bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Screening of Chemopreventive Agents in Animal Models: Results on Reproducibility, Agents of a Given Class, and Agents Tested During Tumor Progression
Authors: Lubet Ronald A. , Steele Vernon E. , Shoemaker Robert H. , Grubbs Clinton J.
Published: March 2024

Abstract
Because of the importance of testing reproducibility of results, we present our findings regarding screening agents in preclinical chemoprevention studies in rodent models performed by the Chemopreventive Agent Development Research Group (CADRG) of the Division of Cancer Prevention of the NCI. These studies were performed via contracts to various commercial and academic laboratories. Primarily, results with positive agents are reported because positive agents may progress to the clinics. In testing reproducibility, a limited number of direct repeats of our standard screening assays were performed; which entailed initiating treatment shortly after carcinogen administration or in young transgenic mice and continuing treatment until the end of the study. However, three additional protocols were employed relating to reproducibility: (i) testing agents at lower doses to determine efficacy and reduced toxicity; (ii) testing agents later in tumor progression when microscopic lesions existed and, (iii) testing multiple agents of the same mechanistic class. Data with six models that were routinely employed are presented: MNU-induced ER-positive mammary cancer in rats; MMTV-Neu ER-negative mammary cancers in transgenic mice; AOM-induced colon tumors in rats; intestinal adenomas in Min mice; OH-BBN–induced invasive rat urinary bladder cancers in rats; and UV-induced skin squamous carcinomas in mice. It was found that strongly positive results were highly reproducible in the preclinical models evaluated. Cancer Prev Res; 11(10); 595–606. ©2018 AACR.
Data from Statin Use, Serum Lipids, and Prostate Inflammation in Men with a Negative Prostate Biopsy: Results from the REDUCE Trial
Authors: Allott Emma H. , Howard Lauren E. , Vidal Adriana C. , Moreira Daniel M. , Castro-Santamaria Ramiro , Andriole Gerald L. , Freedland Stephen J.
Published: March 2024

Abstract
Statin use is associated with lower advanced prostate cancer risk. In addition to cholesterol lowering, statins have systemic anti-inflammatory properties. However, their effect on histologic prostate inflammation is not well understood, particularly among men at increased prostate cancer risk but with a negative prostate biopsy. We examined associations between serum lipid levels, statin use, and histologic prostate inflammation using data from 6,655 men with a negative baseline prostate biopsy in the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial. Statin use and lipid levels [total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides] were assessed at baseline. Inflammation was assessed by central review. Logistic regression was used to examine the effects of lipids and statin use on presence and extent of chronic and acute prostate inflammation [none, moderate (<20%), severe (≥20% biopsy cores)]. Chronic and acute inflammation affected 77% and 15% of men, respectively. Men with high HDL (≥60 vs. <40 mg/dL) had reduced presence of acute inflammation [OR, 0.79; 95% confidence interval (CI), 0.63–0.99] and were less likely to have severe acute inflammation (OR, 0.66; 95% CI, 0.45–0.97), but there were no other associations between lipids and inflammation. Statin users had reduced presence of chronic inflammation (OR, 0.81; 95% CI, 0.69–0.95) and were less likely to have severe chronic (OR, 0.80; 95% CI, 0.68–0.95) and severe acute inflammation (OR, 0.73; 95% CI, 0.53–1.00), relative to non-users. Given the possible role for inflammation in prostate cancer, the inverse association between statins and prostate inflammation suggests a mechanism linking statins with lower advanced prostate cancer risk. Cancer Prev Res; 10(6); 319–26. ©2017 AACR.
Data from No Decreased Risk of Gastrointestinal Cancers in Users of Metformin in The Netherlands; A Time-Varying Analysis of Metformin Exposure
Authors: de Jong Roy G. , Burden Andrea M. , de Kort Sander , van Herk-Sukel Myrthe P. , Vissers Pauline A. , Janssen Paddy K. , Haak Harm R. , Masclee Ad A. , de Vries Frank , Janssen-Heijnen Maryska L.
Published: March 2024

Abstract
Previous studies on metformin use and gastrointestinal (GI) cancer risk have yielded inconclusive results on metformin's chemoprotective effects. We aimed to evaluate GI cancer risk in users of metformin in The Netherlands using a time-varying approach in a large population-based database. A cohort study was performed using the NCR-PHARMO database. Patients using ≥1 non-insulin antidiabetic drug (NIAD) during 1998 to 2011 were included (N = 57,621). Exposure to NIADs was modeled time-varyingly. Cox regression analysis estimated HRs of GI cancers in current metformin users versus current users of other NIADs. Covariables included age, sex, drugs known to impact cancer risk, history of hospitalization, and starting year of follow-up. A sensitivity analysis was performed, applying a new-user design. Current use of metformin was not associated with a decreased risk of GI cancer [HR, 0.97; 95% confidence interval (CI), 0.82–1.15] or specific GI cancer sites. The sensitivity analysis yielded comparable results. No decreasing trends were observed with increasing cumulative dose of metformin [HR 1.05, 95% CI, 0.85–1.28; HR 0.89, 95% CI, 0.73–1.10; HR 0.96, 95% CI, 0.77–1.19 for dose tertiles low (<405 g), medium (405–999 g), and high (≥999 g)]. In contrast, an increased risk of pancreatic cancer was found in current users of metformin plus insulin (HR, 4.90; 95% CI, 2.64–9.10). In conclusion, no decreased risk of GI cancer was found in current metformin users compared with current users of other NIADs. Variations in the exposure definition of metformin use may be one of the explanations of previously found reduced cancer risks in metformin users. Cancer Prev Res; 10(5); 290–7. ©2017 AACR.
Data from Inclusion of a Genetic Risk Score into a Validated Risk Prediction Model for Colorectal Cancer in Japanese Men Improves Performance
Authors: Iwasaki Motoki , Tanaka-Mizuno Sachiko , Kuchiba Aya , Yamaji Taiki , Sawada Norie , Goto Atsushi , Shimazu Taichi , Sasazuki Shizuka , Wang Hansong , Marchand Loïc Le , Tsugane Shoichiro
Published: March 2024

