Showing papers by "Edward Giovannucci published in 2014"
TL;DR: Accumulating results from preclinical and some clinical studies strongly suggest that vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome.
Abstract: Vitamin D is not really a vitamin but the precursor to the potent steroid hormone calcitriol, which has widespread actions throughout the body. Calcitriol regulates numerous cellular pathways that could have a role in determining cancer risk and prognosis. Although epidemiological and early clinical trials are inconsistent, and randomized control trials in humans do not yet exist to conclusively support a beneficial role for vitamin D, accumulating results from preclinical and some clinical studies strongly suggest that vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome.
995 citations
TL;DR: It is suggested that increased whole-body protein breakdown is an early event in development of PDAC, and elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis.
Abstract: Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.
469 citations
Ali Amin Al Olama1, Zsofia Kote-Jarai, Sonja I. Berndt2, David V. Conti3 +176 more•Institutions (53)
TL;DR: These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.
Abstract: Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.
404 citations
Harvard University1, German Cancer Research Center2, Fred Hutchinson Cancer Research Center3, Mayo Clinic4, National Institutes of Health5, New York University6, University of California, San Francisco7, University of Toronto8, Monash University9, American Cancer Society10, Group Health Cooperative11, Johns Hopkins University12, University of Hawaii at Manoa13, University of Texas MD Anderson Cancer Center14, Carlos III Health Institute15, Memorial Sloan Kettering Cancer Center16, Yale University17, University at Buffalo18, University of Washington19, Vanderbilt University20, Institut Gustave Roussy21, Westat22, Heidelberg University23, Utrecht University24, Sapienza University of Rome25, University of Liverpool26, University of Pisa27, Veterans Health Administration28, University of Minnesota29, University of Southern California30, Mercy Medical Center (Baltimore, Maryland)31, University of North Carolina at Chapel Hill32, International Agency for Research on Cancer33, University of Oxford34, University of Cambridge35, Cleveland Clinic36, Lithuanian University of Health Sciences37, National Institute for Health and Welfare38, University of Melbourne39, University of Tokyo40, Duke University41, Imperial College London42, University of Bologna43, Casa Sollievo della Sofferenza44, Autonomous University of Barcelona45, Pompeu Fabra University46, Umeå University47, Medical University of Łódź48, Academy of Sciences of the Czech Republic49
TL;DR: This study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies and an independent signal in exon 2 of TERT at the established region 5p15.
Abstract: We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.
295 citations
TL;DR: Higher intake of yogurt is associated with a reduced risk of type 2 diabetes, whereas other dairy foods and consumption of total dairy are not appreciably associated with incidence of T2D.
Abstract: The relation between consumption of different types of dairy and risk of type 2 diabetes (T2D) remains uncertain. Therefore, we aimed to evaluate the association between total dairy and individual types of dairy consumptions and incident T2D in US adults. We followed 41,436 men in the Health Professionals Follow-Up Study (1986 to 2010), 67,138 women in the Nurses’ Health Study (1980 to 2010), and 85,884 women in the Nurses’ Health Study II (1991 to 2009). Diet was assessed by validated food-frequency questionnaires, and data were updated every four years. Incident T2D was confirmed by a validated supplementary questionnaire. During 3,984,203 person-years of follow-up, we documented 15,156 incident T2D cases. After adjustment for age, body mass index (BMI) and other lifestyle and dietary risk factors, total dairy consumption was not associated with T2D risk and the pooled hazard ratio (HR) (95% confidence interval (CI)) of T2D for one serving/day increase in total dairy was 0.99 (0.98, 1.01). Among different types of dairy products, neither low-fat nor high-fat dairy intake was appreciably associated with risk of T2D. However, yogurt intake was consistently and inversely associated with T2D risk across the three cohorts with the pooled HR of 0.83 (0.75, 0.92) for one serving/day increment (P for trend <0.001). We conducted a meta-analysis of 14 prospective cohorts with 459,790 participants and 35,863 incident T2D cases; the pooled relative risks (RRs) (95% CIs) were 0.98 (0.96, 1.01) and 0.82 (0.70, 0.96) for one serving total dairy/day and one serving yogurt/day, respectively. Higher intake of yogurt is associated with a reduced risk of T2D, whereas other dairy foods and consumption of total dairy are not appreciably associated with incidence of T2D.
287 citations
TL;DR: Dietary intake of lycopene was associated with reduced risk of lethal prostate cancer and with a lesser degree of angiogenesis in the tumor, which may be more relevant than an endpoint of indolent prostate cancer for lycopenes in the era of highly prevalent prostate-specific antigen screening.
