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1.  Additive Interactions Between Susceptibility Single-Nucleotide Polymorphisms Identified in Genome-Wide Association Studies and Breast Cancer Risk Factors in the Breast and Prostate Cancer Cohort Consortium 
Joshi, Amit D. | Lindström, Sara | Hüsing, Anika | Barrdahl, Myrto | VanderWeele, Tyler J. | Campa, Daniele | Canzian, Federico | Gaudet, Mia M. | Figueroa, Jonine D. | Baglietto, Laura | Berg, Christine D. | Buring, Julie E. | Chanock, Stephen J. | Chirlaque, María-Dolores | Diver, W. Ryan | Dossus, Laure | Giles, Graham G. | Haiman, Christopher A. | Hankinson, Susan E. | Henderson, Brian E. | Hoover, Robert N. | Hunter, David J. | Isaacs, Claudine | Kaaks, Rudolf | Kolonel, Laurence N. | Krogh, Vittorio | Le Marchand, Loic | Lee, I-Min | Lund, Eiliv | McCarty, Catherine A. | Overvad, Kim | Peeters, Petra H. | Riboli, Elio | Schumacher, Fredrick | Severi, Gianluca | Stram, Daniel O. | Sund, Malin | Thun, Michael J. | Travis, Ruth C. | Trichopoulos, Dimitrios | Willett, Walter C. | Zhang, Shumin | Ziegler, Regina G. | Kraft, Peter | Joshi, Amit D. | Lindström, Sara | Hunter, David J. | Kraft, Peter | Hüsing, Anika | Barrdahl, Myrto | Kaaks, Rudolf | Kraft, Peter | VanderWeele, Tyler J. | Trichopoulos, Dimitrios | Campa, Daniele | VanderWeele, Tyler J. | Campa, Daniele | Canzian, Federico | Gaudet, Mia M. | Figueroa, Jonine D. | Chanock, Stephen J. | Hoover, Robert N. | Ziegler, Regina G. | Baglietto, Laura | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Giles, Graham G. | Severi, Gianluca | Berg, Christine D. | Buring, Julie E. | Lee, I-Min | Zhang, Shumin | Chirlaque, María-Dolores | Chirlaque, María-Dolores | Diver, W. Ryan | Thun, Michael J. | Dossus, Laure | Dossus, Laure | Giles, Graham G. | Haiman, Christopher A. | Schumacher, Fredrick | Stram, Daniel O. | Henderson, Brian E. | Hankinson, Susan E. | Isaacs, Claudine | Kolonel, Laurence N. | Krogh, Vittorio | Marchand, Loic Le | Lund, Eiliv | McCarty, Catherine A. | Overvad, Kim | Peeters, Petra H. | Peeters, Petra H. | Riboli, Elio | Sund, Malin | Travis, Ruth C. | Trichopoulos, Dimitrios | Trichopoulos, Dimitrios | Willett, Walter C.
American Journal of Epidemiology  2014;180(10):1018-1027.
Additive interactions can have public health and etiological implications but are infrequently reported. We assessed departures from additivity on the absolute risk scale between 9 established breast cancer risk factors and 23 susceptibility single-nucleotide polymorphisms (SNPs) identified from genome-wide association studies among 10,146 non-Hispanic white breast cancer cases and 12,760 controls within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium. We estimated the relative excess risk due to interaction and its 95% confidence interval for each pairwise combination of SNPs and nongenetic risk factors using age- and cohort-adjusted logistic regression models. After correction for multiple comparisons, we identified a statistically significant relative excess risk due to interaction (uncorrected P = 4.51 × 10−5) between a SNP in the DNA repair protein RAD51 homolog 2 gene (RAD51L1; rs10483813) and body mass index (weight (kg)/height (m)2). We also compared additive and multiplicative polygenic risk prediction models using per-allele odds ratio estimates from previous studies for breast-cancer susceptibility SNPs and observed that the multiplicative model had a substantially better goodness of fit than the additive model.
PMCID: PMC4224360  PMID: 25255808
additive interactions; breast cancer; genome-wide association studies; single-nucleotide polymorphisms
2.  Prediagnostic Sex Steroid Hormones in Relation to Male Breast Cancer Risk 
Journal of Clinical Oncology  2015;33(18):2041-2050.
Although previous studies have implicated a variety of hormone-related risk factors in the etiology of male breast cancers, no previous studies have examined the effects of endogenous hormones.
Patients and Methods
Within the Male Breast Cancer Pooling Project, an international consortium comprising 21 case-control and cohort investigations, a subset of seven prospective cohort studies were able to contribute prediagnostic serum or plasma samples for hormone quantitation. Using a nested case-control design, multivariable unconditional logistic regression analyses estimated odds ratios and 95% CIs for associations between male breast cancer risk and 11 individual estrogens and androgens, as well as selected ratios of these analytes.
Data from 101 cases and 217 matched controls were analyzed. After adjustment for age and date of blood draw, race, and body mass index, androgens were found to be largely unrelated to risk, but circulating estradiol levels showed a significant association. Men in the highest quartile had an odds ratio of 2.47 (95% CI, 1.10 to 5.58) compared with those in the lowest quartile (trend P = .06). Assessment of estradiol as a ratio to various individual androgens or sum of androgens showed no further enhancement of risk. These relations were not significantly modified by either age or body mass index, although estradiol was slightly more strongly related to breast cancers occurring among younger (age < 67 years) than older men.
Our results support the notion of an important role for estradiol in the etiology of male breast cancers, similar to female breast cancers.
PMCID: PMC4461805  PMID: 25964249
3.  Excess Body Weight and Colorectal Cancer Survival: The Multiethnic Cohort 
Cancer causes & control : CCC  2015;26(12):1709-1718.