Abstract
We previously developed and validated a risk prediction model for colorectal cancer in Japanese men using modifiable risk factors. To further improve risk prediction, we evaluated the degree of improvement obtained by adding a genetic risk score (GRS) using genome-wide association study (GWAS)-identified risk variants to our validated model. We examined the association between 36 risk variants identified by GWAS and colorectal cancer risk using a weighted Cox proportional hazards model in a nested case–control study within the Japan Public Health Center-based Prospective Study. GRS was constructed using six variants associated with risk in this study of the 36 tested. We assessed three models: a nongenetic model that included the same variables used in our previously validated model; a genetic model that used GRS; and an inclusive model, which included both. The c-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were calculated by the 5-fold cross-validation method. We estimated 10-year absolute risks for developing colorectal cancer. A statistically significant association was observed between the weighted GRS and colorectal cancer risk. The mean c-statistic for the inclusive model (0.66) was slightly greater than that for the nongenetic model (0.60). Similarly, the mean IDI and NRI showed improvement when comparing the nongenetic and inclusive models. These models for colorectal cancer were well calibrated. The addition of GRS using GWAS-identified risk variants to our validated model for Japanese men improved the prediction of colorectal cancer risk. Cancer Prev Res; 10(9); 535–41. ©2017 AACR.
Data from Metformin Use and the Risk of Cancer in Patients with Diabetes: A Nationwide Sample Cohort Study
Authors: Oh Tak Kyu , Song In-Ae
Published: March 2024

Abstract
Metformin is known to have an antitumor effect; however, its effects in the prevention of cancer remain controversial. This study aimed to investigate the association of metformin therapy with the development of cancer. A population-based cohort study was conducted among adult patients with diabetes in 2010 using sample cohort data from the National Health Insurance Service. Metformin users were defined as those who had been prescribed repeated oral metformin administration over a period of ≥90 days. The primary endpoint of this study was the new development of cancer from January 1, 2011, to December 31, 2015. A total of 66,627 adult patients with diabetes were included in the final analysis; 29,974 were metformin users and 36,653 were controls. In the time-dependent Cox regression model, after multivariable adjustment, the risk for the development of cancer among metformin users was not significantly different from that among controls (HR = 0.96; 95% confidence interval, 0.89–1.03; P = 0.250). In the sensitivity analysis, neither low daily dosage (≤1 g/day, P = 0.301) nor high daily dosage (>1 g/day, P = 0.497) of metformin was significantly associated with the development of cancer between 2011 and 2015. We found no association between metformin therapy and the risk of cancer among patients with diabetes, even in the high daily dosage groups of metformin (>1 g/day). However, there might be residual confounders or bias; thus, further prospective, large population-based cohort studies are needed to confirm these findings.
Impact:
This population-based cohort study suggested a lack of association between metformin therapy and the risk of cancer among patients with diabetes. Therefore, the relationship between metformin therapy and the risk of cancer is still controversial.
Data from 5MeCDDO Blocks Metabolic Activation but not Progression of Breast, Intestine, and Tongue Cancers. Is Antioxidant Response Element a Prevention Target?
Authors: Lubet Ronald A. , Townsend Reid , Clapper Margie L. , Juliana M. Margaret , Steele Vernon E. , McCormick David L. , Grubbs Clinton J.
Published: March 2024

Abstract
The preventive efficacy of the triterpenoid 5MeCDDO was tested in two models of mammary cancer, the Min model of intestinal cancer, and a chemically induced model of head and neck cancer. In one model of mammary cancer, female Sprague-Dawley rats were administered MNU at 50 days of age, and 5MeCDDO (27 ppm) was administered in the diet beginning 5 days later for the duration of the study; 5MeCDDO was ineffective. In contrast, in a model examining initiation of mammary cancers by the procarcinogen dimethyl-benzanthracene, 5, 6-benzoflavone (500 ppm, an Ah receptor agonist) or 5MeCDDO (27 or 2.7 ppm) decreased tumor multiplicity by 90%, 80%, and 50%, respectively. This anti-initiating effect which is presumably mediated by altered metabolic activation parallels our observation that 5MeCDDO induced proteins of various antioxidant response element (ARE)-related phase II drug-metabolizing enzymes [e.g., GST Pi, AKR 7A3 (aflatoxicol), epoxide hydrolase, and quinone reductase] in the liver. 5MeCDDO tested in the 4-nitroquinoline-l-oxide (4-NQO) head and neck cancer model failed to decrease tumor incidence or invasiveness. In the Min mouse model of intestinal cancer, a high dose of 5MeCDDO (80 ppm) was weakly effective in reducing adenoma multiplicity [∼30% (P < 0.05)]; however, a lower dose was totally ineffective. These findings question whether measuring increased levels of certain ARE-related genes (e.g., quinone reductase, GST Pi), indicating decreased carcinogen activation are sufficient to imply general chemopreventive efficacy of a given agent or mixture. Cancer Prev Res; 9(7); 616–23. ©2016 AACR.
Data from A Randomized Multicenter Phase II Study of Docosahexaenoic Acid in Patients with a History of Breast Cancer, Premalignant Lesions, or Benign Breast Disease
Authors: Gucalp Ayca , Zhou Xi K. , Cook Elise D. , Garber Judy E. , Crew Katherine D. , Nangia Julie R. , Bhardwaj Priya , Giri Dilip D. , Elemento Olivier , Verma Akanksha , Wang Hanhan , Lee J. Jack , Vornik Lana A. , Mays Carrie , Weber Diane , Sepeda Valerie , O'Kane Holly , Krasne Margaret , Williams Samantha , Morris Patrick G. , Heckman-Stoddard Brandy M. , Dunn Barbara K. , Hudis Clifford A. , Brown Powel H. , Dannenberg Andrew J.
Published: March 2024