Abstract: Background The role of lycopene in prostate cancer prevention remains controversial. We examined the associations between dietary lycopene intake and prostate cancer, paying particular attention to the influence of prostate-specific antigen screening, and evaluated tissue biomarkers in prostate cancers in relation to lycopene intake. Methods Among 49 898 male health professionals, we obtained dietary information through questionnaires and ascertained total and lethal prostate cancer cases from 1986 through January 31, 2010. Cox regression was used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). Tissue microarrays and immunohistochemistry were used to assess tumor biomarker expression in a subset of men. Two-sided χ2 tests were used to calculate the P values. Results Higher lycopene intake was inversely associated with total prostate cancer and more strongly with lethal prostate cancer (top vs bottom quintile: HR = 0.72; 95% CI = 0.56 to 0.94; Ptrend = .04). In a restricted population of screened participants, the inverse associations became markedly stronger (for lethal prostate cancer: HR = 0.47; 95% CI = 0.29 to 0.75; Ptrend = .009). Comparing different measures of dietary lycopene, early intake, but not recent intake, was inversely associated with prostate cancer. Higher lycopene intake was associated with biomarkers in the cancer indicative of less angiogenic potential. Conclusions Dietary intake of lycopene was associated with reduced risk of lethal prostate cancer and with a lesser degree of angiogenesis in the tumor. Because angiogenesis is a strong progression factor, an endpoint of lethal prostate cancer may be more relevant than an endpoint of indolent prostate cancer for lycopene in the era of highly prevalent prostate-specific antigen screening.
184 citations
TL;DR: The combined effect of vitamin D supplementation and body weight on serum 25-hydroxyvitamin (25(OH)D) and serum calcium in healthy volunteers and BMI, relative to absolute body weight, was found to be the better determinant of 25( OH)D.
Abstract: Unlike vitamin D recommendations by the Institute of Medicine, the Clinical Practice Guidelines by the Endocrine Society acknowledge body weight differentials and recommend obese subjects be given two to three times more vitamin D to satisfy their body's vitamin D requirement. However, the Endocrine Society also acknowledges that there are no good studies that clearly justify this. In this study we examined the combined effect of vitamin D supplementation and body weight on serum 25-hydroxyvitamin (25(OH)D) and serum calcium in healthy volunteers. We analyzed 22,214 recordings of vitamin D supplement use and serum 25(OH)D from 17,614 healthy adult volunteers participating in a preventive health program. This program encourages the use of vitamin D supplementation and monitors its use and serum 25(OH)D and serum calcium levels. Participants reported vitamin D supplementation ranging from 0 to 55,000 IU per day and had serum 25(OH)D levels ranging from 10.1 to 394 nmol/L. The dose response relationship between vitamin D supplementation and serum 25(OH)D followed an exponential curve. On average, serum 25(OH)D increased by 12.0 nmol/L per 1,000 IU in the supplementation interval of 0 to 1,000 IU per day and by 1.1 nmol/L per 1,000 IU in the supplementation interval of 15,000 to 20,000 IU per day. BMI, relative to absolute body weight, was found to be the better determinant of 25(OH)D. Relative to normal weight subjects, obese and overweight participants had serum 25(OH)D that were on average 19.8 nmol/L and 8.0 nmol/L lower, respectively (P<0.001). We did not observe any increase in the risk for hypercalcemia with increasing vitamin D supplementation. We recommend vitamin D supplementation be 2 to 3 times higher for obese subjects and 1.5 times higher for overweight subjects relative to normal weight subjects. This observational study provides body weight specific recommendations to achieve 25(OH)D targets.
183 citations
TL;DR: The findings agree with a National Academy of Sciences report, except the cutoff point for all-cause mortality reduction in this analysis was greater than 30 ng/mL rather than greater than 20 ng/ mL.
Abstract: We examined the relationship between serum 25-hydroxyvitamin D (25[OH]D) and all-cause mortality. We searched biomedical databases for articles that assessed 2 or more categories of 25(OH)D from January 1, 1966, to January 15, 2013. We identified 32 studies and pooled the data.The hazard ratio for all-cause mortality comparing the lowest (0–9 nanograms per milliliter [ng/mL]) to the highest (> 30 ng/mL) category of 25(OH)D was 1.9 (95% confidence interval = 1.6, 2.2; P < .001). Serum 25(OH)D concentrations less than or equal to 30 ng/mL were associated with higher all-cause mortality than concentrations greater than 30 ng/mL (P < .01).Our findings agree with a National Academy of Sciences report, except the cutoff point for all-cause mortality reduction in this analysis was greater than 30 ng/mL rather than greater than 20 ng/mL.