Excess body weight is a risk factor for colorectal cancer (CRC) and may also adversely affect survival in CRC patients.
This study examined the relation of body mass index (BMI), which was self-reported at cohort entry and after 5.7±0.8 years, with CRC-specific and all-cause survival among 4,204 incident cases of invasive CRC in the Multiethnic Cohort (MEC). Cox regression analysis with age as time metric and BMI as time-varying exposure was applied to estimate hazard ratios (HR) and 95% confidence intervals (CIs) while adjusting for relevant covariates.
Over 6.0±4.7 years of follow-up, 1,976 all-cause and 1,095 CRC-specific deaths were recorded. The mean time interval between cohort entry and diagnosis was 7.6±4.7 years. No association with CRC-specific survival was detected in men (HR5units=0.94; 95%CI 0.84–1.04) or women (HR5units=0.98; 95%CI 0.89–1.08). In men, all-cause survival also showed no relation with BMI (HR5unit=0.97; 95%CI 0.90–1.06), whereas it was reduced in women (HR5units=1.10; 95%CI 1.03–1.18). Interactions of BMI with ethnicity were only significant for obesity. Obese Latino and overweight Native Hawaiian men as well as overweight African American women, experienced significantly better CRC-specific survival than whites. Overweight Japanese men and African American women had better all-cause survival and obese Latino women had the lowest all-cause survival (HRobese=1.74; 95%CI 1.08–2.80).
This analysis detected little evidence for an adverse effect of excess body weight on CRC-specific survival, but all-cause survival was reduced in women. These findings suggest that adiposity may be less important for CRC survival than as an etiologic factor.
PMCID: PMC4628582  PMID: 26358830
Colorectal cancer; obesity; survival; ethnicity
4.  Physical Activity and Risk of Male Breast Cancer 
The association between leisure-time physical activity (LTPA) and male breast cancer risk (MBC) is unclear. In the MBC pooling project, with 449 cases and 13,855 matched controls, we used logistic regression with study stratification to generate adjusted odds ratios (OR) and 95% confidence intervals (CI) for LTPA tertiles and MBC risk. Compared with low LTPA, medium and high LTPA were not associated with MBC risk (OR=1.01, 95% CI 0.79–1.29; 0.90, 0.69–1.18, respectively). In joint-effects analyses, compared with the referent of high body mass index (BMI) (≥25 kg/m2)/low LTPA, neither medium nor high PA were associated with risk among high BMI men, but normal BMI men (<25 kg/m2) with low or medium LTPA were at a non-significant ~16% reduced risk and those with high LTPA were at a 27% reduced risk (OR=0.73, 95% CI 0.50–1.07). Physical activity alone may not confer protection against MBC risk.
PMCID: PMC4670580  PMID: 26404962
Male breast cancer; epidemiology; physical activity; pooled analysis
5.  Associations Between Genetic Ancestries and Nicotine Metabolism Biomarkers in the Multiethnic Cohort Study 
American Journal of Epidemiology  2015;182(11):945-951.
Differences in internal dose of nicotine and tobacco-derived carcinogens among ethnic/racial groups have been observed. In this study, we explicitly examined the relationships between genetic ancestries (genome-wide average) and 19 tobacco-derived biomarkers in smokers from 3 admixed groups in the Multiethnic Cohort Study (1993–present), namely, African ancestry in African Americans (n = 362), Amerindian ancestry in Latinos (n = 437), and Asian and Native Hawaiian ancestries in Native Hawaiians (n = 300). After multiple comparison adjustment, both African and Asian ancestries were significantly related to a greater level of free cotinine; African ancestry was also significantly related to lower cotinine glucuronidation (P's < 0.00156). The predicted decrease in cotinine glucuronidation was 8.6% (P = 4.5 × 10−6) per a 20% increase in African ancestry. Follow-up admixture mapping revealed that African ancestry in a 12-Mb region on chromosome 4q was related to lower cotinine glucuronidation (P's < 2.7 × 10−7, smallest P = 1.5 × 10−9), although this is the same region reported in our previous genome-wide association study. Our results implicate a genetic ancestral component in the observed ethnic/racial variation in nicotine metabolism. Further studies are needed to identify the underlying genetic variation that could potentially be ethnic/racial specific.