Abstract
Obesity, a cause of subclinical inflammation, is a risk factor for the development of postmenopausal breast cancer and is associated with poorer cancer outcomes. Docosahexaenoic acid (DHA), an omega-3 fatty acid, possesses anti-inflammatory properties. We hypothesized that treatment with DHA would reduce the expression of proinflammatory genes and aromatase, the rate-limiting enzyme for estrogen biosynthesis, in benign breast tissue of overweight/obese women. A randomized, placebo-controlled, double-blind phase II study of DHA given for 12 weeks to overweight/obese women with a history of stage I–III breast cancer, DCIS/LCIS, Paget's disease, or proliferative benign breast disease was carried out. In this placebo controlled trial, the primary objective was to determine whether DHA (1,000 mg by mouth twice daily) reduced breast tissue levels of TNFα. Secondary objectives included evaluation of the effect of DHA on breast tissue levels of COX-2, IL1β, aromatase, white adipose tissue inflammation, and gene expression by RNA-seq. Red blood cell fatty acid levels were measured to assess compliance. From July 2013 to November 2015, 64 participants were randomized and treated on trial (32 women per arm). Increased levels of omega-3 fatty acids in red blood cells were detected following treatment with DHA (P < 0.001) but not placebo. Treatment with DHA did not alter levels of TNFα (P = 0.71), or other biomarkers including the transcriptome in breast samples. Treatment with DHA was overall well-tolerated. Although compliance was confirmed, we did not observe changes in the levels of prespecified biomarkers in the breast after treatment with DHA when compared with placebo. Cancer Prev Res; 11(4); 203–14. ©2018 AACR.

See related editorial by Fabian and Kimler, p. 187
Data from Proof of Concept of a Personalized Genetic Risk Tool to Promote Smoking Cessation: High Acceptability and Reduced Cigarette Smoking
Authors: Ramsey Alex T. , Bourdon Jessica L. , Bray Michael , Dorsey Amelia , Zalik Maia , Pietka Amanda , Salyer Patricia , Chen Li-Shiun , Baker Timothy B. , Munafò Marcus R. , Bierut Laura J.
Published: March 2024

Abstract
Relatively little is known about the possible effects of personalized genetic risk information on smoking, the leading preventable cause of morbidity and mortality. We examined the acceptability and potential behavior change associated with a personalized genetically informed risk tool (RiskProfile) among current smokers. Current smokers (n = 108) were enrolled in a pre-post study with three visits. At visit 1, participants completed a baseline assessment and genetic testing via 23andMe. Participants’ raw genetic data (CHRNA5 variants) and smoking heaviness were used to create a tailored RiskProfile tool that communicated personalized risks of smoking-related diseases and evidence-based recommendations to promote cessation. Participants received their personalized RiskProfile intervention at visit 2, approximately 6 weeks later. Visit 3 involved a telephone-based follow-up assessment 30 days after intervention. Of enrolled participants, 83% were retained across the three visits. Immediately following intervention, acceptability of RiskProfile was high (M = 4.4; SD = 0.6 on scale of 1 to 5); at 30-day follow-up, 89% of participants demonstrated accurate recall of key intervention messages. In the full analysis set of this single-arm trial, cigarettes smoked per day decreased from intervention to 30-day follow-up [11.3 vs. 9.8; difference = 1.5; 95% confidence interval (0.6–2.4); P = 0.001]. A personalized genetically informed risk tool was found to be highly acceptable and associated with a reduction in smoking, although the absence of a control group must be addressed in future research. This study demonstrates proof of concept for translating key basic science findings into a genetically informed risk tool that was used to promote progress toward smoking cessation.

Prevention Relevance: This study demonstrates that personal genetic information can be incorporated into a risk feedback tool that was highly acceptable to current smokers and associated with reductions in smoking. These findings may pave the way for effectiveness and implementation research on genetically-informed behavior change interventions to enhance cancer prevention efforts.
Data from Methylation and Expression of Nonclustered Protocadherins Encoding Genes and Risk of Precancerous Gastric Lesions in a High-Risk Population
Authors: Wu Si , Zhang Yang , Zhang Lian , Ma Jun-Ling , Zhou Tong , Li Zhe-Xuan , Liu Wei-Dong , Li Wen-Qing , You Wei-Cheng , Pan Kai-Feng
Published: March 2024

