity indices (ISIs) and cancer-mortality over 3.5 decades in a cohort of adult men and women. We hypothesized that higher insulin resistance will be associated with greater cancer-mortality risk. A cohort of 1,612 men and women free of diabetes during baseline were followed since 1979 through 2016 according to level of insulin resistance (IR) for cause specific mortality, as part of the Israel study on Glucose Intolerance, Obesity and Hypertension (GOH). IR was defined according to the Mcauley index (MCAi), calculated by fasting insulin and triglycerides, the Homeostatic Model Assessment (HOMA), the Matsuda Insulin Sensitivity Index (MISI), and the Quantitative Insulin Sensitivity Check Index (QUICKI), calculated by plasma glucose and insulin. Mean age at baseline was 51.5 ± 8.0 years, 804 (49.9%) were males and 871 (54.0%) had prediabetes. Mean follow-up was 36.7±0.2 years and 47,191 person years were accrued. Cox proportional hazard model and competing risks analysis adjusted for age, sex, country of origin, BMI, blood pressure, total cholesterol, smoking and glycemic status, revealed an increased risk for cancer-mortality, HR = 1.5 (95% CI: 1.1-2.0, p = 0.005) for the MCAi Q1 compared with Q2-4. No statistically significant associations were observed between the other ISIs and cancer-mortality. The MCAi was independently associated with an increased risk for cancer-mortality in adult men and women free of diabetes and should be further studied as an early biomarker for cancer risk.

TP53 mutations in Pap test DNA are a potential biomarker of ovarian cancer risk in high-risk women (226)

<b>Objectives:</b> The use of Pap tests as a molecular diagnostic for high-grade serous ovarian carcinoma (HGSOC) is a promising concept, but studies to detect tumor DNA report limited sensitivity. <i>TP53</i> somatic mutations from clonal expansions in non-neoplastic tissue can be detected in Pap tests and blood and could potentially be utilized for cancer risk assessment. We aimed to determine whether <i>TP53</i> somatic mutations in blood and Pap test DNA are associated with HGSOC in women with and without germline <i>BRCA1</i> or <i>BRCA2 (BRCA)</i> mutations. <b>Methods:</b> Peripheral blood and Pap samples were collected from 30 women with HGSOC (10 with a germline <i>BRCA</i> mutation) and 40 women without cancer (20 with a germline <i>BRCA</i> mutation) who underwent gynecologic surgery at the University of Washington. Genomic DNA from buffy coats and Pap cell pellets was used for ultra-deep sequencing of the <i>TP53</i> coding region (mean depth ~3300x) using duplex sequencing for error correction. Mutations were characterized based on pathogenicity and presence in the UMD <i>TP53</i> Cancer Database. Mutation frequencies (total coding mutations divided by nucleotides sequenced) were compared between groups using t-tests. Fitted linear regression models were used to explore age-related trends, and logistic regression models were used to predict cancer with adjustments for age. <b>Results:</b> Total 436 coding <i>TP53</i> mutations were identified in DNA from Pap tests, and 262 mutations were identified in the DNA from blood. Pap tests demonstrated an overall higher <i>TP53</i> mutation frequency in patients with HGSOC than in those without cancer (2.0x10^-6 vs 1.4x10^-6, p=0.03), but this effect was driven by and limited to patients with <i>BRCA</i> mutations (2.4x10^-6 vs 1.4x10^-6, p=0.01). Women with <i>BRCA</i> mutations and HGSOC also demonstrated a greater frequency of mutations affecting the DNA-binding domain, predicted to be pathogenic, and frequently found in cancer (referred to as ‘cancerlike') (all p<0.05). Cancer-like mutations increased with age in Pap test samples from women without cancer (p<0.01, R²=0.23) but not in patients with HGSOC. Age-adjusted logistic regression confirmed that cancer-like <i>TP53</i> mutation frequency was associated with HGSOC in patients with germline <i>BRCA</i> mutations (OR: 4.2, 95% CI: 1.2-14.3). There were no significant differences between HGSOC and non-cancer cases when examining <i>TP53</i> mutations in blood samples. Among 22 cases with known <i>TP53</i> tumor mutations, the tumor mutation was identified in six Pap samples (27%) and zero blood samples. <b>Conclusions:</b> The identification of HGSOC-specific mutations in Pap tests, even with highly accurate DNA sequencing methods, has limited sensitivity for cancer detection. However, Pap tests can detect abundant low-frequency cancer-like <i>TP53</i> mutations at a higher rate in women with germline <i>BRCA</i> mutations and HGSOC compared to women without cancer. Somatic <i>TP53</i> mutation frequency using age-related thresholds should be further explored as a biomarker for ovarian cancer risk in high-risk women.