PMCID: PMC4805060  PMID: 26568573
association study; blacks; health disparity; Hispanics; nicotine addiction; Pacific Islanders
6.  Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types 
Sampson, Joshua N. | Wheeler, William A. | Yeager, Meredith | Panagiotou, Orestis | Wang, Zhaoming | Berndt, Sonja I. | Lan, Qing | Abnet, Christian C. | Amundadottir, Laufey T. | Figueroa, Jonine D. | Landi, Maria Teresa | Mirabello, Lisa | Savage, Sharon A. | Taylor, Philip R. | Vivo, Immaculata De | McGlynn, Katherine A. | Purdue, Mark P. | Rajaraman, Preetha | Adami, Hans-Olov | Ahlbom, Anders | Albanes, Demetrius | Amary, Maria Fernanda | An, She-Juan | Andersson, Ulrika | Andriole, Gerald | Andrulis, Irene L. | Angelucci, Emanuele | Ansell, Stephen M. | Arici, Cecilia | Armstrong, Bruce K. | Arslan, Alan A. | Austin, Melissa A. | Baris, Dalsu | Barkauskas, Donald A. | Bassig, Bryan A. | Becker, Nikolaus | Benavente, Yolanda | Benhamou, Simone | Berg, Christine | Van Den Berg, David | Bernstein, Leslie | Bertrand, Kimberly A. | Birmann, Brenda M. | Black, Amanda | Boeing, Heiner | Boffetta, Paolo | Boutron-Ruault, Marie-Christine | Bracci, Paige M. | Brinton, Louise | Brooks-Wilson, Angela R. | Bueno-de-Mesquita, H. Bas | Burdett, Laurie | Buring, Julie | Butler, Mary Ann | Cai, Qiuyin | Cancel-Tassin, Geraldine | Canzian, Federico | Carrato, Alfredo | Carreon, Tania | Carta, Angela | Chan, John K. C. | Chang, Ellen T. | Chang, Gee-Chen | Chang, I-Shou | Chang, Jiang | Chang-Claude, Jenny | Chen, Chien-Jen | Chen, Chih-Yi | Chen, Chu | Chen, Chung-Hsing | Chen, Constance | Chen, Hongyan | Chen, Kexin | Chen, Kuan-Yu | Chen, Kun-Chieh | Chen, Ying | Chen, Ying-Hsiang | Chen, Yi-Song | Chen, Yuh-Min | Chien, Li-Hsin | Chirlaque, María-Dolores | Choi, Jin Eun | Choi, Yi Young | Chow, Wong-Ho | Chung, Charles C. | Clavel, Jacqueline | Clavel-Chapelon, Françoise | Cocco, Pierluigi | Colt, Joanne S. | Comperat, Eva | Conde, Lucia | Connors, Joseph M. | Conti, David | Cortessis, Victoria K. | Cotterchio, Michelle | Cozen, Wendy | Crouch, Simon | Crous-Bou, Marta | Cussenot, Olivier | Davis, Faith G. | Ding, Ti | Diver, W. Ryan | Dorronsoro, Miren | Dossus, Laure | Duell, Eric J. | Ennas, Maria Grazia | Erickson, Ralph L. | Feychting, Maria | Flanagan, Adrienne M. | Foretova, Lenka | Fraumeni, Joseph F. | Freedman, Neal D. | Beane Freeman, Laura E. | Fuchs, Charles | Gago-Dominguez, Manuela | Gallinger, Steven | Gao, Yu-Tang | Gapstur, Susan M. | Garcia-Closas, Montserrat | García-Closas, Reina | Gascoyne, Randy D. | Gastier-Foster, Julie | Gaudet, Mia M. | Gaziano, J. Michael | Giffen, Carol | Giles, Graham G. | Giovannucci, Edward | Glimelius, Bengt | Goggins, Michael | Gokgoz, Nalan | Goldstein, Alisa M. | Gorlick, Richard | Gross, Myron | Grubb, Robert | Gu, Jian | Guan, Peng | Gunter, Marc | Guo, Huan | Habermann, Thomas M. | Haiman, Christopher A. | Halai, Dina | Hallmans, Goran | Hassan, Manal | Hattinger, Claudia | He, Qincheng | He, Xingzhou | Helzlsouer, Kathy | Henderson, Brian | Henriksson, Roger | Hjalgrim, Henrik | Hoffman-Bolton, Judith | Hohensee, Chancellor | Holford, Theodore R. | Holly, Elizabeth A. | Hong, Yun-Chul | Hoover, Robert N. | Horn-Ross, Pamela L. | Hosain, G. M. Monawar | Hosgood, H. Dean | Hsiao, Chin-Fu | Hu, Nan | Hu, Wei | Hu, Zhibin | Huang, Ming-Shyan | Huerta, Jose-Maria | Hung, Jen-Yu | Hutchinson, Amy | Inskip, Peter D. | Jackson, Rebecca D. | Jacobs, Eric J. | Jenab, Mazda | Jeon, Hyo-Sung | Ji, Bu-Tian | Jin, Guangfu | Jin, Li | Johansen, Christoffer | Johnson, Alison | Jung, Yoo Jin | Kaaks, Rudolph | Kamineni, Aruna | Kane, Eleanor | Kang, Chang Hyun | Karagas, Margaret R. | Kelly, Rachel S. | Khaw, Kay-Tee | Kim, Christopher | Kim, Hee Nam | Kim, Jin Hee | Kim, Jun Suk | Kim, Yeul Hong | Kim, Young Tae | Kim, Young-Chul | Kitahara, Cari M. | Klein, Alison P. | Klein, Robert J. | Kogevinas, Manolis | Kohno, Takashi | Kolonel, Laurence N. | Kooperberg, Charles | Kricker, Anne | Krogh, Vittorio | Kunitoh, Hideo | Kurtz, Robert C. | Kweon, Sun-Seog | LaCroix, Andrea | Lawrence, Charles | Lecanda, Fernando | Lee, Victor Ho Fun | Li, Donghui | Li, Haixin | Li, Jihua | Li, Yao-Jen | Li, Yuqing | Liao, Linda M. | Liebow, Mark | Lightfoot, Tracy | Lim, Wei-Yen | Lin, Chien-Chung | Lin, Dongxin | Lindstrom, Sara | Linet, Martha S. | Link, Brian K. | Liu, Chenwei | Liu, Jianjun | Liu, Li | Ljungberg, Börje | Lloreta, Josep | Lollo, Simonetta Di | Lu, Daru | Lund, Eiluv | Malats, Nuria | Mannisto, Satu | Marchand, Loic Le | Marina, Neyssa | Masala, Giovanna | Mastrangelo, Giuseppe | Matsuo, Keitaro | Maynadie, Marc | McKay, James | McKean-Cowdin, Roberta | Melbye, Mads | Melin, Beatrice S. | Michaud, Dominique S. | Mitsudomi, Tetsuya | Monnereau, Alain | Montalvan, Rebecca | Moore, Lee E. | Mortensen, Lotte Maxild | Nieters, Alexandra | North, Kari E. | Novak, Anne J. | Oberg, Ann L. | Offit, Kenneth | Oh, In-Jae | Olson, Sara H. | Palli, Domenico | Pao, William | Park, In Kyu | Park, Jae