Abstract
Nonclustered protocadherins (PCDH) family is a group of cell–cell adhesion molecules. We have found differentially methylated genes in the nonclustered PCDHs family associated with Helicobacter pylori (H. pylori) infection in prior genome-wide methylation analysis. To further investigate the methylation and expression of nonclustered PCDHs encoding genes in H. pylori--related gastric carcinogenesis process, four candidate genes including PCDH7, PCDH10, PCDH17, and PCDH20 were selected, which were reported to be tumor suppressors for digestive cancers. A total of 747 participants with a spectrum of gastric lesions were enrolled from a high-risk population of gastric cancer. Promoter methylation levels of four genes were significantly higher in H. pylori–positive subjects than the negative group (all P < 0.001). Elevated methylation levels of PCDH10 and PCDH17 were observed with the increasing severity of gastric lesions (both Ptrend < 0.001). In the protein expression analysis, PCDH17 expression was inversely associated with gastric lesions; the OR [95% confidence interval (CI)] was 0.49 (0.26–0.95) for chronic atrophic gastritis (CAG), 0.31 (0.15–0.63) for intestinal metaplasia, and 0.38 (0.19–0.75) for indefinite dysplasia and dysplasia, compared with superficial gastritis. In addition, PCDH10 expression was significantly lower in CAG (OR, 0.40; 95% CI, 0.24–0.68). The inverse association between methylation and protein expression of PCDH10 and PCDH17 was further supported when we explored the methylation and mRNA expression in The Cancer Genome Atlas database (all P < 0.001). Our study found elevated promoter methylation and decreased expression of PCDH10 and PCDH17 in advanced gastric lesions, suggesting that elevated PCDH10 and PCDH17 methylation may be an early event in gastric carcinogenesis. Cancer Prev Res; 11(11); 717–26. ©2018 AACR.
Data from Benefits of Multifaceted Chemopreventives in the Suppression of the Oral Squamous Cell Carcinoma (OSCC) Tumorigenic Phenotype
Authors: Mallery Susan R. , Wang Daren , Santiago Brian , Pei Ping , Schwendeman Steven P. , Nieto Kari , Spinney Richard , Tong Meng , Koutras George , Han Brian , Holpuch Andrew , Lang James
Published: March 2024

Abstract
Over one third of patients who have undergone oral squamous cell carcinoma (OSCC) surgical resections develop life-threatening and often untreatable recurrences. A variety of drugs, intended for management of recurrent or disseminated cancers, were designed to exploit cancer cells' reliance upon overexpressed receptors and gratuitous signaling. Despite their conceptual promise, clinical trials showed these agents lacked efficacy and were often toxic. These findings are consistent with evasion of pathway-targeted treatments via extensive signaling redundancies and compensatory mechanisms common to cancers. Optimal secondary OSCC chemoprevention requires long-term efficacy with multifaceted, nontoxic agents. Accordingly, this study evaluated the abilities of three complementary chemopreventives, that is, the vitamin A derivative fenretinide (4-HPR, induces apoptosis and differentiation, inhibits signaling proteins, and invasion), the estrogen metabolite 2-methoxyestradiol (2-ME, apoptosis-inducing, antiangiogenic), and the humanized mAb to the IL6R receptor tocilizumab (TOC, reduces IL6 signaling) to suppress OSCC gratuitous signaling and tumorigenesis. Modeling studies demonstrated 4-HPR's high-affinity binding at STAT3′s dimerization site and c-Abl and c-Src ATP-binding kinase sites. Although individual agents suppressed cancer-promoting pathways including STAT3 phosphorylation, STAT3-DNA binding, and production of the trans-signaling enabling sIL6R, maximal chemopreventive effects were observed with agent combinations. OSCC tumor xenograft studies showed that locally delivered TOC, TOC+4-HPR, and TOC+4-HPR+2-ME treatments all prevented significant tumor growth. Notably, the TOC+4-HPR+2-ME treatment resulted in the smallest overall increase in tumor volume. The selected agents use diverse mechanisms to disrupt tumorigenesis at multiple venues, that is, intracellular, tumor cell-ECM, and tumor microenvironment; beneficial qualities for secondary chemopreventives. Cancer Prev Res; 10(1); 76–88. ©2016 AACR.
Data from Characteristics of Breast Ducts in Normal-Risk and High-risk Women and Their Relationship to Ductal Cytologic Atypia
Authors: Danforth David N. , Filie Armando C. , Warner Andrew C. , Wright George W. , Sun Zhonghe , Ried Thomas , McGowan Christine T. , Prindiville Sheila A.
Published: March 2024

Abstract
Breast ductal cytologic atypia is an important risk factor for sporadic breast cancer. Characterization of the associated normal breast tissue is needed to develop additional methods of risk assessment and new targets for breast cancer prevention. We conducted a prospective clinical trial evaluating women at normal-risk or at high-risk for sporadic breast cancer. Breast ductal cells were collected and studied cytologically and by gene expression profiling, and breast ductal architectural changes were studied by breast ductal endoscopy (BDE) and breast MRI. One hundred and forty subjects were studied, 70 at high risk (RR, 2.0–4.6) and 70 at normal risk. Cytologic atypia was present in 22.9% of high-risk and 25.7% of normal-risk subjects. Ductal endoscopy was performed in 89 subjects and revealed benign intraductal abnormalities, primarily intraductal fibrous webbing suggesting chronic inflammation, in 40.4% of high-risk and 5.4% of normal-risk subjects, respectively (P2 = 0.0002). Two high-risk subjects with atypia and no normal-risk subjects with atypia developed invasive breast cancer. Gene expression profiling of ductal cells showed comparable gene expression profiles without enriched expression of previously defined oncogenic signatures in subjects with cellular atypia compared with those without atypia, and in high-risk subjects compared with normal-risk subjects (FDR > 0.5). Cytologic ductal atypia in normal-risk subjects does not appear to be of clinical significance. Atypia in women at high risk may be associated with benign and malignant breast ductal abnormalities; these characteristics of high-risk ductal cells may not be reflected in gene expression profiles.
Data from Targeting the Cholecystokinin Receptor: A Novel Approach for Treatment and Prevention of Hepatocellular Cancer
Authors: Gay Martha D. , Safronenka Anita , Cao Hong , Liu Felice H. , Malchiodi Zoe X. , Tucker Robin D. , Kroemer Alexander , Shivapurkar Narayan , Smith Jill P.
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC) is the fastest growing cancer worldwide in part due to the obesity epidemic and fatty liver disease, particularly nonalcoholic steatohepatitis (NASH). Chronic inflammation with the release of cytokines and chemokines with activation of hepatic stellate cells results in changes of the liver extracellular matrix (ECM) that predisposes to the development of HCC. Blood levels of the gastrointestinal peptide cholecystokinin (CCK) are increased in humans and mice consuming a high-fat diet. We found that the CCK-B receptor (CCK-BR) expression increased in the livers of mice with NASH. Treatment of mice with a CCK-BR antagonist, proglumide, prevented NASH, lowered hepatic inflammatory cytokines and chemokines, reduced oxidative stress, decreased F4/80+ hepatic macrophages, and prevented HCC. CCK-AR and CCK-BR expression was increased in both murine and human HCC cell lines compared with that of normal liver, and CCK stimulated the growth of wild-type and CCK-A receptor knockout HCC cells in vitro, but not CCK-BR knockout cells suggesting that the CCK-BR mediates proliferation. Proglumide therapy significantly reduced growth by 70% and 73% in mice bearing Dt81Hepa1–6 or in RIL-75 HCC tumors, respectively. IHC of a human liver tissue array with a selective CCK-BR antibody revealed staining of human HCC and no staining in normal liver.
Prevention Relevance:
This investigation demonstrates the role of the gastrointestinal peptide cholecystokinin (CCK) in hepatocellular carcinoma (HCC) and how CCK-BR blockade reverses the premalignant state of the hepatic extracellular matrix hence, rendering it less susceptible to the development of HCC. Thereby, CCK-BR blockade is a novel approach for the prevention/treatment of HCC.
Data from BRIP1, a Gene Potentially Implicated in Familial Colorectal Cancer Type X
Authors: Martín-Morales Lorena , Garre Pilar , Lorca Víctor , Cazorla Marta , Llovet Patricia , Bando Inmaculada , García-Barberan Vanesa , González-Morales María Luisa , Esteban-Jurado Clara , de la Hoya Miguel , Castellví-Bel Sergi , Caldés Trinidad
Published: March 2024