160 citations
National Institutes of Health1, University of Texas MD Anderson Cancer Center2, Institute of Cancer Research3, Imperial College London4, University of Southern California5, Fred Hutchinson Cancer Research Center6, Institut Gustave Roussy7, French Institute of Health and Medical Research8, Harvard University9, University of Brescia10, Carlos III Health Institute11, American Cancer Society12, Science Applications International Corporation13, Utrecht University14, Academy of Athens15, Umeå University16, University of Oxford17, International Agency for Research on Cancer18, German Cancer Research Center19, University of Santiago de Compostela20, Memorial Sloan Kettering Cancer Center21, University of Pittsburgh22, Pierre-and-Marie-Curie University23, Broad Institute24, University of Padua25, Baylor College of Medicine26, University of Oviedo27, Pompeu Fabra University28, Hospital Universitario de Canarias29, Dartmouth College30, New Hampshire Department of Health & Human Services31, Washington University in St. Louis32, National Institute for Health and Welfare33
TL;DR: This study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
Abstract: andidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a ...
135 citations
Mayo Clinic1, National Institutes of Health2, Memorial Sloan Kettering Cancer Center3, Centre national de la recherche scientifique4, International Agency for Research on Cancer5, City of Hope National Medical Center6, University of California, Berkeley7, Utrecht University8, University of Freiburg9, Emory University10, Fred Hutchinson Cancer Research Center11, Drexel University12, Simon Fraser University13, University of British Columbia14, University of Melbourne15, Cancer Council Victoria16, Stanford University17, Statens Serum Institut18, University of Texas MD Anderson Cancer Center19, Ohio State University20, University of York21, American Cancer Society22, University of New South Wales23, Public Health England24, Harvard University25, University of Cagliari26, New York University27, Westat28, University of Alabama at Birmingham29, University of Iowa30, University of Paris31, Uppsala University32, Karolinska Institutet33, University of California, San Francisco34, University of Southern California35, Wayne State University36, University of North Carolina at Chapel Hill37, German Cancer Research Center38, Icahn School of Medicine at Mount Sinai39, University of Burgundy40, Dublin City University41, Yale University42, University of Sydney43, Macquarie University44, National Institute for Health and Welfare45, Imperial College London46, Academy of Athens47, University of Florence48, Dalian Maritime University49, University of Chicago50, Dongguk University51, Claude Bernard University Lyon 152
TL;DR: This paper conducted a meta-analysis of three new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls.
Abstract: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.
128 citations
Mayo Clinic1, National Institutes of Health2, Memorial Sloan Kettering Cancer Center3, Centre national de la recherche scientifique4, International Agency for Research on Cancer5, City of Hope National Medical Center6, University of California, Berkeley7, Utrecht University8, University of Freiburg9, Emory University10, Fred Hutchinson Cancer Research Center11, Drexel University12, Simon Fraser University13, University of British Columbia14, Cancer Council Victoria15, University of Melbourne16, Stanford University17, Statens Serum Institut18, University of Texas MD Anderson Cancer Center19, Ohio State University20, University of York21, American Cancer Society22, University of New South Wales23, Public Health England24, Harvard University25, University of Cagliari26, New York University27, Westat28, University of Alabama at Birmingham29, University of Iowa30, University of Paris31, Karolinska Institutet32, Uppsala University33, University of California, San Francisco34, University of Southern California35, Wayne State University36, University of North Carolina at Chapel Hill37, German Cancer Research Center38, Icahn School of Medicine at Mount Sinai39, University of Burgundy40, Dublin City University41, Yale University42, University of Sydney43, Macquarie University44, National Institute for Health and Welfare45, Imperial College London46, Academy of Athens47, University of Florence48, Dalian Maritime University49, University of Chicago50, Dongguk University51, Claude Bernard University Lyon 152
TL;DR: Data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.
Abstract: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.
TL;DR: Both dietary and supplementary calcium intake may continue to decrease CRC risk beyond 1,000 mg/day, and calcium supplements and non‐dairy products fortified with calcium may serve as additional targets in the prevention of CRC.