Yong | Park, Kyong Hwa | Patiño-Garcia, Ana | Pavanello, Sofia | Peeters, Petra H. M. | Perng, Reury-Perng | Peters, Ulrike | Petersen, Gloria M. | Picci, Piero | Pike, Malcolm C. | Porru, Stefano | Prescott, Jennifer | Prokunina-Olsson, Ludmila | Qian, Biyun | Qiao, You-Lin | Rais, Marco | Riboli, Elio | Riby, Jacques | Risch, Harvey A. | Rizzato, Cosmeri | Rodabough, Rebecca | Roman, Eve | Roupret, Morgan | Ruder, Avima M. | de Sanjose, Silvia | Scelo, Ghislaine | Schned, Alan | Schumacher, Fredrick | Schwartz, Kendra | Schwenn, Molly | Scotlandi, Katia | Seow, Adeline | Serra, Consol | Serra, Massimo | Sesso, Howard D. | Setiawan, Veronica Wendy | Severi, Gianluca | Severson, Richard K. | Shanafelt, Tait D. | Shen, Hongbing | Shen, Wei | Shin, Min-Ho | Shiraishi, Kouya | Shu, Xiao-Ou | Siddiq, Afshan | Sierrasesúmaga, Luis | Sihoe, Alan Dart Loon | Skibola, Christine F. | Smith, Alex | Smith, Martyn T. | Southey, Melissa C. | Spinelli, John J. | Staines, Anthony | Stampfer, Meir | Stern, Marianna C. | Stevens, Victoria L. | Stolzenberg-Solomon, Rachael S. | Su, Jian | Su, Wu-Chou | Sund, Malin | Sung, Jae Sook | Sung, Sook Whan | Tan, Wen | Tang, Wei | Tardón, Adonina | Thomas, David | Thompson, Carrie A. | Tinker, Lesley F. | Tirabosco, Roberto | Tjønneland, Anne | Travis, Ruth C. | Trichopoulos, Dimitrios | Tsai, Fang-Yu | Tsai, Ying-Huang | Tucker, Margaret | Turner, Jenny | Vajdic, Claire M. | Vermeulen, Roel C. H. | Villano, Danylo J. | Vineis, Paolo | Virtamo, Jarmo | Visvanathan, Kala | Wactawski-Wende, Jean | Wang, Chaoyu | Wang, Chih-Liang | Wang, Jiu-Cun | Wang, Junwen | Wei, Fusheng | Weiderpass, Elisabete | Weiner, George J. | Weinstein, Stephanie | Wentzensen, Nicolas | White, Emily | Witzig, Thomas E. | Wolpin, Brian M. | Wong, Maria Pik | Wu, Chen | Wu, Guoping | Wu, Junjie | Wu, Tangchun | Wu, Wei | Wu, Xifeng | Wu, Yi-Long | Wunder, Jay S. | Xiang, Yong-Bing | Xu, Jun | Xu, Ping | Yang, Pan-Chyr | Yang, Tsung-Ying | Ye, Yuanqing | Yin, Zhihua | Yokota, Jun | Yoon, Ho-Il | Yu, Chong-Jen | Yu, Herbert | Yu, Kai | Yuan, Jian-Min | Zelenetz, Andrew | Zeleniuch-Jacquotte, Anne | Zhang, Xu-Chao | Zhang, Yawei | Zhao, Xueying | Zhao, Zhenhong | Zheng, Hong | Zheng, Tongzhang | Zheng, Wei | Zhou, Baosen | Zhu, Meng | Zucca, Mariagrazia | Boca, Simina M. | Cerhan, James R. | Ferri, Giovanni M. | Hartge, Patricia | Hsiung, Chao Agnes | Magnani, Corrado | Miligi, Lucia | Morton, Lindsay M. | Smedby, Karin E. | Teras, Lauren R. | Vijai, Joseph | Wang, Sophia S. | Brennan, Paul | Caporaso, Neil E. | Hunter, David J. | Kraft, Peter | Rothman, Nathaniel | Silverman, Debra T. | Slager, Susan L. | Chanock, Stephen J. | Chatterjee, Nilanjan
Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.
Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.
GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl 2, on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.
Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
PMCID: PMC4806328  PMID: 26464424
7.  Smoking and Risk of Breast Cancer in a Racially/Ethnically Diverse Population of Mainly Women Who Do Not Drink Alcohol 
American Journal of Epidemiology  2015;182(11):917-925.
We prospectively examined the association between smoking and the risk of breast cancer in a racially/ethnically diverse population comprising mainly women who did not drink alcohol. From 1993 to 2010, we followed 83,300 women who were enrolled in the Multiethnic Cohort Study at 45–75 years of age. We identified cancer cases via linkage to the Surveillance, Epidemiology, and End Results Program cancer registries that covered the states of Hawaii and California through December 2010. We used Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals while adjusting for confounders that were decided a priori. During a mean follow-up of 15 years, 4,484 women developed invasive breast cancer. Compared with parous never smokers, women who had smoked for more than 20 pack-years and initiated smoking more than 5 years before their first childbirth had an overall risk of breast cancer that was 35% higher (hazard ratio = 1.35, 95% confidence interval: 1.13, 1.63). Among women who did not drink alcohol, the risk was 40% higher (hazard ratio = 1.40, 95% confidence interval: 1.08, 1.81). This higher risk did not significantly differ among racial/ethnic groups (Pinteraction = 0.82). We found that various measures of smoking exposure were associated with a higher risk of breast cancer, especially smoking initiated many years before first childbirth, and that risk did not differ by alcohol consumption (yes vs. no) or racial/ethnic group.
PMCID: PMC4836396  PMID: 26493265
breast cancer; cohort studies; confounding; ethnic differences; Multiethnic Cohort Study; alcohol abstinence; smoking; smoking duration before first childbirth
8.  Racial/ethnic differences in lifestyle-related factors and prostate cancer risk: the Multiethnic Cohort Study 
Cancer causes & control : CCC  2015;26(10):1507-1515.
