Genetically Determined Circulating Lactase/Phlorizin Hydrolase Concentrations and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study.

Previous research has found that milk is associated with a decreased risk of colorectal cancer (CRC). However, it is unclear whether the milk digestion by the enzyme lactase-phlorizin hydrolase (LPH) plays a role in CRC susceptibility. Our study aims to investigate the direct causal relationship of CRC risk with LPH levels by applying a two-sample Mendelian Randomization (MR) strategy. Genetic instruments for LPH were derived from the Fenland Study, and CRC-associated summary statistics for these instruments were extracted from the FinnGen Study, PLCO Atlas Project, and Pan-UK Biobank. Primary MR analyses focused on a cis-variant (rs4988235) for LPH levels, with results integrated via meta-analysis. MR analyses using all variants were also undertaken. This analytical approach was further extended to assess CRC subtypes (colon and rectal). Meta-analysis across the three datasets illustrated an inverse association between genetically predicted LPH levels and CRC risk (OR: 0.92 [95% CI, 0.89-0.95]). Subtype analyses revealed associations of elevated LPH levels with reduced risks for both colon (OR: 0.92 [95% CI, 0.89-0.96]) and rectal cancer (OR: 0.92 [95% CI, 0.87, 0.98]). Consistency was observed across varied analytical methods and datasets. Further exploration is warranted to unveil the underlying mechanisms and validate LPH's potential role in CRC prevention.

Evidence for a causal link between intra-pancreatic fat deposition and pancreatic cancer: A prospective cohort and Mendelian randomization study.

Prior observational studies suggest an association between intra-pancreatic fat deposition (IPFD) and pancreatic ductal adenocarcinoma (PDAC); however, the causal relationship is unclear. To elucidate causality, we conduct a prospective observational study using magnetic resonance imaging (MRI)-measured IPFD data and also perform a Mendelian randomization study using genetic instruments for IPFD. In the observational study, we use UK Biobank data (N = 29,463, median follow-up: 4.5 years) and find that high IPFD (>10%) is associated with PDAC risk (adjusted hazard ratio [HR]: 3.35, 95% confidence interval [95% CI]: 1.60-7.00). In the Mendelian randomization study, we leverage eight out of nine IPFD-associated genetic variants (p < 5 × 10-8) from a genome-wide association study in the UK Biobank (N = 25,617) and find that genetically determined IPFD is associated with PDAC (odds ratio [OR] per 1-standard deviation [SD] increase in IPFD: 2.46, 95% CI: 1.38-4.40) in the Pancreatic Cancer Cohort Consortium I, II, III (PanScan I-III)/Pancreatic Cancer Case-Control Consortium (PanC4) dataset (8,275 PDAC cases and 6,723 non-cases). This study provides evidence for a potential causal role of IPFD in the pathogenesis of PDAC. Thus, reducing IPFD may lower PDAC risk.

Genetic Evidence Causally Linking Pancreas Fat to Pancreatic Cancer: A Mendelian Randomization Study.

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, and any clues to understanding its elusive etiology could lead to breakthroughs in prevention, early detection, or treatment. Observational studies have shown a relationship between pancreas fat accumulation and PDAC, but the causality of this link is unclear. We therefore investigated whether pancreas fat is causally associated with PDAC using two-sample Mendelian randomization. Methods: We leveraged eight genetic variants associated with pancreas fat (P<5×10 -8 ) from a genome-wide association study (GWAS) in the UK Biobank (25,617 individuals), and assessed their association with PDAC in the Pancreatic Cancer Cohort Consortium I-III and the Pancreatic Cancer Case-Control Consortium dataset (8,275 PDAC cases and 6,723 non-cases). Causality was assessed using the inverse-variance weighted method. Although none of these genetic variants were associated with body mass index (BMI) at genome-wide significance, we further conducted a sensitivity analysis excluding genetic variants with a nominal BMI association in GWAS summary statistics from the UK Biobank and the Genetic Investigation of Anthropometric Traits consortium dataset (806,834 individuals). Results: Genetically determined higher levels of pancreas fat using the eight genetic variants was associated with increased risk of PDAC. For one standard deviation increase in pancreas fat levels (i.e., 7.9% increase in pancreas fat fraction), the odds ratio of PDAC was 2.46 (95%CI:1.38-4.40, P=0.002). Similar results were obtained after excluding genetic variants nominally linked to BMI (odds ratio:3.79, 95%CI:1.66-8.65, P=0.002). Conclusions: This study provides genetic evidence for a causal role of pancreas fat in the pathogenesis of PDAC. Thus, reducing pancreas fat could lower the risk of PDAC.