Effect of Dietary Energy Restriction on the Expression of Genes Encoding the Enzymes Involved in Steroidogenesis in Normal Breast Epithelium and Abdominal Adipose Tissue of Women with Excessive Adiposity

Background: Weight gain and excessive adiposity are associated with an increased risk of breast cancer, especially in postmenopausal women with a high circulating level of testosterone. In this in silico study, the effect of the dietary energy restriction (DER) on the expression of a panel of genes coding for the main enzymes involved in androgens and estrogens production was investigated in breast epithelium and abdominal adipose tissue of healthy women with excessive adiposity and randomly allocated to DER for one menstrual cycle or asked to continue their usual diet. Methods: Wilcoxon-Signed-Rank test was used to assess the difference between paired samples before and after DER in the breast epithelium or adipose tissue, and Spearman’s rank correlation was used to investigate the correlation between genes. Results: In response to DER, the expression of HSD17B12, the gene encoding the enzyme that catalyzes the conversion of inactive estrone into bioactive estradiol, was significantly (P=0.0059) downregulated in breast epithelium and adipose tissue. Furthermore, the expression of HSD17B12 negatively correlated with that of the LRP1 gene (r= -0.91, P&lt;0.0001), which codes for a multitasking protein recently proposed as a tumor suppressor in breast epithelium. Conclusion: Present results showed that, in addition to the recognized systemic effects (reduction of the fatty mass and decrease of circulating biomarkers of breast cancer risk), DER could act locally by down-regulating the expression of some genes pivotally involved in the production of biologically active estrogens, thus contributing to prevent the estrogen-dependent initiation of breast cancer.

Viscoelastic or Viscoplastic Glucose Theory (VGT #36): Applying the VEGT or VPGT to Study the Cancer Risk Probability Percentage Versus Medical Conditions and Lifestyle Details over 10+ Years from Y2012 to Y2022 Based on the GH-Method: Math-Physical Medicine (No. 617)

Since 2012, the author has collected his body weight and finger-piercing glucose values each day. Next, he accumulated medical conditions data including blood pressure (BP), heart rate (HR), and blood lipids along with lifestyle details of diet, exercise, sleep, stress, water intake, and daily routine details. Based on these collected big data, he organized them into two main categories. The first is medical conditions (MC) with 4 categories: weight, glucose, BP, and lipids. The second is lifestyle details (LD) with 6 categories: food, exercise, water intake, sleep, stress, and daily routines. Furthermore, he summarized and calculated the two separate individual category scores of MC and LD. In this article, the author applies the viscoelasticity and viscoplasticity theories to conduct his research to discover some hidden behavior or relationship between the Cancer risk probability (as an output or strain) versus either MC score or LD score (as inputs or stresses). The hidden behaviors and relationships between the output biomarker of Cancer Risk and the two input biomarkers, MC score and LD score, are time-dependent and change from time to time.

The role of smoking history in longitudinal changes in C-reactive protein between Black and White older adults in the US

Smoking cessation is associated with decreases in C-reactive protein (CRP), a biomarker of systemic inflammation and cancer risk; yet CRP levels remain higher long-term in individuals who quit vs. those who never smoked. While non-Hispanic, Black/African American (NHB) have higher levels of CRP vs. non-Hispanic, White/Caucasian (NHW) adults, the association between CRP and race has not been examined in individuals with smoking history. Utilizing longitudinal data from the Health and Retirement Study (HRS), the current study examined the effects of race and smoking history on CRP in older adults. NHB (n = 242) and NHW (n = 1529) participants completed HRS assessments in 2006, 2010, and 2014. Dried blood spots collected at each wave were assayed for CRP. Linear mixed models were used to examine the effect of race and smoking history on CRP across waves – controlling for sociodemographics, physical activity, body mass index (BMI), and current smoking. Overall, results showed no significant effects of race or current smoking on CRP; rather age, sex, education, BMI, physical activity, smoking history, and time × race predicted CRP (ps<.04). However, while age, sex, education, BMI, physical activity, and smoking history were also predictive of CRP in NHWs (ps<.04) in race-stratified models, only BMI was a significant predictor of CRP in NHBs (p=.012). BMI may be important in explaining inflammation-related disease risk in NHBs with a history of smoking. NHBs may not experience the same reductions in CRP with smoking cessation as NHWs – potentially contributing to tobacco-related health disparities.