Older age, African ancestry, and family history of prostate cancer are well-established risk factors for prostate cancer and all are non-modifiable. Various lifestyle factors have been examined in relation to prostate cancer risk, including diet, obesity, and physical activity; however, none of them has been consistently related to risk. In the Multiethnic Cohort Study, we investigated whether lifestyle-related factors are associated with prostate cancer risk and whether such factors explain the racial/ethnic differences in risk.
During a mean follow-up of 13.9 years, 7,115 incident cases were identified among 75,216 white, African American, Native Hawaiian, Japanese American, and Latino men. Cox proportional hazards models were used to calculate relative risks (RR) and 95% confidence intervals (95% CI) for prostate cancer.
Among selected lifestyle-related factors including body mass index, height, education, physical activity, and intakes of alcohol, calcium, legumes, lycopene, and selenium, only smoking (RR for current (≥20 cigarettes/day) vs. never smoking = 0.72; 95% CI: 0.63-0.83) and history of diabetes (RR for yes vs. no = 0.78; 95% CI: 0.72-0.85) were significantly associated with prostate cancer risk. Compared to whites, the risk of incident prostate cancer was two-fold higher in African Americans and 16% higher in Latinos. Additional adjustment for a history of PSA testing did not change the results.
The findings suggest that racial/ethnic differences in prostate cancer risk are not explained by the lifestyle factors examined, and that underlying genetic factors may be involved.
PMCID: PMC4567936  PMID: 26243447
cohort; lifestyle factors; multiethnic population; prostate cancer; racial/ethnic difference
9.  Ethnic Admixture Affects Diabetes Risk in Native Hawaiians: The Multiethnic Cohort 
Obesity and diabetes rates are high in Native Hawaiians (NH) who commonly have mixed ancestries. Persons of Asian ancestry experience a high risk of type 2 diabetes despite the relatively low body weight. We evaluated the impact of ethnic admixture on diabetes risk among NH in the Multiethnic Cohort (MEC).
Based on self-reports, 11,521 eligible men and women were categorized into NH/white, NH/other, NH alone, NH/Asian, and the most common three ancestry admixture, NH/Chinese/white. Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with the NH/white category as the reference group; covariates included known confounders, i.e., body mass index (BMI), dietary and other life-style factors.
The NH alone category had the highest proportion of overweight and obese individuals and the NH/Asian category the lowest proportion. During 12 years of follow-up after cohort entry at 56 years, 2,072 incident cases were ascertained through questionnaires and health plan linkages. All NH categories had higher HRs than the NH/white category before and after adjustment for BMI. In fully-adjusted models, the NH/Asian category showed the highest risk (HR=1.45; 95%CI: 1.27–1.65), followed by NH/other (HR=1.20; 95%CI: 1.03–1.39), NH/Chinese/white (HR=1.19; 95%CI: 1.04–1.37), and NH alone (HR=1.19; 95%CI: 1.03–1.37). The elevated risk by Asian admixture was more pronounced in normal weight than overweight/obese individuals.
These findings indicate that Asian admixture in NHs is associated with higher risk for type 2 diabetes independent of known risk factors and suggest a role for ethnicity-related genetic factors in the development of this disease.
PMCID: PMC5014576  PMID: 27026423
10.  Adherence to recommendations for fruit and vegetable intake, ethnicity and ischemic heart disease mortality 
Background and aims
Ischemic heart disease (IHD) accounts for one-third of annual deaths in the U.S. and mortality rates vary by ethnicity. The association between adherence to dietary guidelines for fruit and vegetable intake with IHD mortality among different ethnic groups has not previously been examined.
Methods and results
A prospective cohort design was used to examine the incidence of fatal IHD among participants in the Multiethnic Cohort Study. Participants included 164,617 men and women from five ethnic groups: African American, Native Hawaiian, Japanese American, Latino, and Caucasian. Cox proportional hazards models, stratified by ethnicity and sex, were used to examine associations between adherence with recommended dietary guidelines for fruit and vegetable intake and risk for fatal IHD. The results did not provide evidence that the association between adherence with dietary recommendations for fruit or vegetable intake and IHD mortality varies by ethnicity. Pooled data did provide evidence that adhering to the recommendations for vegetables lowered risk among men (RR Z 0.84, 95% CI: 0.74e0.96) and women (RR Z 0.80, 95% CI: 0.69e0.94). No significant effects were observed for fruit intake.
The effect of dietary intake of fruit and vegetables did not vary by ethnicity, providing evidence that recommendations do not need to be individualized for these special populations. The protective effect observed for vegetable intake among both sexes confirms previous findings and supports the evidence base for promoting diet modification in this direction.
PMCID: PMC5028136  PMID: 23725771
Dietary recommendations; fatal ischemic heart disease; ethnicity; Multiethnic Cohort Study
11.  Fruit and vegetable consumption, ethnicity and risk of fatal ischemic heart disease 
Mortality rates from ischemic heart disease vary among ethnic groups. Dietary intake of fruit and vegetables has been associated with a lower risk of ischemic heart disease, but ethnic-specific data are limited.
Prospective cohort study.
Hawaii and Los Angeles County, between 1993 and 1996.
These analyses included 164,617 older adults age 45 to 75, representing five ethnic groups who were enrolled in the Multiethnic Cohort Study. Dietary data were collected at baseline using a validated food frequency questionnaire and fatal ischemic heart disease cases were identified up to December 31, 2001. Associations between fruit and vegetable consumption and fatal ischemic heart disease were examined using multivariate Cox proportional hazard models.