Abstract
Familial colorectal cancer Type X (FCCTX) comprises a heterogeneous group of families with an increased risk of developing colorectal cancer and other related tumors, but with mismatch repair–proficient, microsatellite-stable (MSS) tumors. Unfortunately, the genetic basis underlying their cancer predisposition remains unknown. Although pathogenic germline variants in BRIP1 increase the risk of developing hereditary ovarian cancer, the involvement of BRIP1 in hereditary colorectal cancer is still not well known. In order to identify new BRIP1 variants associated with inherited colorectal cancer, affected and nonaffected individuals from 18 FCCTX or high-risk MSS colorectal cancer families were evaluated by whole-exome sequencing, and another 62 colorectal cancer patients from FCCTX or high-risk MSS colorectal cancer families were screened by a next-generation sequencing (NGS) multigene panel. The families were recruited at the Genetic Counseling Unit of Hospital Clínico San Carlos of Madrid. A total of three different BRIP1 mutations in three unrelated families were identified. Among them, there were two frameshift variants [c.1702_1703del, p.(Asn568TrpfsTer9) and c.903del, p.(Leu301PhefsTer2)] that result in the truncation of the protein and are thus classified as pathogenic (class 5). The remaining was a missense variant [c.2220G>T, p.(Gln740His)] considered a variant of uncertain significance (class 3). The segregation and loss-of-heterozygosity studies provide evidence linking the two BRIP1 frameshift variants to colorectal cancer risk, with suggestive but not definitive evidence that the third variant may be benign. The results here presented suggest that germline BRIP1 pathogenic variants could be associated with hereditary colorectal cancer predisposition.

Prevention Relevance: We suggest that BRIP1 pathogenic germline variants may have a causal role in CRC as moderate cancer susceptibility alleles and be associated with hereditary CRC predisposition. A better understanding of hereditary CRC may provide important clues to disease predisposition and could contribute to molecular diagnostics, improved risk stratification, and targeted therapeutic strategies.
Data from Plasma Metabolomics Analysis of Aspirin Treatment and Risk of Colorectal Adenomas
Authors: Barry Elizabeth L. , Fedirko Veronika , Jin Yutong , Liu Ken , Mott Leila A. , Peacock Janet L. , Passarelli Michael N. , Baron John A. , Jones Dean P.
Published: March 2024

Abstract
Despite substantial observational and experimental evidence that aspirin use can provide protection against the development of colorectal neoplasia, our understanding of the molecular mechanisms involved is inadequate and limits our ability to use this drug effectively and safely for chemoprevention. We employed an untargeted plasma metabolomics approach using liquid chromatography with high-resolution mass spectroscopy to explore novel metabolites that may contribute to the chemopreventive effects of aspirin. Associations between levels of metabolic features in plasma and aspirin treatment were investigated among 523 participants in a randomized placebo-controlled clinical trial of two doses of aspirin (81 or 325 mg/day) and were linked to risk of colorectal adenoma occurrence over 3 years of follow-up. Metabolic pathways that were altered with aspirin treatment included linoleate and glycerophospholipid metabolism for the 81-mg dose and carnitine shuttle for both doses. Metabolites whose levels increased with 81 mg/day aspirin treatment and were also associated with decreased risk of adenomas during follow-up included certain forms of lysophosphatidylcholine and lysophosphatidylethanolamine as well as trihydroxyoctadecenoic acid, which is a derivative of linoleic acid and is upstream of cyclooxygenase inhibition by aspirin in the linoleate and arachidonic acid metabolism pathways. In conclusion, our findings regarding lysophospholipids and metabolites in the linoleate metabolism pathway may provide novel insights into the chemopreventive effects of aspirin in the colorectum, although they should be considered hypothesis-generating at this time.
Prevention Relevance:
This research used metabolomics, an innovative discovery-based approach, to identify molecular changes in human blood that may help to explain how aspirin use reduces the risk of colorectal neoplasia in some individuals. Ultimately, this work could have important implications for optimizing aspirin use in the prevention of colorectal cancer.
Data from Dietary Pterostilbene for MTA1-Targeted Interception in High-Risk Premalignant Prostate Cancer
Authors: Hemani Rutu , Patel Ishani , Inamdar Ninad , Campanelli Gisella , Donovan Virginia , Kumar Avinash , Levenson Anait S.
Published: March 2024