Viscoelastic or Viscoplastic Glucose Theory (VGT #36): Applying the VEGT or VPGT to Study the Cancer Risk Probability Percentage Versus Medical Conditions and Lifestyle Details Over a 10+ Year Period from Y2012 to Y2022 based on the GH-Method: MathPhysical Medicine (No. 617)

Since 2012, the author has collected his body weight and finger-piercing glucose values each day. Next, he accumulated medical conditions data including blood pressure (BP), heart rate (HR), blood lipids along with lifestyle details of diet, exercise, sleep, stress, water intake and daily routine details. Based on these collected big data, he organized them into two main categories. The first is medical conditions (MC) with 4 categories: weight, glucose, BP, and lipids. The second is lifestyle details (LD) with 6 categories: food, exercise, water intake, sleep, stress, and daily routines. Furthermore, he summarized and calculated the two separate individual category scores of MC and LD. In this article, the author applies the viscoelasticity and viscoplasticity theories to conduct his research to discover some hidden behavior or relationship between the Cancer risk probability (as an output or strain) versus either MC score or LD score (as inputs or stresses). The hidden behaviors and relationships between the output biomarker of Cancer Risk and the two input biomarkers, MC score and LD score, are time-dependent which change from time to time. The following two defined equations are used to establish the stress-strain diagram in a space-domain (SD): strain = ε = individual Cancer risk value at present year Stress = σ = η * (dε/dt) = η * (d-strain/d-time) = (viscosity factor η using individual MC score or LD score at present year) * (Cancer risk at present year - Cancer risk at previous year) / 1 year To offer a simple explanation to readers who do not have a physics or engineering background, the author includes a brief excerpt from Wikipedia regarding the description of basic concepts for elasticity and plasticity theories, viscoelasticity and viscoplasticity theories from the disciplines of engineering and physics in the Method section. In summary, the following three observations outline the findings from this research work: 1. From the TD waveforms, the correlation between Cancer risk and MC is 96%, while the correlation between Cancer risk and LD is also 96%. This means that the Cancer risk is highly correlated with both MC and LD, but lifestyle is more like a “root-cause” for Cancer risk even though many patients with cancer also suffer from other chronic diseases such as obesity, diabetes, hypertension, and hyperlipidemia. 2. From the SD stress-strain diagrams between CVD risk vs. MC and CVD risk vs. LD, these two curves are similar in shapes and appearance except for their stress scale (y-axis scale) which has a ratio of 1.75 to 1 (-1.4% for stress of MC and -0.8% for stress of LD; or an average MC score of 88% to the average LD score of 50%). This 1.75/1=1.75 ratio also influences the hysteresis loop area ratio of 0.005/0.003 = 1.72. In addition, both of these two stress-strain curves demonstrate viscoplastic behavior. Their largest strain change rate (Cancer risk change rate) occurs during the period between Y2012 and Y2017. 3. The comparisons for the calculated Cancer risk waveform versus two predicted Cancer risk waveforms due to both MC and LD using a viscoelastic perturbation model has shown an extremely high 98% to 99% prediction accuracy. However, the calculated Cancer risk versus the predicted Cancer risk based on LD has a 96% correlation, while the calculated Cancer risk versus the predicted Cancer risk based on MC has also a 96% correlation. This 96% of correlations further demonstrates the importance of MC and LD for Cancer risk reduction.

Viscoelastic and Viscoplastic Glucose Theory (VGT #22): Applying the Concepts of Viscoelasticity, Viscoplasticity and Perturbation Theories to Predict Cancer Risk Percentages using the overall Lifestyle Scores and Calculated Cancer Risk Change Rates with Corresponding Lifestyle Scores as the Respective Viscosity Factors along with Studying the Relationship between Cancer Risks and Diabetic Glucoses Based on the GH-Method: Math-Physical Medicine (No. 601)

Viscoelastic and Viscoplastic Glucose Theory (VGT #22): Applying the Concepts of Viscoelasticity, Viscoplasticity and Perturbation Theories to Predict Cancer Risk Percentages using the overall Lifestyle Scores and Calculated Cancer Risk Change Rates with Corresponding Lifestyle Scores as the Respective Viscosity Factors along with Studying the Relationship between Cancer Risks and Diabetic Glucoses Based on the GH-Method: Math-Physical Medicine (No. 601)

Detection of DNA adducts derived from the tobacco carcinogens, benzo[a]pyrene and dibenzo[def,p]chrysene in human oral buccal cells.