The associations between fruit and vegetable intake and fatal ischemic heart disease were similar among the five ethnic groups. When data for the ethnic groups were combined, higher vegetable intake was associated with a protective effect against ischemic heart disease in men with all intake levels above 2.3 servings per day (over 6.6 servings per day: hazard ratio, 0.73; 95% confidence interval, 0.58–0.92), and for women with intakes levels between 3.4 and 6.6 servings per day (4.6 to 6.6 servings per day: hazard ratio, 0.77; 95% confidence interval, 0.59–0.99). There was no evidence of an association for fruit intake.
Associations between fruit and vegetable intake and ischemic heart disease do not appear to vary among ethnic groups. Additional research is needed to clarify associations for fruit versus vegetable intake and impact on cardiovascular outcomes.
PMCID: PMC5025250  PMID: 24950146
Diet; Myocardial Ischemia; Mortality; Ethnicity
12.  Impact of Diet on Mortality From Stroke: Results From the U.S. Multiethnic Cohort Study 
Stroke is the fourth leading cause of death in the United States and stroke mortality rates vary by ethnicity. The purpose of this study was to examine the associations between food group consumption and risk of death from stroke among 5 ethnic groups in the United States.
The Multiethnic Cohort includes >215,000 participants, the majority of whom are African American, Native Hawaiian, Japanese American, Latino, and Caucasian men and women recruited by mail survey in Hawaii and Los Angeles in 1993–1996. Deaths from stroke were identified by linkage to the state death files and the U.S. National Death Index. Diet was assessed using a validated food frequency questionnaire. Associations were examined using multivariable Cox proportional hazards models, stratified by ethnicity and gender.
A total of 860 deaths from stroke were identified among the cohort participants. Vegetable intake was associated with a significant reduction in risk for fatal stroke among African American women (relative risk [RR] = 0.60; 95% CI: 0.36–0.99). Among Japanese American women only, high fruit intake was significantly associated with a risk reduction for stroke mortality (RR = 0.43; 95% confidence interval [CI]: 0.22–0.85), whereas meat intake increased risk (RR = 2.36; 95% CI: 1.31–4.26). Among men, a significant reduction in stroke mortality was observed among Native Hawaiians (RR = 0.26; 95% CI: 0.07–0.95). After pooling the data for the ethnic groups, the findings support an elevated risk for high meat intake among women overall (RR = 1.56; 95% CI: 1.12–2.16); no significant effects of dietary intake on risk for fatal stroke were observed among men.
Although some variations were observed for the associations between diet and stroke mortality among ethnic groups, the findings suggest that these differences are not substantial and may be due to dietary intake of specific food subgroups. Additional investigations including dietary subgroups and nutrients sources are needed to clarify these findings.
PMCID: PMC5023006  PMID: 23885988
stroke mortality; food groups; ethnicity; Multiethnic Cohort Study
13.  Contribution of meat to vitamin B-12, iron, and zinc intakes in five ethnic groups in the U.S.: Implications for developing food-based dietary guidelines 
To describe the sources of meat and their contributions to vitamin B-12, iron, and zinc in five ethnic groups in the USA.
Dietary data for the Multiethnic Cohort, established in Hawaii and Los Angeles, were collected using a quantitative food frequency questionnaire from more than 215,000 subjects aged 45–75 years at baseline (1993–1996). Participants included African American, Latino, Japanese American (JpAm), Native Hawaiian (NH) and Caucasian men and women. Servings of meat items were calculated based on the USDA recommendations and their contributions to intakes of total meat, red meat, vitamin B-12, iron, and zinc were determined.
Of all types of meat, poultry contributed the most to meat consumption, followed by red meat and fish among all ethnicities, except for Latino (born in Mexico and Central/South America) men who consumed more beef. Lean beef was the most commonly consumed red meat for all ethnic-sex groups (9.3–14.3%), except for NH and JpAm men, and JpAm women whose top contributor was stew/curry with beef/lamb and stir-fried beef/pork with vegetables respectively. The contribution of meat was most substantial for zinc (11.1–29.3%) and vitamin B-12 (19.7–40%), and to a lesser extent for iron (4.3–14.2%).
This is the first large multiethnic cohort study to describe meat sources and their contributions to selected nutrients among ethnic minorities in the U.S. These findings may be used to develop ethnic-specific recommendations for meat consumption to improve dietary quality among these groups.
PMCID: PMC5023012  PMID: 23398393
ethnic groups; food contribution; iron; meat; vitamin B12; zinc
14.  Fruits, Vegetables, and Hypersensitive Disease Mortality 
Epidemiology (Cambridge, Mass.)  2014;25(2):317-319.
PMCID: PMC5021510  PMID: 24487224
15.  Diet impacts mortality from cancer: Results from the Multiethnic Cohort study 
Cancer causes & control : CCC  2013;24(4):685-693.
Cancer is the second leading cause of death in the United States and mortality varies by ethnicity. The objective of this study was to examine the association between cancer mortality and dietary intake among a large multiethnic population.
A prospective cohort design was used to examine the incidence of fatal cancer cases among participants in the Multiethnic Cohort Study. Participants included >215,000 men and women from five ethnic groups: African American, Native Hawaiian, Japanese American, Latino, and Caucasian. Hazard ratios (HR) for cancer mortality by intake levels of food groups and dietary components were calculated using Cox proportional hazards models stratified by sex and ethnicity.
There were a total of 2,028 male and 1,464 female cancer fatal cases at the end of follow-up. Stratified analyses results suggest that the effect of grain consumption on risk of total cancer mortality varies by ethnicity and sex. Among Japanese American men only, there was a significant protective effect among those reporting a high grain intake (HR=0.49, 95% CI: 0.35–0.69); there was no effect of grain consumption in any other ethnic-sex group. There was no evidence that ethnicity modified associations between fruit, vegetable, meat, dairy, or discretionary fat intake and risk of developing cancer among men. Associations between food group consumption and risk for cancer mortality among women were similar across ethnic groups.