Abstract: Mechanistic and epidemiologic studies provide considerable evidence for a protective association between calcium intake and incident colorectal cancer (CRC). While the relationship has not been substantiated by short-duration randomized controlled trials (RCTs) of CRC, trials do show a benefit on adenomas, a precursor to CRC. To address some of this inconsistency, we conducted dose-response meta-analyses by sources of calcium intake, based on prospective observational studies published up to December 2013 identified from PubMed, Embase, and BIOSIS. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. For total calcium intake, each 300 mg/day increase was associated with an approximately 8% reduced risk of CRC (summary RR = 0.92, 95% CI = 0.89-0.95, I(2) = 47%, 15 studies with 12,305 cases, intake = 250-1,900 mg/day, follow-up = 3.3-16 years). While the risk decreased less steeply in higher range of total calcium intake (P(non-linearity) = 0.04), the degree of curvature was mild and statistical significance of non-linearity was sensitive to one study. For supplementary calcium, each 300 mg/day increase was associated with an approximately 9% reduced risk of CRC (summary RR = 0.91, 95% CI = 0.86-0.98, I(2) = 67%, six studies with 8,839 cases, intake = 0-1,150 mg/day, follow-up = 5-10 years). The test for non-linearity was not statistically significant (P(non-linearity) = 0.11). In conclusion, both dietary and supplementary calcium intake may continue to decrease CRC risk beyond 1,000 mg/day. Calcium supplements and non-dairy products fortified with calcium may serve as additional targets in the prevention of CRC. RCTs of calcium supplements with at least 10 years of follow-up are warranted to confirm a benefit of calcium supplements on CRC risk.
TL;DR: Over 2–7 years of duration, the benefit of vitamin D supplementation may be limited to cancer mortality.
Abstract: Observational studies suggest that effects of vitamin D may be stronger for cancer mortality than for incidence. Yet, existing randomised controlled trials (RCTs) of vitamin D supplementation have limited power to examine the relationships as their primary end points are not cancer incidence or mortality. Meta-analyses of RCTs of vitamin D supplementation and total cancer incidence and mortality were conducted. Over 2–7 years of duration, vitamin D supplementations had little effect on total cancer incidence (400–1100 IU per day, summary relative risk (RR)=1.00, 95% confidence interval (CI)=0.94–1.06, I2=0%; four RCTs with combined 4333 cases), but significantly reduced total cancer mortality (400–833 IU per day, summary RR=0.88, 95% CI=0.78–0.98, I2=0%, three RCTs with combined 1190 deaths). Over 2–7 years of duration, the benefit of vitamin D supplementation may be limited to cancer mortality.
TL;DR: Recent ‘molecular pathological epidemiology’ (MPE) research has shown that aspirin use is associated with better prognosis and clinical outcome in PIK3CA-mutated colorectal carcinoma, suggesting somatic Pik3CA mutation as a molecular biomarker that predicts response to aspirin therapy.
Abstract: Regular use of aspirin reduces incidence and mortality of various cancers, including colorectal cancer. Anticancer effect of aspirin represents one of the ‘Provocative Questions’ in cancer research. Experimental and clinical studies support a carcinogenic role for PTGS2 (cyclooxygenase-2), which is an important enzymatic mediator of inflammation, and a target of aspirin. Recent ‘molecular pathological epidemiology’ (MPE) research has shown that aspirin use is associated with better prognosis and clinical outcome in PIK3CA-mutated colorectal carcinoma, suggesting somatic PIK3CA mutation as a molecular biomarker that predicts response to aspirin therapy. The PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase) enzyme has a pivotal role in the PI3K-AKT signaling pathway. Activating PIK3CA oncogene mutations are observed in various malignancies including breast cancer, ovarian cancer, brain tumor, hepatocellular carcinoma, lung cancer and colon cancer. The prevalence of PIK3CA mutations increases continuously from rectal to cecal cancers, supporting the ‘colorectal continuum’ paradigm, and an important interplay of gut microbiota and host immune/inflammatory reaction. MPE represents an interdisciplinary integrative science, conceptually defined as ‘epidemiology of molecular heterogeneity of disease’. As exposome and interactome vary from person to person and influence disease process, each disease process is unique (the unique disease principle). Therefore, MPE concept and paradigm can extend to non-neoplastic diseases including diabetes mellitus, cardiovascular diseases, metabolic diseases, and so on. MPE research opportunities are currently limited by paucity of tumor molecular data in the existing large-scale population-based studies. However, genomic, epigenomic and molecular pathology testings (for example, analyses for microsatellite instability, MLH1 promoter CpG island methylation, and KRAS and BRAF mutations in colorectal tumors) are becoming routine clinical practices. In order for integrative molecular and population science to be routine practice, we must first reform education curricula by integrating both population and molecular biological sciences. As consequences, next-generation hybrid molecular biological and population scientists can advance science, moving closer to personalized precision medicine and health care.
TL;DR: Postdiagnostic Med-Diet and risk of lethal (metastases or PCa death) and fatal PCa as well as overall mortality among men diagnosed with nonmetastatic disease and Cox proportional hazards models were examined.