Polycyclic aromatic hydrocarbons (PAHs) are recognized as potential etiological agents in the development of oral cancer in smokers. In particular, benzo[a]pyrene (B[a]P) and dibenzo[def,p]chrysene (DB[a,l]P) are detected in cigarette smoke and the environment and can induce DNA damage, mutagenesis and carcinogenesis in the oral cavity of rodents. Consequently, DNA adducts are regarded as the most direct markers of genotoxicity and can be used as biomarkers of cancer risk. Thus, this study used LC-MS/MS analysis with isotope labeled internal standard to detect and quantify DNA adducts derived from B[a]P and DB[a,l]P in buccal cells of cigarette smokers and non-smokers. Participants in this study include 21 smokers and 16 non-smokers. Our data are the first to report that levels (mean ± SD) of BPDE-N2-dG were significantly (P < 0.001) higher in smokers (20.18 ± 8.40 adducts/108 dG) than in non-smokers (0.84 ± 1.02 adducts/108 dG). Likewise, levels of DBPDE-N6-dA in smokers (5.49 ± 3.41 adducts/108 dA) were significantly higher (P = 0.019) than non-smokers (2.76 ± 2.29 adducts/108 dA). Collectively, the results of this clinical study support that PAHs in tobacco smoke can contribute to the development of oral cancer in humans.

MicroRNA-126 expression in the peripheral white blood cells of patients with breast and ovarian cancer is a potential biomarker for the early prediction of cancer risk in the carriers of methylated BRCA1.

Constitutive breast cancer type 1 gene (BRCA1) promoter methylation is associated with increased cancer risk, but its role in cancer-free (CF) female carriers is incompletely understood. MicroRNA (miR) is modulated during early tumorigenesis. The present study assessed the modulation of miR-126 expression in the peripheral white blood cells (WBC) of patients with breast cancer (BC) and ovarian cancer (OC) as a biomarker of cancer risk in BRCA1 methylation carriers. A total of 1,114 female subjects [502 patients with BC, 187 patients with OC and 425 CF volunteers] were involved. Screening for BRCA1 promoter methylation in WBC was performed using the methylation–specific polymerase chain reaction (PCR) assay, BRCA1 mRNA was analyzed using a reverse transcription-quantitative PCR assay and miR-126 expression was analyzed using a stem-loop RT-qPCR assay. WBC BRCA1 promoter methylation status was significantly associated with OC (P=0.0266), early-onset BC (P=0.0003) and triple-negative BC (P=0.0066). Notably, 9.4% of the CF group exhibited WBC BRCA1 promoter methylation. In addition, high levels of miR-126 in WBCs were detected in all three groups. The increased level of miR-126 was significantly associated with a lower risk of distant metastasis (P=0.045) in BC, but a higher risk of disease progression and death (P=0.0029) in OC. There was a positive correlation between BRCA1 mRNA and miR-126 levels in the WBCs of all three groups, regardless of BRCA1 promoter methylation status. Notably, circulating miR-126 level was decreased in the BC and OC groups, but not in the CF group. Together, these results suggest the likely involvement of miR-126 in the constitutional methylation of BRCA1 promoter-related malignancies. Therefore, miR-126 may be a candidate biomarker for the early prediction of BC and OC risk in CF BRCA1 methylation carriers.

MICRONUCLEI IN SQUAMOUS CELL CARCINOMA

Micronuclei are small chromatin bodies that appear in the cytoplasm by the condensation of acrocentric chromosomal fragments or by whole chromosome, lagging behind the cell division.Micronuclei in oral exfoliated epithelial cells are widely used as a biomarker of chromosomal damage, genome instability and cancer risk in humans.In oral exfoliated cells these micronuclei are induced by variety of carcinogenic compounds ,which have been suggested to be most common cause of premalignant lesion ,conditions and oral cancer and thus can be used as a biomarker for cytogenetic damage.In this review ,the formation of these important nuclear anomalies that are commonly seen in cancer and are indicative of genome dmage that could increase the risk of developmental and degenerative diseases.