The considerable reduction in cancer risk associated with high grain consumption among a specific ethnic-sex group, Japanese American men, warrants further investigation. Additional research is needed to validate this observation and determine whether this was a chance finding, or possibly due to differential intake of specific grain subtypes, and/or related to a sex-specific cancer type.
PMCID: PMC5017587  PMID: 23329368
Cancer mortality; USDA food groups; ethnicity; Multiethnic Cohort study; Diet
16.  Intakes of caffeine, coffee and tea and risk of Amyotrophic Lateral Sclerosis: Results from five cohort studies 
Caffeine is thought to be neuroprotective by antagonizing the adenosine A2A receptors in the brain and thereby protecting motor neurons from excitotoxicity. We examined the association between consumption of caffeine, coffee and tea and risk of Amyotrophic Lateral Sclerosis (ALS).
Longitudinal analyses based on over 1 010 000 men and women in 5 large cohort studies [the Nurses’ Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health – AARP Diet and Health Study]. Cohort-specific multivariable-adjusted risk ratios (RR) and 95% confidence intervals (CI) estimates of ALS incidence or death was estimated by Cox proportional hazards regression and pooled using random-effects models.
A total of 1279 cases of ALS were documented during a mean of 18 years of follow-up. Caffeine intake was not associated with ALS risk; the pooled multivariable-adjusted RR comparing the highest to the lowest quintile of intake was 0.96 (95% CI 0.81-1.16). Similarly, neither coffee nor tea was associated with ALS risk.
The results of this large study do not support associations of caffeine or caffeinated beverages with ALS risk.
PMCID: PMC4589421  PMID: 25822002
Amyotrophic Lateral Sclerosis; Motor Neuron Disease; caffeine; epidemiology; longitudinal cohort studies
17.  Identification of a common variant with potential pleiotropic effect on risk of inflammatory bowel disease and colorectal cancer 
Carcinogenesis  2015;36(9):999-1007.
We identified the minor allele (T) in SNP rs11676348 to have pleiotropic effect on risk of UC and CRC, particularly in tumors with an inflammatory component. Our findings offer the promise of risk stratification of UC patients for developing CRC.
Although genome-wide association studies (GWAS) have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn’s disease (CD) and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies. Among 11794 CRC cases and 14190 controls, rs11676348, the susceptibility single nucleotide polymorphism (SNP) for UC, was significantly associated with reduced risk of CRC (P = 7E−05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI 0.89–0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (P heterogeneity = 0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn’s-like reaction but not tumors without such immune infiltrate (P heterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (P heterogeneity = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn’s-like reaction and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC.
PMCID: PMC4573660  PMID: 26071399
18.  Important Role of Menarche in Development of Estrogen Receptor–Negative Breast Cancer in African American Women 
Menarche is a critical time point for diverging fates of mammary cells of origin. African American women have young age at menarche, which could be associated with their high rates of estrogen receptor–negative (ER-) breast cancer.
In the AMBER Consortium, using harmonized data from 4426 African American women with breast cancer and 17 474 controls, we used polytomous logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for ages at menarche and first live birth (FLB), and the interval between, in relation to ER+ and ER- breast cancer. All statistical tests were two-sided.
Risk of ER- breast cancer was reduced with later age at menarche among both parous and nulliparous women (≥15 vs <11 years OR = 0.62, 95% CI = 0.48 to 0.81 and OR = 0.56, 95% CI = 0.29 to 1.10, respectively), with no effect of age at FLB. For ER+ breast cancer, the inverse association was weaker among nulliparous women. While longer intervals between menarche and FLB were associated with increased risk of ER+ breast cancer in a dose-response fashion (OR for 20 year interval = 1.39, 95% CI = 1.08 to 1.79, P trend = .003), ER- risk was only increased for intervals up to 14 years and not beyond (P trend = .33).
While ER- breast cancer risk was markedly reduced in women with a late age at menarche, there was not a clear pattern of increased risk with longer interval between menarche and FLB, as was observed for ER+ breast cancer. These findings indicate that etiologic pathways involving adolescence and pregnancy may differ for ER- and ER+ breast cancer.
PMCID: PMC4836800  PMID: 26085483
19.  Genome-wide association study of colorectal cancer identifies six new susceptibility loci 
Schumacher, Fredrick R. | Schmit, Stephanie L. | Jiao, Shuo | Edlund, Christopher K. | Wang, Hansong | Zhang, Ben | Hsu, Li | Huang, Shu-Chen | Fischer, Christopher P. | Harju, John F. | Idos, Gregory E. | Lejbkowicz, Flavio | Manion, Frank J. | McDonnell, Kevin | McNeil, Caroline E. | Melas, Marilena | Rennert, Hedy S. | Shi, Wei | Thomas, Duncan C. | Van Den Berg, David J. | Hutter, Carolyn M. | Aragaki, Aaron K. | Butterbach, Katja | Caan, Bette J. | Carlson, Christopher S. | Chanock, Stephen J. | Curtis, Keith R. | Fuchs, Charles S. | Gala, Manish | Giovannucci, Edward L. | Gogarten, Stephanie M. | Hayes, Richard B. | Henderson, Brian | Hunter, David J. | Jackson, Rebecca D. | Kolonel, Laurence N. | Kooperberg, Charles | Küry, Sébastien | LaCroix, Andrea | Laurie, Cathy C. | Laurie, Cecelia A. | Lemire, Mathieu | Levine, David | Ma, Jing | Makar, Karen W. | Qu, Conghui | Taverna, Darin | Ulrich, Cornelia M. | Wu, Kana | Kono, Suminori | West, Dee W. | Berndt, Sonja I. | Bezieau, Stéphane | Brenner, Hermann | Campbell, Peter T. | Chan, Andrew T. | Chang-Claude, Jenny | Coetzee, Gerhard A. | Conti, David V. | Duggan, David | Figueiredo, Jane C. | Fortini, Barbara K. | Gallinger, Steven J. | Gauderman, W. James | Giles, Graham | Green, Roger | Haile, Robert | Harrison, Tabitha A. | Hoffmeister, Michael | Hopper, John L. | Hudson, Thomas J. | Jacobs, Eric | Iwasaki, Motoki | Jee, Sun Ha | Jenkins, Mark | Jia, Wei-Hua | Joshi, Amit | Li, Li | Lindor, Noralene M. | Matsuo, Keitaro | Moreno, Victor | Mukherjee, Bhramar | Newcomb, Polly A. | Potter, John D. | Raskin, Leon | Rennert, Gad | Rosse, Stephanie | Severi, Gianluca | Schoen, Robert E. | Seminara, Daniela | Shu, Xiao-Ou | Slattery, Martha L. | Tsugane, Shoichiro | White, Emily | Xiang, Yong-Bing | Zanke, Brent W. | Zheng, Wei | Le Marchand, Loic | Casey, Graham | Gruber, Stephen B. | Peters, Ulrike
Nature communications  2015;6:7138.