TL;DR: Analysis of 24 094 adult patients showed that 25(OH)D levels less than 20 ng/mL and 60 ng/ mL or greater before hospitalization were associated with an increased odds of 90-day mortality, which raises the issue of potential harm from high serum 25-hydroxyvitamin D levels, provide a rationale for an upper limit to supplementation, and emphasize the need for caution in the use of extremely high doses of vitamin D among patients.
Abstract: Objective: The objective of the study was to examine the association between prehospital serum 25-hydroxyvitamin D [25(OH)D]and the risk of mortality after hospital admission. Design: We performed a retrospective cohort study of adults hospitalized for acute care between 1993 and 2011. Setting: The study was conducted at two Boston teaching hospitals. Patients: A total of 24 094 adult inpatients participated in the study. Intervention: There was no intervention. Measurements: All patients had serum 25(OH)D measured before hospitalization. The exposure of interest was 25(OH)D categorized as less than 10 ng/mL, 10–19.9 ng/mL, 20–29.9 ng/mL, 30–49.9 ng/mL, 50–59.9 ng/mL, 60–69.9 ng/mL, and 70 ng/mL or greater. The main outcome measure was 90-day mortality. Adjusted odds ratios (ORs) were estimated by multivariable logistic regression with inclusion of potential confounders. Results: After adjustment for age, gender, race (white vs nonwhite), patient type (surgical vs medical), season of 25(OH)D draw, and the...
TL;DR: It is discovered that patients who used aspirin for colon cancer prevention were less likely to develop colon cancer with a high expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which suggests that 15-PG DH expression level in normal colon mucosa may serve as a biomarker that may predict stronger benefit from aspirin chemoprevention.
Abstract: Aspirin use reduces the risk of colorectal neoplasia, at least in part, through inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2)–related pathways. Hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (15-PGDH, HPGD) is down-regulated in colorectal cancers and functions as a metabolic antagonist of PTGS2. We hypothesized that the effect of aspirin may be antagonized by low 15-PGDH expression in the normal colon. In the Nurses’ Health Study and the Health Professionals Follow-Up Study, we collected data on aspirin use every 2 years and followed up participants for diagnoses of colorectal cancer. Duplication-method Cox proportional, multivariable-adjusted, cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for incident colorectal cancer according to 15-PGDH mRNA expression level measured in normal mucosa from colorectal cancer resections. Among 127,865 participants, we documented 270 colorectal cancer cases from which we could assess 15-PGDH expression. Compared with nonuse, regular aspirin use was associated with lower risk of colorectal cancer that developed within a background of colonic mucosa with high 15-PGDH expression [multivariable HR, 0.49; 95% confidence interval (CI), 0.34 to 0.71], but not with low 15-PGDH expression (multivariable HR, 0.90; 95% CI, 0.63 to 1.27) ( P for heterogeneity = 0.018). Regular aspirin use was associated with lower incidence of colorectal cancers arising in association with high 15-PGDH expression, but not with low 15-PGDH expression in normal colon mucosa. This suggests that 15-PGDH expression level in normal colon mucosa may serve as a biomarker that may predict stronger benefit from aspirin chemoprevention.
University of California, Berkeley1, University of Alabama at Birmingham2, National Institutes of Health3, Memorial Sloan Kettering Cancer Center4, Utrecht University5, Harvard University6, University of New South Wales7, Genome Institute of Singapore8, University of California, San Francisco9, Mayo Clinic10, City of Hope National Medical Center11, Claude Bernard University Lyon 112, Centre national de la recherche scientifique13, University of Melbourne14, Cancer Council Victoria15, Statens Serum Institut16, University of York17, Stanford University18, University of Texas MD Anderson Cancer Center19, University of Iowa20, Fred Hutchinson Cancer Research Center21, American Cancer Society22, University of Sydney23, German Cancer Research Center24, University of British Columbia25, Yale University26, Imperial College London27, French Institute of Health and Medical Research28, University of Paris-Sud29, New York University30, University of Cagliari31, Westat32, Dalian Maritime University33, Karolinska Institutet34, Uppsala University35, Wayne State University36, Drexel University37, University of Southern California38, Ohio State University39, University of North Carolina at Chapel Hill40, Macquarie University41, Icahn School of Medicine at Mount Sinai42, International Agency for Research on Cancer43, University of Burgundy44, Dublin City University45, Simon Fraser University46, Lund University47, University of Oxford48, National Institute for Health and Welfare49, University of Chicago50, University of Freiburg51
TL;DR: The findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.