Genome-wide association study of abdominal MRI-measured visceral fat: The multiethnic cohort adiposity phenotype study.

Few studies have explored the genetic underpinnings of intra-abdominal visceral fat deposition, which varies substantially by sex and race/ethnicity. Among 1,787 participants in the Multiethnic Cohort (MEC)-Adiposity Phenotype Study (MEC-APS), we conducted a genome-wide association study (GWAS) of the percent visceral adiposity tissue (VAT) area out of the overall abdominal area, averaged across L1-L5 (%VAT), measured by abdominal magnetic resonance imaging (MRI). A genome-wide significant signal was found on chromosome 2q14.3 in the sex-combined GWAS (lead variant rs79837492: Beta per effect allele = -4.76; P = 2.62 × 10-8) and in the male-only GWAS (lead variant rs2968545: (Beta = -6.50; P = 1.09 × 10-9), and one suggestive variant was found at 13q12.11 in the female-only GWAS (rs79926925: Beta = 6.95; P = 8.15 × 10-8). The negatively associated variants were most common in European Americans (T allele of rs79837492; 5%) and African Americans (C allele of rs2968545; 5%) and not observed in Japanese Americans, whereas the positively associated variant was most common in Japanese Americans (C allele of rs79926925, 5%), which was all consistent with the racial/ethnic %VAT differences. In a validation step among UK Biobank participants (N = 23,699 of mainly British and Irish ancestry) with MRI-based VAT volume, both rs79837492 (Beta = -0.026, P = 0.019) and rs2968545 (Beta = -0.028, P = 0.010) were significantly associated in men only (n = 11,524). In the MEC-APS, the association between rs79926925 and plasma sex hormone binding globulin levels reached statistical significance in females, but not in males, with adjustment for total adiposity (Beta = -0.24; P = 0.028), on the log scale. Rs79837492 and rs2968545 are located in intron 5 of CNTNAP5, and rs79926925, in an intergenic region between GJB6 and CRYL1. These novel findings differing by sex and racial/ethnic group warrant replication in additional diverse studies with direct visceral fat measurements.

Race-specific prostate cancer outcomes in a cohort of military health care beneficiaries undergoing surgery: 1990-2017.

BACKGROUND: There is substantial variability in prostate cancer (PCa) mortality rates across Caucasian American (CA), African American (AA), Asian, and Hispanic men; however, these estimates are unable to disentangle race or ethnicity from confounding factors. The current study explores survival differences in long-term PCa outcomes between self-reported AA and CA men, and examines clinicopathologic features across self-reported CA, AA, Asian, and Hispanic men. METHODS: This retrospective cohort study utilized the Center for Prostate Disease Research (CPDR) Multi-center National Database from 1990 to 2017. Subjects were consented at military treatment facilities nationwide. AA, CA, Asian, or Hispanic men who underwent radical prostatectomy (RP) for localized PCa within the first year of diagnosis were included in the analyses. Time from RP to biochemical recurrence (BCR), BCR to metastasis, and metastasis to overall death were evaluated using Kaplan-Meier unadjusted estimation curves and adjusted Cox proportional hazards regression. RESULTS: This study included 7067 men, of whom 5155 (73%) were CA, 1468 (21%) were AA, 237 (3%) were Asian, and 207 (3%) were Hispanic. AA men had a significantly decreased time from RP to BCR compared to CA men (HR = 1.25, 95% CI = 1.06-1.48, p = 0.01); however, no difference was observed between AA and CA men for a time from BCR to metastasis (HR = 0.73, 95% CI = 0.39-1.33, p = 0.302) and time from metastasis to overall death (HR = 0.67, 95% CI = 0.36-1.26, p = 0.213). CONCLUSIONS: In an equal access health care setting, AA men had a shorter survival time from RP to BCR, but comparable survival time from BCR to metastasis and metastasis to overall death.