Abstract
Prostate cancer remains one of the most prevalent cancers in aging men. Active surveillance subpopulation of patients with prostate cancer includes men with varying cancer risk categories of precancerous disease due to prostatic intraepithelial neoplasia (PIN) heterogeneity. Identifying molecular alterations associated with PIN can provide preventable measures through finding novel pharmacologic targets for cancer interception. Targeted nutritional interception may prove to be the most appropriate chemoprevention for intermediate- and high-risk active surveillance patients. Here, we have generated two prostate-specific transgenic mouse models, one overexpressing MTA1 (R26MTA1) and the other overexpressing MTA1 on the background of Pten heterozygosity (R26MTA1; Pten+/f), in which we examined the potential chemopreventive efficacy of dietary pterostilbene. We show that MTA1 promotes neoplastic transformation of prostate epithelial cells by activating cell proliferation and survival, leading to PIN development. Moreover, MTA1 cooperates with PTEN deficiency to accelerate PIN development by increasing cell proliferation and MTA1-associated signaling. Further, we show that mice fed with a pterostilbene-supplemented diet exhibited more favorable histopathology with decreased severity and number of PIN foci accompanied by reduced proliferation, angiogenesis, and inflammation concomitant to reduction in MTA1 and MTA1-associated CyclinD1, Notch2, and oncogenic miR-34a and miR-22 levels.
Prevention Relevance:
Developing novel interceptive strategies for prostate cancer chemoprevention is a paramount goal in clinical oncology. We offer preclinical evidence for the potential of pterostilbene as a promising natural agent for MTA1-targeted interceptive strategy in future cancer prevention trials towards protecting select patients with prostate cancer under active surveillance from developing cancer.
Data from Combined Performance of Fecal Immunochemical Tests and a Genetic Risk Score for Advanced Neoplasia Detection
Authors: Niedermaier Tobias , Guo Feng , Weigl Korbinian , Hoffmeister Michael , Brenner Hermann
Published: March 2024

Abstract
Fecal immunochemical tests (FITs) are increasingly used as noninvasive screening tests in colorectal cancer–screening programs. Polygenic risk scores (PRS) are increasingly propagated for risk stratification in colorectal cancer screening. We aimed to assess the potential of combining FIT results and PRS to enhance diagnostic accuracy of detecting advanced neoplasia (AN) compared with using FIT results alone. Of 10,362 participants of screening colonoscopy in Southern Germany who conducted either one of two quantitative FITs, genotyping was done in all participants with AN (colorectal cancer or advanced adenoma) and a random subset of controls. Among 5,306 individuals, a PRS was calculated on the basis of the number of risk alleles in 140 SNPs. Partial areas under the receiver operating characteristics (ROC) curves (pAUCs) were computed for FIT and PRS alone and combined, focusing on a specificity range of 100%–80%. Both FITs showed similar performance characteristics with pAUCs of 0.661 (95% confidence interval (CI), 0.625–0.698; Ridascreen Hemoglobin) and 0.682 (95% CI, 0.661–0.701; FOB Gold) for AN detection. PRS alone reached a pAUC of 0.524 (95% CI, 0.499–0.550) and 0.530 (95% CI, 0.516–0.545), respectively, and its addition to FIT did not improve pAUCs (0.659; 95% CI, 0.622–0.697) and 0.667 (95% CI, 0.650–0.687), respectively. This finding was confirmed by investigating sensitivities at fixed specificities at 85%, 90%, and 95%. Partial AUCs also did not improve when adding the weighted PRS to FIT instead of the unweighted PRS. In summary, the combination with PRS did not improve diagnostic accuracy of FIT-based screening in a large asymptomatic colorectal cancer screening population from South-Western Germany.
Prevention Relevance:
In our study, combining polygenic risk score with fecal immunochemical test (FIT) did not improve diagnostic accuracy for advanced colorectal neoplasia detection compared with FIT alone. So far, such a combination cannot be recommended because it would come at extra costs and effort despite no relevant gain in neoplasia detection.
Data from Hyperglycemia, Classified with Multiple Biomarkers Simultaneously in Men without Diabetes, and Risk of Fatal Prostate Cancer
Authors: Marrone Michael T. , Selvin Elizabeth , Barber John R. , Platz Elizabeth A. , Joshu Corinne E.
Published: March 2024