Abstract: Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10−20) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10−11) near ETS1; 3q28 (rs6444305, p = 1.10 × 10−10) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10−10) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10−8) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10−67 to 2.67 × 10−70). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 × 10−16) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 × 10−9). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.
TL;DR: A meta-analysis of prospective cohort studies of coffee consumption and total mortality indicates that coffee consumption is associated with a reduced risk of total mortality.
Abstract: Coffee consumption has been shown to be associated with various health outcomes, but no comprehensive review and meta-analysis of the association between coffee consumption and total mortality has been conducted. To quantitatively assess this association, we conducted a meta-analysis of prospective cohort studies. Eligible studies were identified by searching the PubMed and EMBASE databases for all articles published through June 2013 and reviewing the reference lists of the retrieved articles. Pooled relative risks (RR) with 95% CI were calculated using a random-effects model. We identified twenty studies of coffee consumption and total mortality, including 129,538 cases of deaths among the 973,904 participants. The RR of total mortality for the high v. low category of coffee consumption was 0.86 (95% CI 0.80, 0.92). The pooled RR for studies using ≥ 2-4 cups/d as a cut-off for the high category was similar to that for studies using ≥ 5-9 cups/d as the cut-off. By geographical region, the inverse association tended to be stronger for the eight studies conducted in Europe (RR 0.78, 95% CI 0.70, 0.88) and three studies carried out in Japan (RR 0.82, 95% CI 0.73, 0.92) than for the nine studies conducted in the USA (RR 0.92, 95% CI 0.84, 1.00). The inverse association was similar for men (RR 0.81, 95% CI 0.73, 0.90) and women (RR 0.84, 95% CI 0.79, 0.89). A weak, but significant, inverse association was found with moderate coffee consumption (1-2 cups/d; RR 0.92, 95% CI 0.87, 0.98). High decaffeinated coffee consumption was also found to be associated with a lower risk of death, but the data are limited. Our findings indicate that coffee consumption is associated with a reduced risk of total mortality.
TL;DR: In this article, the authors conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls.
Abstract: Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
American Cancer Society1, National Institutes of Health2, Harvard University3, City of Hope National Medical Center4, George Washington University5, Karolinska Institutet6, Cancer Council Victoria7, University of Melbourne8, Loma Linda University9, Brigham and Women's Hospital10, Washington University in St. Louis11, Veterans Health Administration12, Fred Hutchinson Cancer Research Center13, Johns Hopkins University14, University of Washington15, New York University16
TL;DR: It is suggested that overall, and possibly also central, obesity influence myeloma mortality, and women have the highest risk of death from this cancer if they remain heavy throughout adulthood.
Abstract: Multiple myeloma (MM) is a rare but highly fatal malignancy. High body weight is associated with this cancer, but several questions remain regarding the aetiological relevance of timing and location of body weight. To address these questions, we conducted a pooled analysis of MM mortality using 1·5 million participants (including 1388 MM deaths) from 20 prospective cohorts in the National Cancer Institute Cohort Consortium. Proportional hazards regression was used to calculate pooled multivariate hazard ratios (HRs) and 95% confidence intervals (CIs). Associations with elevated MM mortality were observed for higher early-adult body mass index (BMI; HR = 1·22, 95% CI: 1·09-1·35 per 5 kg/m(2) ) and for higher cohort-entry BMI (HR 1·09, 95% CI: 1·03-1·16 per 5 kg/m(2) ) and waist circumference (HR = 1·06, 95% CI: 1·02-1·10 per 5 cm). Women who were the heaviest, both in early adulthood (BMI 25+) and at cohort entry (BMI 30+) were at greater risk compared to those with BMI 18·5 ≤ 25 at both time points (HR = 1·95, 95% CI: 1·33-2·86). Waist-to-hip ratio and height were not associated with MM mortality. These observations suggest that overall, and possibly also central, obesity influence myeloma mortality, and women have the highest risk of death from this cancer if they remain heavy throughout adulthood.
University of Southern California1, Fred Hutchinson Cancer Research Center2, National Institutes of Health3, American Cancer Society4, University of North Carolina at Chapel Hill5, Harvard University6, Cancer Care Ontario7, Ontario Institute for Cancer Research8, University Health Network9, University of Hawaii at Manoa10, University of Utah11, Kaiser Permanente12, University of Ottawa13, German Cancer Research Center14, Translational Genomics Research Institute15, Stanford University16, New York University17, University of Melbourne18, University of Pittsburgh19, Mayo Clinic20, Massey University21
TL;DR: The results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.
Abstract: Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.