Genome-wide association study of pancreatic fat: The Multiethnic Cohort Adiposity Phenotype Study.

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10-8) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUTO, and rs79967607 is in intron 1 of EPM2A. PLUTO, a lncRNA, regulates transcription of an adjacent gene, PDX1, that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.

Racial/ethnic disparities in weight or BMI change in adulthood and pancreatic cancer incidence: The multiethnic cohort.

INTRODUCTION: Compared to non-Hispanic Whites, Japanese Americans, Native Hawaiians, and African Americans have higher incidences of pancreatic cancer (PCa) that are not entirely explained by rates of obesity but may be explained by weight changes throughout adulthood. METHODS: The multiethnic cohort is a population-based prospective cohort study that has followed 155,308 participants since its establishment between 1993 and 1996. A total of 1,328 incident cases with invasive PCa were identified through 2015. We conducted separate multivariable Cox proportional hazards models for self-reported weight-change and BMI-change (age 21 to cohort entry) to determine the association with PCa risk, adjusting for potential confounders including weight or BMI at age 21. RESULTS: The mean age at cohort entry was 59.3 years (SD 8.9). An increased risk of PCa was associated with: 1) weight (HR per10 lbs = 1.06; 95% CI = 1.03-1.09) or BMI (HR per kg/m2  = 1.04; 95% CI = 1.02-1.05) at age 21; and 2) weight (HR per 10 lbs = 1.03; 95% CI = 1.01-1.05) or BMI (HR = 1.02; 95% CI = 1.00-1.03) at cohort entry. We found increased risk of PCa between weight (HR per 10 lbs = 1.03; 95% CI = 1.01-1.05) and BMI (HR per 5 kg/m2  = 1.08; 95% CI = 1.01-1.15) change from age 21 to baseline. There were significant interactions between race/ethnicity and weight (p = 0.008) or BMI (p = 0.03) at baseline, and weight (p = 0.02) or BMI (p = 0.02) change. Weight and BMI change through adulthood significantly increased the risk of PCa for Japanese Americans and Latinos, but not for African American, White, or Hawaiian participants. CONCLUSION: Our findings indicate that weight or BMI gain has a significant and independent impact on PCa risk, specifically among Latinos and Japanese Americans.

A pooled genome-wide association study identifies pancreatic cancer susceptibility loci on chromosome 19p12 and 19p13.3 in the full-Jewish population.

Jews are estimated to be at increased risk of pancreatic cancer compared to non-Jews, but their observed 50-80% excess risk is not explained by known non-genetic or genetic risk factors. We conducted a GWAS in a case-control sample of American Jews, largely Ashkenazi, including 406 pancreatic cancer patients and 2332 controls, identified in the dbGaP, PanScan I/II, PanC4 and GERA data sets. We then examined resulting SNPs with P < 10-7 in an expanded sample set, of 539 full- or part-Jewish pancreatic cancer patients and 4117 full- or part-Jewish controls from the same data sets. Jewish ancestries were genetically determined using seeded FastPCA. Among the full Jews, a novel genome-wide significant association was detected on chromosome 19p12 (rs66562280, per-allele OR = 1.55, 95% CI = 1.33-1.81, P = 10-7.6). A suggestive relatively independent association was detected on chromosome 19p13.3 (rs2656937, OR = 1.53, 95% CI = 1.31-1.78, P = 10-7.0). Similar associations were seen for these SNPs among the full and part Jews combined. This is the first GWAS conducted for pancreatic cancer in the increased-risk Jewish population. The SNPs rs66562280 and rs2656937 are located in introns of ZNF100-like and ARRDC5, respectively, and are known to alter regulatory motifs of genes that play integral roles in pancreatic carcinogenesis.

Race, tumor location, and disease progression among low-risk prostate cancer patients.