Abstract
The association between hyperglycemia and prostate cancer risk is inconsistent, and its association with prostate cancer mortality is understudied. Thus, we investigated the association between hyperglycemia and prostate cancer risk and mortality using multiple biomarkers simultaneously to classify hyper- and normoglycemia. We conducted a prospective analysis of 5,162 cancer-free men attending visit 2 (1990–1992) of the Atherosclerosis Risk in Communities (ARIC) study followed for total (N = 671) and lethal (N = 69) prostate cancer incidence and prostate cancer mortality (N = 64) through 2012. Men without diagnosed diabetes were classified as normo- or hyperglycemic using joint categories of fasting glucose, glycated hemoglobin, and glycated albumin (or fructosamine) defined by clinical or research cutpoints. We evaluated the multivariable-adjusted association of hyperglycemia with prostate cancer incidence and mortality using Cox proportional hazards regression; men with diagnosed diabetes were included as a separate exposure category. Among 4,753 men without diagnosed diabetes, 61.5% were classified as having hyperglycemia (high on ≥1 biomarker). HbA1c and glycated albumin together classified 61.9% of 1,736 men with normal fasting glucose as normoglycemic. Compared with men who were normal on all three biomarkers, men who were high on ≥1 biomarker had an increased risk of lethal [HR, 2.50; 95% confidence interval (CI), 1.12–5.58] and fatal (HR, 3.20; 95% CI, 1.26–8.48) disease, but not total prostate cancer incidence (HR, 0.98; 95% CI, 0.81–1.20); associations were similar including fructosamine instead of glycated albumin. Our findings indicate hyperglycemia is associated with an increased risk of lethal and fatal prostate cancer, but not total prostate cancer incidence.
Data from Oral Health and Risk of Upper Gastrointestinal Cancers in a Large Prospective Study from a High-risk Region: Golestan Cohort Study
Authors: Yano Yukiko , Abnet Christian C. , Poustchi Hossein , Roshandel Gholamreza , Pourshams Akram , Islami Farhad , Khoshnia Masoud , Amiriani Taghi , Norouzi Alireza , Kamangar Farin , Boffetta Paolo , Brennan Paul , Dawsey Sanford M. , Vogtmann Emily , Malekzadeh Reza , Etemadi Arash
Published: March 2024

Abstract
Tooth loss and periodontal disease have been associated with several cancers, and poor oral health may be an important risk factor for upper gastrointestinal (UGI, i.e., esophageal and gastric) cancers. We assessed the relationship between oral health and UGI cancers using a large prospective study of over 50,000 adults living in Golestan Province, Iran, a high-incidence area for these cancers. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated for the association between three different measures of oral health [frequency of tooth brushing; number of missing teeth; and the sum of decayed, missing, and filled teeth (DMFT)] and UGI cancers. During a median follow-up duration of 13 years, there were 794 incident UGI cancers (396 esophageal and 398 gastric cancers). Daily tooth brushing was associated with a decreased risk of developing both esophageal (HR = 0.670; 95% CI: 0.486–0.924) and gastric (HR = 0.741; 95% CI: 0.544–1.01) cancers (combined UGI cancer HR = 0.697; 95% CI: 0.558–0.871) compared with never brushing. Tooth loss in excess of the loess smoothed, age- and sex-specific median number of teeth lost was significantly associated with esophageal (HR = 1.64; 95% CI: 1.08–2.47) and gastric cancers (HR = 1.58; 95% CI: 1.05–2.38). There were some adverse associations between DMFT and UGI cancers but most were not statistically significant. These results suggest increased risk of developing UGI cancers among individuals with poor oral health, and those who do not perform regular oral hygiene.
Prevention Relevance:
Poor oral health is associated with the risk of upper gastrointestinal cancers, and oral hygiene practices may help prevent these cancers.
Data from Lipidomic Profiles of Plasma Exosomes Identify Candidate Biomarkers for Early Detection of Hepatocellular Carcinoma in Patients with Cirrhosis
Authors: Sanchez Jessica I. , Jiao Jingjing , Kwan Suet-Ying , Veillon Lucas , Warmoes Marc O. , Tan Lin , Odewole Mobolaji , Rich Nicole E. , Wei Peng , Lorenzi Philip L. , Singal Amit G. , Beretta Laura
Published: March 2024

Abstract
Novel biomarkers for HCC surveillance in cirrhotic patients are urgently needed. Exosomes and their lipid content in particular represent potentially valuable noninvasive diagnostic biomarkers. We isolated exosomes from plasma of 72 cirrhotic patients, including 31 with HCC. Exosomes and unfractionated plasma were processed for untargeted lipidomics using ultra–high-resolution mass spectrometry. A total of 2,864 lipid species, belonging to 52 classes, were identified. Both exosome fractionation and HCC diagnosis had significant impact on the lipid profiles. Ten lipid classes were enriched in HCC exosomes compared with non-HCC exosomes. Dilysocardiolipins were detected in 35% of the HCC exosomes but in none of the non-HCC exosomes (P < 0.001). Cardiolipins and sphingosines had the highest differential effects (fold change of 133.08, q = 0.001 and 38.57, q < 0.001, respectively). In logistic regression analysis, high abundances of exosomal sphingosines, dilysocardiolipins, lysophosphatidylserines, and (O-acyl)-1-hydroxy fatty acids were strongly associated with HCC [OR (95% confidence interval (CI)), 271.1 (14.0–5,251.9), P < 0.001; 46.5 (2.3–939.9), P = 0.012; 14.9 (4.3–51.2), P < 0.001; 10.3 (3.2–33.1), P < 0.001]. Four lipid classes were depleted in HCC exosomes compared with non-HCC exosomes. In logistic regression analysis, lack of detection of sulfatides and acylGlcSitosterol esters was strongly associated with HCC [OR (95% CI): 215.5 (11.5–4,035.9), P < 0.001; 26.7 (1.4–528.4), P = 0.031]. These HCC-associated changes in lipid composition of exosomes reflected alterations in glycerophospholipid metabolism, retrograde endocannabinoid signaling, and ferroptosis. In conclusion, this study identified candidate biomarkers for early detection of HCC as well as altered pathways in exosomes that may contribute to tumor development and progression.
Prevention Relevance:
This study identifies lipids in circulating exosomes, that could serve as biomarkers for the early detection of hepatocellular carcinoma as well as altered pathways in exosomes that may contribute to tumor development and progression.
Data from THBS2/CA19-9 Detecting Pancreatic Ductal Adenocarcinoma at Diagnosis Underperforms in Prediagnostic Detection: Implications for Biomarker Advancement
Authors: Udgata Shirsa , Takenaka Naomi , Bamlet William R. , Oberg Ann L. , Yee Stephanie S. , Carpenter Erica L. , Herman Daniel , Kim Jungsun , Petersen Gloria M. , Zaret Kenneth S.
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed too late for effective therapy. The classic strategy for early detection biomarker advancement consists of initial retrospective phases of discovery and validation with tissue samples taken from individuals diagnosed with disease, compared with controls. Using this approach, we previously reported the discovery of a blood biomarker panel consisting of thrombospondin-2 (THBS2) and CA19-9 that together could discriminate resectable stage I and IIa PDAC as well as stages III and IV PDAC, with c-statistic values in the range of 0.96 to 0.97 in two phase II studies. We now report that in two studies of blood samples prospectively collected from 1 to 15 years prior to a PDAC diagnosis (Mayo Clinic and PLCO cohorts), THBS2 and/or CA19-9 failed to discriminate cases from healthy controls at the AUC = 0.8 needed. We conclude that PDAC progression may be heterogeneous and for some individuals can be more rapid than generally appreciated. It is important that PDAC early-detection studies incorporate high-risk, prospective prediagnostic cohorts into discovery and validation studies.