TL;DR: Marine ω‐3 PUFA may be differentially associated with risk of distal colon and rectal cancers and a long latency may be needed for its protection against CRC in men.
Abstract: The association between fish, ω-3 and ω-6 polyunsaturated fatty acid (PUFA) intake and risk of colorectal cancer (CRC) remains inconclusive. Recent prospective studies suggest that the relationship may vary by gender, subsite and duration of follow-up. We followed 123,529 US adults (76,386 women and 47,143 men) without a history of cancer at baseline for 24 to 26 years. Fish and PUFA intake was assessed at baseline and updated every 4 years by using a validated food-frequency questionnaire. We found no overall association between fish, ω-3 and ω-6 PUFA intake and CRC risk with hazard ratio (HR) of 1.03 [95% confidence interval (CI): 0.89-1.20] comparing marine ω-3 intake of ≥ 0.30 g/d versus <0.15 g/d among women and 1.05 (95% CI: 0.85-1.30) comparing intake of ≥ 0.41 g/d versus <0.16 g/d among men. However, fish and marine ω-3 PUFA intake appeared to be positively associated with risk of distal colon cancer in both men and women and inversely with risk of rectal cancer in men. In an analysis based on a limited number of cases, marine ω-3 PUFA intake assessed 12-16 years before diagnosis tended to be inversely associated with CRC risk in men (HR: 0.76; 95% CI: 0.52-1.10). In conclusion, although no overall association between fish, ω-3 or ω-6 PUFA intake was observed with CRC risk, marine ω-3 PUFA may be differentially associated with risk of distal colon and rectal cancers and a long latency may be needed for its protection against CRC in men.
TL;DR: A dose-dependent significant inverse association across quintiles of the predicted 25(OH)D score and incidence of tooth loss is suggestive of an association between predictors of vitamin D and lower incidence of Tooth loss and periodontitis.
Abstract: Objective
Vitamin D insufficiency is highly prevalent, with particular subgroups at greater risk (e.g. the elderly and those with darker skin). Vitamin D insufficiency may partly explain US racial/ethnic disparities in the prevalence of periodontitis and tooth loss. We evaluated the association between a predictor score of plasma 25-hydroxyvitamin D (25(OH)D) and incidence of periodontitis and tooth loss.
Harvard University1, Brigham and Women's Hospital2, German Cancer Research Center3, Johns Hopkins University4, University Medical Center Utrecht5, Imperial College London6, University of Colorado Denver7, American Cancer Society8, University of Melbourne9, Cancer Council Victoria10, University of Southern California11, International Agency for Research on Cancer12, Umeå University13, University of Hawaii14, University of Murcia15, Aarhus University16, Cancer Epidemiology Unit17, Academy of Athens18
TL;DR: Eight established PCa risk variants were associated with progression to PCSM after diagnosis, and one predicted an increased risk of PCSM, while seven wereassociated with decreased risk.
TL;DR: Higher AHEI-2010 score may be associated with lower overall mortality, moderate alcohol consumption and lower consumption of sugar sweetened beverages and juices combined appeared to account for most of the observed associations.
Abstract: Background
Dietary factors are known to influence colorectal cancer (CRC) risk, however, their association with CRC survival is unclear. Therefore, we prospectively examined the association between diet quality scores, dietary patterns and colorectal cancer (CRC) survival.
TL;DR: The results support an association between higher levels of circulating MIC-1 (GDF15) and CRC, and aspirin/NSAID use appeared to lower risk of PTGS2-positive cancers, particularly among individuals with high levels of circulate plasma inflammatory markers.
Abstract: Considerable evidence suggests that chronic inflammation plays an important role in the development of colorectal cancer (CRC). Individuals with long-standing colonic inflammation due to inflammatory bowel disease have an increased susceptibility to CRC (1). Furthermore, nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, are associated with a lower risk of CRC and improved clinical outcomes after diagnosis (2,3,4).
One proposed pathway through which inflammation promotes carcinogenesis is the overexpression of PTGS2 (prostaglandin-endoperoxide synthase 2, also known as cyclooxygenase-2 [COX-2]) (5,6). PTGS2-positive colorectal tumors appear to respond more favorably to aspirin and NSAIDs than PTGS2-negative tumors (2).