BACKGROUND: The relationship between race, prostate tumor location, and BCR-free survival is inconclusive. This study examined the independent and joint roles of patient race and tumor location on biochemical recurrence-free (BCR) survival. METHODS: A retrospective cohort study was conducted among men with newly diagnosed, biopsy-confirmed, NCCN-defined low risk CaP who underwent radical prostatectomy (RP) at the Walter Reed National Military Medical Center from 1996 to 2008. BCR-free survival was modeled using Kaplan-Meier estimation curves and multivariable Cox proportional hazards (PH) analyses. RESULTS: There were 539 eligible patients with low-risk CaP (25% African American, AA; 75% Caucasian American, CA). Median age at CaP diagnosis and post-RP follow-up time was 59.2 and 8.1 years, respectively. Kaplan-Meier analyses showed no significant association between race (P = .52) or predominant tumor location (P = .98) on BCR-free survival. In Cox PH multivariable analysis, neither race (HR = 1.18; 95% CI = 0.68-2.02; P = .56) nor predominant tumor location (HR = 1.13; 95% CI = 0.59-2.15; P = .71) was an independent predictor of BCR-free survival. CONCLUSIONS: Neither race nor predominant tumor location was associated with adverse oncologic outcome.

Impact of Sixteen Established Pancreatic Cancer Susceptibility Loci in American Jews.

Background: The higher risk of pancreatic cancer in Ashkenazi Jews compared with non-Jews is only partially explained by the increased frequency of BRCA1 and BRCA2 mutations in Ashkenazi Jews.Methods: We evaluated the impact of 16 established pancreatic cancer susceptibility loci in a case-control sample of American Jews, largely Ashkenazi, including 406 full-Jewish pancreatic cancer patients and 2,332 full-Jewish controls, genotyped as part of the Pancreatic Cancer Cohort and Case-Control Consortium I/II (PanScan I/II), Pancreatic Cancer Case-Control Consortium (PanC4), and Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) datasets. We compared risk in full-Jewish subjects with risk in part-Jewish; non-Jewish Southern European; and in the combined non-Jewish Eastern, Northern, Southern, and Western European (non-Jewish white European) subjects from the same datasets. Jewish ancestries were genetically identified using seeded Fast principal component analysis. Data were analyzed by unconditional logistic regression, and adjusted for age, sex, and principal components.Results: One SNP on chromosome 13q22.1 (rs9543325; OR, 1.36; 95% confidence interval, 1.16-1.58; P = 10-4.1) was significant in full-Jews. Individual ORs and minor allele frequencies were similar between Jewish and non-Jewish white European subjects. The average ORs across the 16 pancreatic cancer susceptibility loci for full-Jewish, full- plus part-Jewish, non-Jewish Southern European, and non-Jewish white European subjects were 1.25, 1.30, 1.31, and 1.26, respectively.Conclusions: The 16 pancreatic cancer susceptibility loci similarly impact Jewish and non-Jewish white European subjects, both individually and as summary odds.Impact: These 16 pancreatic cancer susceptibility loci likely do not explain the higher risk seen in Ashkenazi Jews. Cancer Epidemiol Biomarkers Prev; 26(10); 1540-8. ©2017 AACR.

Aspirin Use and Reduced Risk of Pancreatic Cancer.