Prevention Relevance: A blood biomarker panel of THBS2 and CA19-9 detects early stages of pancreatic ductal adenocarcinoma at diagnosis, but not when tested across a population up to 1 year earlier. Our findings suggest serial sampling over time, using prospectively collected samples for biomarker discovery, and more frequent screening of high-risk individuals.
Data from Distinct Chemopreventive Effects of Aspirin in Diffuse and Intestinal-Type Gastric Cancer
Authors: Niikura Ryota , Hayakawa Yoku , Hirata Yoshihiro , Konishi Mitsuru , Suzuki Nobumi , Ihara Sozaburo , Yamada Atsuo , Ushiku Tetsuo , Fujishiro Mitsuhiro , Fukayama Masashi , Koike Kazuhiko
Published: March 2024

Abstract
Introduction: Although aspirin/NSAIDs may have potential preventive effects on several cancers, it remains unclear on gastric cancer. The purpose of this study is to compare the risk of developing gastric cancer and the histologic changes of intestinal metaplasia and neutrophil infiltration, between aspirin/NSAID users and nonusers.

Methods: Using an electronic endoscopy database in two hospitals from 1996 to 2017, we analyzed the data from patients with chronic gastritis who received aspirin or NSAIDs prior to upper gastrointestinal endoscopy. One-to-one propensity score matching was performed to compare the proportion of gastric cancer, intestinal metaplasia, and neutrophil infiltration between these drug users and nonusers.

Results: We analyzed 2,082 aspirin users and 2,082 nonusers as well as 898 NSAID users and 898 nonusers. Six diffuse-type and 19 intestinal-type gastric cancer, 1,243 intestinal metaplasia, and 1,503 neutrophil infiltration patients were identified. The proportion of diffuse-type gastric cancer (0.05%) was 80% lower in aspirin users compared with the nonusers (0.24%), and there was no case of diffuse-type cancer in patients who took aspirin for more than 2 years. In contrast, intestinal-type gastric cancer incidence was significantly higher in aspirin users (0.72%) compared with nonusers (0.14%). No significant differences in the incidence of gastric cancer were found between NSAID use and nonusers. NSAID use was significantly associated with decreased proportion of neutrophil infiltration compared with nonusers.

Conclusion: Aspirin may have distinct effects between intestinal-type and diffuse-type gastric cancer development. Cancer Prev Res; 11(5); 279–86. ©2018 AACR.
Data from Detection and Genotyping of HPV DNA in a Group of Unvaccinated Young Women from Colombia: Baseline Measures Prior to Future Monitoring Program
Authors: Puerto Devi , Reyes Viviana , Lozano Cristina , Buitrago Lina , Garcia Diego , Murillo Raúl H. , Muñoz Nubia , Hernandez Gustavo A. , Sanchez Laura , Wiesner Carolina , Combita Alba L.
Published: March 2024

Abstract
In 2012, Colombia launched human papillomavirus (HPV) vaccination program for girls ages 9 to 12, and in 2013, the target age was expanded to 9 to 17 years. Monitoring the changes of HPV infection prevalence among young women has been proposed as an endpoint for early assessment of HPV vaccination programs. However, the data on HPV prevalence in young ages are very limited. The purpose of this study was to determine the prevalence of HPV infection and the distribution of genotypes in a group of nonvaccinated women ages 18 to 25 years old in three Colombian cities as baseline for the monitoring of the HPV national vaccination program. A total of 1,782 sexually active women were included. Cervical smear samples were collected to perform the Pap smear and HPV DNA detection using a Linear Array HPV assay. Of the 1,782 specimens analyzed, 60.3% were positive for any HPV type; 42.2% were positive for high-risk HPV (HR-HVP) types, and 44.4% for low-risk HPV (LR-HPV) types. Multiple and single infections were identified in 37.1% and 23.2% of samples, respectively. HR-HPV types -16, -52, and -51 were the most predominant with proportions of 11.3%, 7.92%, and 7.9%, correspondingly. The prevalence for HR-HPV 16/18 was 14.4%. HR-HPV prevalence in women with abnormal cytology (75.16%) was higher than in women with normal cytology (38.6%). In conclusion, a high prevalence of HR-HPV was observed among younger women. This HPV type-specific prevalence baseline may be used to monitor postvaccination longitudinal changes and to determine its impact on HPV-related disease incidence in Colombia population. Cancer Prev Res; 11(9); 581–92. ©2018 AACR.