Abstract 6333: Quantification of oxylipins as biomarkers of inflammation and cancer risk in breast tissue

Abstract Arachidonic acid (AA) metabolizing enzymes, including cyclooxygenases (COX), lipoxygenases, and cytochrome P450s (CYP450), are expressed in breast cancer (BC). Elevated levels of metabolites of COX-derived, pro-inflammatory prostaglandin (PGs) metabolites in urine have been linked to increased risk of developing breast cancer (BC) in two large prospective cohorts. Further, CYP450-derived EETs in BC tumors are associated with metastasis. We hypothesize that measuring levels of AA-derived oxylipins in breast tissues could enable improved BC risk prediction, provide insights into pro-carcinogenic inflammatory mechanisms, and serve as potential surrogate endpoints in chemoprevention trials. Thus, we performed a pilot study to assess the feasibility of measuring these analytes in small breast tissue samples. We analyzed two sample sets, collected under Institutional Review Board (IRB) approved protocols: 50 normal breast tissue cores donated to the Komen Tissue Bank (KTB) via vacuum-assisted biopsy and 10 tissues removed surgically at Mayo Clinic beyond resection margins of lumpectomy samples performed for atypical ductal hyperplasia (ADH). Tissues were frozen and maintained at -80°C. Normal KTB tissue cores were split in half. Tissues for analysis were weighed, extracted in cold methanol containing a cyclooxygenase inhibitor, and assayed for a panel of 42 oxylipins using validated mass spectrometric methods with a limit of detection per analyte of 0.010 ng/mL in supernatant and CVs of approximately &amp;lt;11%. Analyte measurements in paired cores (ng/g tissue) were compared with Spearman correlations and intra-class correlation coefficients. Measurements in surgical samples were assessed descriptively and levels were compared with normal KTB breast tissues.Median weight of the 50 split KTB cores was 0.055 grams. 17 oxylipins were detected in the tissue samples. PGD2 demonstrated the weakest correlation between split cores (r=0.12; p=0.40), whereas 15-HETE demonstrated the strongest correlation (r=0.68; p&amp;lt;0.0001). ICCs ranged from non-significant to nearly perfect, with highest values for 12-HETE (ICC=0.98, 95%CI: 0.97-0.99). Exploratory analyses of the KTB cores demonstrated significant associations between two BC risk factors, alcohol use and family history of breast/ovarian cancer, and several analytes. Levels of most eicosanoids tested were substantially and highly significantly elevated in tissues surrounding ADH versus KTB normal breast tissues. We conclude that eicosanoids can be readily measured in small frozen breast tissue samples obtained via percutaneous biopsy or at surgery. Future studies to assess the associations of eicosanoid levels with BC risk factors and development of BC after a benign biopsy may inform risk prediction and potentially inhibitable inflammatory mechanisms of breast carcinogenesis. Citation Format: Ginger L. Milne, Robert A. Vierkant, Amy C. Degnim, Anna Maria Storniolo, Jill E. Henry, Laura M. Pacheco-Spann, Derek C. Radisky, Mark E. Sherman. Quantification of oxylipins as biomarkers of inflammation and cancer risk in breast tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6333.

Abstract 3825: Germline modifiers of the tumor immune microenvironment reveal drivers of immunotherapy response

Abstract With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer risk screening and treatment strategies. Using genotypes from over 8,000 European individuals in The Cancer Genome Atlas and 137 heritable tumor immune phenotype components (IP components), we identified and investigated 532 TIME-SNPs. Focusing on 77 variants that were relevant to cancer risk, survival, or treatment response, we explored their potential to reveal novel targets for immunotherapy. Many variants overlapped regions with histone marks indicating active transcription, and influenced gene activities in specific immune cell subsets, such as macrophages and dendritic cells. TIME-SNPs implicated genes such as LAIR1, TREX1, CTSS, CTSW and LILRB2 were differentially expressed between responders and non-responders to immune-checkpoint blockade (ICB) in preclinical studies. Of these, LILRB2 and LAIR1 have already been identified as putative targets for immunotherapy. Here we found that inhibition of CTSS led to better tumor control and survival in murine models, alone or in combination with anti-PD-1. Collectively we show that through an integrative approach, it is possible to link host genetics to TIME characteristics, informing novel biomarkers for cancer risk and target identification in immunotherapy. Citation Format: Meghana Pagadala, Victoria Wu, Eva Pérez-Guijarro, Hyo Kim, Andrea Castro, James Talwar, Cristian Gonzalez-Colin, Steven Cao, Benjamin J. Schmiedel, Timothy Sears, Shervin Goudarzi, Divya Kirani, Rany M. Salem, Gerald P. Morris, Olivier Harismendy, Sandip P. Patel, Jill P. Mesirov, Maurizio Zanetti, Chi-Ping Day, Chun C. Fan, Wesley K. Thompson, Glenn Merlino, J. Silvio Gutkind, Pandurangan Vijayanand, Hannah Carter. Germline modifiers of the tumor immune microenvironment reveal drivers of immunotherapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3825.