BACKGROUND: Few options besides the avoidance of smoking and obesity are available to prevent pancreatic cancer. The association between aspirin use and risk of pancreatic cancer has been inconsistent across studies. METHODS: We performed a population-based study of 761 case and 794 control subjects frequency matched on sex and age during 2006 to 2011 in Shanghai, China. Participants were asked about episodes of regular use of aspirin, tablets per day or week, and ages that the use started and stopped. Data were analyzed by unconditional logistic regression, with adjustments for age, sex, education, body mass index, years of cigarette smoking, cigarettes smoked per day, Helicobacter pylori CagA seropositivity, ABO blood group, and history of diabetes mellitus. Meta-regression was carried out to summarize the literature. RESULTS: Ever-regular use of aspirin was associated with lowered risk of pancreatic cancer: OR = 0.54; 95% confidence interval (CI), 0.40-0.73; P = 10-4.2 Risk decreased 8% per each cumulative year of use: ORtrend = 0.92; 95% CI, 0.87-0.97; P = 0.0034. Across this and 18 published studies of this association, the OR for ever-regular use decreased with increasingly more recent mid-study year, for any aspirin type (Ptrend = 10-5.1), and for low-dose aspirin (Ptrend = 0.0014). CONCLUSIONS: Regular use of aspirin thus appears to reduce risk of pancreatic cancer by almost half. IMPACT: People who take aspirin for prevention of other diseases likely also reduce their risk of pancreatic cancer. Aside from benefits for both cardiovascular disease and certain cancers, long-term aspirin use entails some risks of bleeding complications, which necessitates risk-benefit analysis for individual decisions about use. Cancer Epidemiol Biomarkers Prev; 26(1); 68-74. ©2016 AACR.

Case-control study of aspirin use and risk of pancreatic cancer.

BACKGROUND: Pancreas-cancer prognosis is dismal, with 5-year survival less than 5%. Significant relationships between aspirin use and decreased pancreas-cancer incidence and mortality have been shown in four of 13 studies. METHODS: To evaluate further a possible association between aspirin use and risk of pancreatic cancer, we used data from a population-based Connecticut study conducted from January 2005 to August 2009, of 362 pancreas-cancer cases frequency matched to 690 randomly sampled controls. RESULTS: Overall, regular use of aspirin was associated with reduced risk of pancreatic cancer [odds ratio (OR), 0.52; 95% confidence interval (CI), 0.39-0.69]. Increments of decreasing risk of pancreatic cancer were observed for each year of low-dose or regular-dose aspirin use (OR, 0.94; 95% CI, 0.91-0.98 and OR, 0.98; 95% CI, 0.96-1.01, respectively) and for increasing years in the past that low-dose or regular-dose aspirin use had started (OR, 0.95; 95% CI, 0.92-0.99 and OR, 0.98; 95% CI, 0.96-1.00, respectively). Reduced risk of pancreatic cancer was seen in most categories of calendar time period of aspirin use, for both low-dose aspirin and regular-dose aspirin use. Relative to continuing use at the time of interview, termination of aspirin use within 2 years of interview was associated with increased risk of pancreatic cancer (OR, 3.24; 95% CI, 1.58-6.65). CONCLUSIONS: Our results provide some support that a daily aspirin regimen may reduce risk of developing pancreatic cancer. IMPACT: Long-term aspirin use has benefits for both cardiovascular disease and cancer, but appreciable bleeding complications that necessitate risk-benefit analysis for individual applications.

Reasons for participating and genetic information needs among racially and ethnically diverse biobank participants: a focus group study.

In order for DNA biobanks to be a valuable reservoir of genetic information, large numbers of participants from all racial and ethnic backgrounds need to be recruited. This study explored reasons for participating in a new biobank among primarily Hispanic and African American individuals, as well as their general attitudes towards genetic research, and their views on obtaining genetic tests. Focus groups were conducted with Mount Sinai Biobank participants recruited from predominantly lower income, minority communities. The topic guide included questions on The Mount Sinai Biobank, genetic research, and genetic testing. All focus groups were audio recorded, transcribed, and analyzed using thematic analysis. The six focus groups comprised 43 participants: 39 females and four males, aged 27-76 years, with a median household income category of $20,000-$39,999. Twenty-one participants were Hispanic, 20 African American, one Asian, and one White. Participants' reasons for participating in the biobank included altruism, personal and family benefit, and general curiosity. Although there was evidence of conflation between genetic research and genetic testing, most participants held positive views of genetic research and expressed interest in receiving personal genetic test results. Participants wanted to learn more about genetic research and suggested various venues such as health fairs for disseminating information. Participation in biobanks by racial and ethnic minorities is apparently driven by altruism, and desire for personal or collective health benefits. Participants had generally positive attitudes, limited understanding of genetics and genetic research, and made useful suggestions regarding information dissemination mechanisms.