The circulating inflammatory cytokine growth differentiation factor 15 (GDF15), also known as macrophage inhibitory cytokine-1 (MIC-1), may be an important mediator in the systemic inflammatory response (7). MIC-1 levels rise in the circulation in response to injury or inflammation (8). Elevated levels of MIC-1 have been previously associated with an increased risk of diseases hypothesized to result from chronic inflammation, such as atherosclerosis and inflammatory arthritis (8,9). MIC-1 has also been linked to the development of cancers, including those of the prostate, thyroid, pancreas, and colon (7,10,11). Recently, within the Polyp Prevention Trial, MIC-1 levels were associated with an increased risk of recurrent adenoma among patients with a history of prior adenoma (12). Experimental evidence also suggests that MIC-1, as a member of the human transforming growth factor-β (TGFβ1) superfamily (8), may play a specific role in carcinogenesis (7,13–15).
Although we and others have examined the relationship between other inflammatory markers—including C-reactive protein (CRP), interleukin 6 (IL-6), soluble tumor necrosis factor receptor 2 (also known as TNFRSF1B), and adiponectin—and the risk of CRC, prospective data relating MIC-1 levels and incident CRC are limited (16,17). Therefore, we examined the association between prediagnostic levels of MIC-1 risk of CRC in a prospective, nested, case–control study of men and women enrolled in the Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS). We also explored the association between MIC-1 levels and CRC according to the expression status of intratumoral PTGS2.
TL;DR: Within an unselected population of African Americans, short-term exposure to vitamin D supplementation produced no change in circulating inflammatory markers and the strong independent association of CRP with 25(OH)D status even after adjusting for body mass index is confirmed.
Abstract: African Americans have a disproportionate burden of inflammation-associated chronic diseases such as cancer and lower circulating levels of 25-hydroxyvitamin D [25(OH)D]. The effect of vitamin D3 (cholecalciferol) supplementation on inflammatory markers is uncertain. We conducted a randomized, double-blind, placebo-controlled trial of supplemental oral vitamin D (placebo, 1,000, 2,000, or 4,000 IU/day of vitamin D3 orally for 3 months) in 328 African Americans (median age, 51 years) of public housing communities in Boston, MA, who were enrolled over three consecutive winter periods (2007-2010). Change from 0 to 3 months of plasma levels of 25(OH)D, high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, IL-10, and soluble TNF-α receptor type 2 (sTNF-R2) in 292 (89%) participants were measured. Overall, no statistically significant changes in CRP, IL-6, IL-10, and sTNF-R2 were observed after the vitamin D supplementation period. Baseline CRP was significantly inversely associated with the baseline 25(OH)D level (P < 0.001) in unadjusted and adjusted models. An interaction between baseline 25(OH)D and vitamin D supplementation was observed for outcome change in log CRP (month 3-month 0; P for interaction = 0.04). Within an unselected population of African Americans, short-term exposure to vitamin D supplementation produced no change in circulating inflammatory markers. This study confirms the strong independent association of CRP with 25(OH)D status even after adjusting for body mass index. Future studies of longer supplemental vitamin D3 duration are necessary to examine the complex influence of vitamin D3 on CRP and other chronic inflammatory cytokines for possible reduction of cancer health disparities in African Americans.
TL;DR: Higher sugar-sweetened beverage intake was associated with a significantly increased risk of cancer recurrence and mortality in stage III colon cancer patients.
Abstract: Background: In colon cancer patients, obesity, sedentary lifestyle, and high dietary glycemic load have been associated with increased risk of cancer recurrence. High sugar-sweetened beverage intake has been associated with obesity, diabetes, and cardio-metabolic diseases, but the influence on colon cancer survival is unknown. Methods: We assessed the association between sugar-sweetened beverage consumption on cancer recurrence and mortality in 1,011 stage III colon cancer patients who completed food frequency questionnaires as part of a U.S. National Cancer Institute-sponsored adjuvant chemotherapy trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazard models. Results: Patients consuming $2 servings of sugar-sweetened beverages per day experienced an adjusted HR for disease recurrence or mortality of 1.67 (95% CI, 1.04–2.68), compared with those consuming ,2 servings per month (Ptrend=0.02). The association of sugar-sweetened beverages on cancer recurrence or mortality appeared greater among patients who were both overweight (body mass index $25 kg/m 2 ) and less physically active (metabolic equivalent task-hours per week , 18) (HR=2.22; 95% CI, 1.29–3.81, Ptrend=0.0025). Conclusion: Higher sugar-sweetened beverage intake was associated with a significantly increased risk of cancer recurrence and mortality in stage III colon cancer patients.
TL;DR: Within African Americans, an estimated 1640 IU vitamin D₃/d was required to achieve concentrations of plasma 25(OH)D recommended by the Institute of Medicine, whereas 4000 IU/dwas needed to reach concentrations predicted to reduce cancer and cardiovascular disease risk in prospective observational studies.