University of Hawaii Cancer Center Faculty & Researcher Works

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    Sources of vegetables, fruits, and vitamins A, C and E among five ethnic groups: Results from the Multiethnic Cohort Study
    (Nature Publishing Group, 2014-03) Sharma, Sangita ; Sheehy, Tony ; Kolonel, Laurence N.
    Objectives: Data are limited on how dietary sources of food and nutrients differ among ethnic groups. The objective of this study was to determine the main sources of fruit, vegetables, and vitamins A, C, and E for five ethnic groups. Methods: Dietary data were collected using a validated quantitative food frequency questionnaire from participants in the Multiethnic Cohort in Hawaii and Los Angeles County between 1993 and 1996. Data were analyzed for 186,916 participants representing five ethnic groups; African Americans, Japanese Americans, Native Hawaiians, Latinos, and Caucasians. Results: Lettuce was the most consumed vegetable (6.0%-9.9%) in all ethnic-sex groups, except African American women and Mexican-born Latino men and women. Oranges and bananas contributed more than one quarter to total fruit intake among all groups. Overall, more ethnic variation in food choices was observed for the top ten vegetables than fruit. The top sources for vitamins A, C and E were carrots, orange/grapefruit/pomelo and combined dishes, respectively. Between micronutrients studied, the greatest ethnic variation in foods consumed was observed among the top ten food sources of vitamin A. Conclusions: This is the first study providing data on the main types of fruit and vegetables consumed and the major sources of vitamins A, C, and E among these ethnic groups in the U.S. Such data are valuable for developing and implementing public health strategies to meet the USDA dietary recommendations and guiding ethnic-specific nutrition education and intervention programs.
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    Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation
    (Nature, 2015-07) Gagliani, Nicola ; Vesely, Maria Carolina Amezcua ; Iseppon, Andrea ; Brockmann, Leonie ; Xu, Hao ; Palm, Noah W. ; de Zoete, Marcel R. ; Licona-Limon, Paula ; Paiva, Ricardo S. ; Ching, Travers ; Weaver, Casey ; Zi, Xiaoyuan ; Pan, Xinghua ; Fan, Rong ; Garmire, Lana X. ; Cotton, Matthew J. ; Drier, Yotam ; Bernstein, Bradley ; Geginat, Jens ; Stockinger, Brigitta ; Esplugues, Enric ; Huber, Samuel ; Flavell, Richard A.
    Inflammation is a beneficial host response to infection but can contribute to inflammatory disease if unregulated. The TH17 lineage of T helper (TH) cells can cause severe human inflammatory diseases. These cells exhibit both instability (they can cease to express their signature cytokine, IL-17A)1 and plasticity (they can start expressing cytokines typical of other lineages)1,2 upon in vitro re-stimulation. However, technical limitations have prevented the transcriptional profiling of pre- and post-conversion TH17 cells ex vivo during immune responses. Thus, it is unknown whether TH17 cell plasticity merely reflects change in expression of a few cytokines, or if TH17 cells physiologically undergo global genetic reprogramming driving their conversion from one T helper cell type to another, a process known as transdifferentiation3,4. Furthermore, although TH17 cell instability/plasticity has been associated with pathogenicity1,2,5, it is unknown whether this could present a therapeutic opportunity, whereby formerly pathogenic TH17 cells could adopt an anti-inflammatory fate. Here we used two new fate-mapping mouse models to track TH17 cells during immune responses to show that CD4+ T cells that formerly expressed IL-17A go on to acquire an anti-inflammatory phenotype. The transdifferentiation of TH17 into regulatory T cells was illustrated by a change in their signature transcriptional profile and the acquisition of potent regulatory capacity. Comparisons of the transcriptional profiles of pre- and postconversion TH17 cells also revealed a role for canonical TGF-β signalling and consequently for the aryl hydrocarbon receptor (AhR) in conversion. Thus, TH17 cells transdifferentiate into regulatory cells, and contribute to the resolution of inflammation. Our data suggest that TH17 cell instability and plasticity is a therapeutic opportunity for inflammatory diseases.
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    Genome-wide significant risk associations for mucinous ovarian carcinoma
    (Nature, 2015-08) Goodman, Marc T. ; Wilkens, Lynne R.

    Note: A full list of authors and affiliations appears at the end of the article.

    Genome-wide association studies have identified several risk associations for ovarian carcinomas (OC) but not for mucinous ovarian carcinomas (MOC). Genotypes from OC cases and controls were imputed into the 1000 Genomes Project reference panel. Analysis of 1,644 MOC cases and 21,693 controls identified three novel risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 ×10^−12) and rs688187 at 19q13.2 (P = 6.8 × 10^−13). Expression Quantitative Trait Locus (eQTL) analysis in ovarian and colorectal tumors (which are histologically similar to MOC) identified significant eQTL associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10^−4, FDR = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors, and for PAX8 at 2q13 in colorectal tumors (P=0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

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    Genome-wide association study of colorectal cancer identifies six new susceptibility loci
    (Nature, 2015-07) Le Marchand, Loic

    Note: A full list of authors and affiliations appears at the end of the article.

    Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.

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    New genetic loci link adipose and insulin biology to body fat distribution
    (Nature, 2015-02) Le Marchand, Loic

    Note: A full list of authors and affiliations appears at the end of the article.

    Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

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    Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation
    (Nature, 2014-09) Le Marchand, Loic

    Note: A full list of authors and affiliations appears at the end of the article.

    GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the ‘iCOGS’ genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval = 0.84-0.87; P = 1.7 x 10^-43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

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    Genetic studies of body mass index yield new insights for obesity biology
    (Nature, 2015-02) Lim, Unhee ; Le Marchand, Loic ; Wilkens, Lynne

    Note: A full list of authors and affiliations appears at the end of the article.

    Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10^−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

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    Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma
    (Nature Oncogene, 2015-06) Napolitano, Andrea ; Pellegrini, Laura ; Dey, A. ; Larson, David ; Tanji, Mika ; Flores, Erin G. ; Kendrick, Brian ; Lapid, Danica ; Powers, Amy ; Kanodia, S. ; Pastorino, Sandra ; Pass, H.I. ; Dixit, V. ; Yang, Haining ; Cabone, Michele
    Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated to professional exposure to asbestos. However, to date we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after minimal exposure. Using a BAP1+/- mouse model, we found that, compared to their wild type littermates, BAP1+/- mice exposed to low-dose asbestos fibers showed significant alterations of the peritoneal inflammatory response, including significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1+/- mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, doses that rarely induced mesothelioma in wild type mice. Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response.
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    Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25
    (Nature Communications, 2014-10) Fejerman, Laura ; Ahmadiyeh, Nasim ; Hu, Donglei ; Huntsman, Scott ; Beckman, Kenneth B. ; Caswell, Jennifer L. ; Tsung, Karen ; John, Esther M. ; Torres-Mejia, Gabriela ; Carvajal-Carmona, Luis ; Echeverry, Maria Magdalena ; Tuazon, Anna Marie D. ; Ramirez, Carolina ; COLUMBUS Consortium ; Gignoux, Christopher R. ; Eng, Celeste ; Gonzalez-Burchard, Esteban ; Henderson, Brian ; Le Marchand, Loic ; Kooperberg, Charles ; Hou, Lifang ; Agalliu, Ilir ; Kraft, Peter ; Lindstrom, Sara ; Perez-Stable, Eliseo J. ; Haiman, Christopher A. ; Ziv, Elad
    The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 50 of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53–0.67, P = 9 x 10^-18), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21–0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49–0.80; P heterogeneity = 0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P = 0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.
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    Two susceptibility loci identified for prostate cancer aggressiveness
    (Nature Communications, 2015-05) Berndt, Sonja I. ; Wang, Zhaoming ; Yeager, Meredith ; Alavanja, Michael C. ; Albanes, Demetrius ; Amundadottir, Laufey ; Andriole, Gerald ; Freeman, Laura Beane ; Campa, Daniele ; Cancel-Tassin, Geraldine ; Canzian, Federico ; Cornu, Jean-Nicolas ; Cussenot, Olivier ; Diver, W. Ryan ; Gapstur, Susan M. ; Gronberg, Henrik ; Haiman, Christopher A. ; Henderson, Brian ; Hutchinson, Amy ; Hunter, David J. ; Key, Timothy J. ; Kolb, Suzanne ; Koutros, Stella ; Kraft, Peter ; Le Marchand, Loic ; Lindstrom, Sara ; Machiela, Mitchell J. ; Ostrander, Elaine A. ; Riboli, Elio ; Schumacher, Fred ; Siddiq, Afshan ; Stanford, Janet L. ; Stevens, Victoria L. ; Travis, Ruth C. ; Tsilidis, Konstantinos K. ; Virtamo, Jarmo ; Weinstein, Stephanie ; Wilkund, Fredrik ; Xu, Jianfeng ; Zheng, S. Lilly ; Yu, Kai ; Wheeler, William ; Zhang, Han ; African Ancestry Prostate Cancer GWAS Consortium ; Sampson, Joshua ; Black, Amanda ; Jacobs, Kevin ; Hoover, Robert N. ; Tucker, Margaret ; Chanock, Stephen J.
    Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P = 6.49 x 10^-9) and rs78943174 at 3q26.31 (NAALADL2, P = 4.18 x 10^-8). In a stratified case–control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P = 8.85 x 10^-5) with no association for nonaggressive prostate cancer compared with controls (P = 0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.