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.
PMCID: PMC4967357  PMID: 26151821
20.  Plasma Coenzyme Q10 levels and Prostate Cancer Risk: The Multiethnic Cohort Study 
Coenzyme Q10 (CoQ10) is considered to be a potential anti-cancer agent, but epidemiological evidence regarding CoQ10 and prostate cancer risk is lacking. We examined the association of circulating CoQ10 levels with prostate cancer risk using pre-diagnostic blood samples.
Each of the 307 cases was individually-matched to approximately 2 controls on age, ethnicity, geographic location, date/time of specimen collection, and hours of fasting, for a total of 596 controls. Logistic regression was used to compute odds ratios and 95% confidence intervals.
There was no overall statistically significant association of plasma CoQ10 levels with prostate cancer risk (Ptrend = 0.50). However, after matched sets in which controls had possible undiagnosed prostate cancer (PSA > 4.0) were excluded, the odds ratios for quintiles 2–5 were all <1.0.
The results suggest the possibility that moderate levels of circulating CoQ10 may be optimal for the reduction of prostate cancer risk; however, the findings were weak and not statistically significant. Since this is the first epidemiologic study of the association between CoQ10 and prostate cancer, further research on this topic is needed.
If a nutritional factor like CoQ10 were determined to reduce prostate cancer risk, it would have considerable public health significance because of the very high incidence of this cancer.
PMCID: PMC4439209  PMID: 21297042
Coenzyme Q10 prostate cancer
21.  Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome 
Machiela, Mitchell J. | Zhou, Weiyin | Karlins, Eric | Sampson, Joshua N. | Freedman, Neal D. | Yang, Qi | Hicks, Belynda | Dagnall, Casey | Hautman, Christopher | Jacobs, Kevin B. | Abnet, Christian C. | Aldrich, Melinda C. | Amos, Christopher | Amundadottir, Laufey T. | Arslan, Alan A. | Beane-Freeman, Laura E. | Berndt, Sonja I. | Black, Amanda | Blot, William J. | Bock, Cathryn H. | Bracci, Paige M. | Brinton, Louise A. | Bueno-de-Mesquita, H Bas | Burdett, Laurie | Buring, Julie E. | Butler, Mary A. | Canzian, Federico | Carreón, Tania | Chaffee, Kari G. | Chang, I-Shou | Chatterjee, Nilanjan | Chen, Chu | Chen, Constance | Chen, Kexin | Chung, Charles C. | Cook, Linda S. | Crous Bou, Marta | Cullen, Michael | Davis, Faith G. | De Vivo, Immaculata | Ding, Ti | Doherty, Jennifer | Duell, Eric J. | Epstein, Caroline G. | Fan, Jin-Hu | Figueroa, Jonine D. | Fraumeni, Joseph F. | Friedenreich, Christine M. | Fuchs, Charles S. | Gallinger, Steven | Gao, Yu-Tang | Gapstur, Susan M. | Garcia-Closas, Montserrat | Gaudet, Mia M. | Gaziano, J. Michael | Giles, Graham G. | Gillanders, Elizabeth M. | Giovannucci, Edward L. | Goldin, Lynn | Goldstein, Alisa M. | Haiman, Christopher A. | Hallmans, Goran | Hankinson, Susan E. | Harris, Curtis C. | Henriksson, Roger | Holly, Elizabeth A. | Hong, Yun-Chul | Hoover, Robert N. | Hsiung, Chao A. | Hu, Nan | Hu, Wei | Hunter, David J. | Hutchinson, Amy | Jenab, Mazda | Johansen, Christoffer | Khaw, Kay-Tee | Kim, Hee Nam | Kim, Yeul Hong | Kim, Young Tae | Klein, Alison P. | Klein, Robert | Koh, Woon-Puay | Kolonel, Laurence N. | Kooperberg, Charles | Kraft, Peter | Krogh, Vittorio | Kurtz, Robert C. | LaCroix, Andrea | Lan, Qing | Landi, Maria Teresa | Marchand, Loic Le | Li, Donghui | Liang, Xiaolin | Liao, Linda M. | Lin, Dongxin | Liu, Jianjun | Lissowska, Jolanta | Lu, Lingeng | Magliocco, Anthony M. | Malats, Nuria | Matsuo, Keitaro | McNeill, Lorna H. | McWilliams, Robert R. | Melin, Beatrice S. | Mirabello, Lisa | Moore, Lee | Olson, Sara H. | Orlow, Irene | Park, Jae Yong | Patiño-Garcia, Ana | