Obesity and diabetes are potentially alterable risk factors for pancreatic cancer. Genetic factors that modify the associations of obesity and diabetes with pancreatic cancer have previously not been examined at the genome-wide level.Using genome-wide association studies (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study of 2,028 cases and 2,109 controls to examine gene-obesity and gene-diabetes interactions in relation to pancreatic cancer risk by using the likelihood-ratio test nested in logistic regression models and Ingenuity Pathway Analysis (IPA).After adjusting for multiple comparisons, a significant interaction of the chemokine signaling pathway with obesity (P = 3.29 × 10(-6)) and a near significant interaction of calcium signaling pathway with diabetes (P = 1.57 × 10(-4)) in modifying the risk of pancreatic cancer were observed. These findings were supported by results from IPA analysis of the top genes with nominal interactions. The major contributing genes to the two top pathways include GNGT2, RELA, TIAM1, and GNAS. None of the individual genes or single-nucleotide polymorphism (SNP) except one SNP remained significant after adjusting for multiple testing. Notably, SNP rs10818684 of the PTGS1 gene showed an interaction with diabetes (P = 7.91 × 10(-7)) at a false discovery rate of 6%.Genetic variations in inflammatory response and insulin resistance may affect the risk of obesity- and diabetes-related pancreatic cancer. These observations should be replicated in additional large datasets.A gene-environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer.

Genome-wide Association Study

SNP

Genetic Association

10.1158/1055-9965.epi-13-0437-t

Cite

Citations (34)

The Persistence of HIV Diversity, Transcription, and Nef Protein in Kaposi’s Sarcoma Tumors during Antiretroviral Therapy

Viruses (2022)

David J. Nolan Rebecca Rose Rongzhen Zhang Alan Leong Gary B. Fogel

Epidemic Kaposi’s sarcoma (KS), defined by co-infection with Human Herpes Virus 8 (HHV-8) and the Human Immunodeficiency Virus (HIV), is a major cause of mortality in sub-Saharan Africa. Antiretroviral therapy (ART) significantly reduces the risk of developing KS, and for those with KS, tumors frequently resolve with ART alone. However, for unknown reasons, a significant number of KS cases do not resolve and can progress to death. To explore how HIV responds to ART in the KS tumor microenvironment, we sequenced HIV env-nef found in DNA and RNA isolated from plasma, peripheral blood mononuclear cells, and tumor biopsies, before and after ART, in four Ugandan study participants who had unresponsive or progressive KS after 180–250 days of ART. We performed immunohistochemistry experiments to detect viral proteins in matched formalin-fixed tumor biopsies. Our sequencing results showed that HIV diversity and RNA expression in KS tumors are maintained after ART, despite undetectable plasma viral loads. The presence of spliced HIV transcripts in KS tumors after ART was consistent with a transcriptionally active viral reservoir. Immunohistochemistry staining found colocalization of HIV Nef protein and tissue-resident macrophages in the KS tumors. Overall, our results demonstrated that even after ART reduced plasma HIV viral load to undetectable levels and restored immune function, HIV in KS tumors continues to be transcriptionally and translationally active, which could influence tumor maintenance and progression.

Kaposi's sarcoma

10.3390/v14122774

Cite

Citations (3)

Data from Circulating Levels of the Innate and Humoral Immune Regulators CD14 and CD23 Are Associated with Adult Glioma

Mi Zhou Joseph L. Wiemels Paige M. Bracci Margaret Wrensch Lucie McCoy

<div>AbstractAllergy history has been consistently inversely associated with glioma risk. Two serologic markers, soluble CD23 (sCD23) and soluble CD14 (sCD14), are part of the innate and adaptive humoral immune systems and modulate allergic responses in opposite directions, with sCD23 enhancing and sCD14 blunting inflammatory responses. We measured sCD23 and sCD14 in serum from blood that was drawn at a single time point from 1,079 glioma patients postdiagnosis and 736 healthy controls. Glioma was strongly associated with high sCD14 [highest versus lowest quartile odds ratio (OR), 3.94; 95% confidence interval (95% CI), 2.98–5.21] and low sCD23 (lowest versus highest quartile OR, 2.5; 95% CI, 1.89–3.23). Results were consistent across glioma histologic types and grades, but were strongest for glioblastoma. Whereas temozolomide treatment was not associated with either sCD14 or sCD23 levels among cases, those taking dexamethasone had somewhat lower sCD23 levels than those not taking dexamethasone. However, sCD23 was associated with case status regardless of dexamethasone treatment. These results augment the long-observed association between allergies and glioma and support a role for the innate and adaptive humoral functions of the immune system, in particular immunoregulatory proteins, in gliomagenesis. Cancer Res; 70(19); 7534–42. ©2010 AACR.</div>

Quartile

CD23

10.1158/0008-5472.c.6500900.v1

Cite

Citations (0)

Supplementary Tables 1-9 from Circulating Levels of the Innate and Humoral Immune Regulators CD14 and CD23 Are Associated with Adult Glioma

Mi Zhou Joseph L. Wiemels Paige M. Bracci Margaret Wrensch Lucie McCoy

Supplementary Tables 1-9 from Circulating Levels of the Innate and Humoral Immune Regulators CD14 and CD23 Are Associated with Adult Glioma

CD23

10.1158/0008-5472.22384433

Cite

Citations (0)

Family cancer history and risk of brain tumors in children: results of the SEARCH international brain tumor study

Cancer Causes & Control (2008)

Susan Searles Nielsen Beth A. Mueller Susan Preston‐Martin Elizabeth A. Holly Julian Little

Brain tumor

First-degree relatives

Childhood Cancer

10.1007/s10552-008-9128-7

Cite

Citations (16)

Supplementary table 8 from Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3

Evelina Mocci Prosenjit Kundu William Wheeler Alan A. Arslan Laura E. Beane Freeman

Supplemental Table 8. Enrichment in regulatory regions for rs842357 and related SNPs

Table (database)

10.1158/0008-5472.22430071

Cite

Citations (0)

Data from Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3

Evelina Mocci Prosenjit Kundu William Morton Wheeler Alan A. Arslan Laura E. Beane Freeman

<div>AbstractGermline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10–8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82–0.93; former smokers 1.00, 95% CI, 0.91–1.07; current smokers 1.25, 95% CI 1.12–1.40, Pinteraction = 3.08 × 10–9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.Significance:This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.</div>

Genome-wide Association Study

SNP

Linkage Disequilibrium

Genetic Association

10.1158/0008-5472.c.6513538.v1

Cite

Citations (0)

Signs and symptoms of pancreatic cancer: a population-based case-control study in the San Francisco Bay area

Clinical Gastroenterology and Hepatology (2004)

Elizabeth A. Holly Indranushi Chaliha Paige M. Bracci Manjushree Gautam

Bloating

10.1016/s1542-3565(04)00171-5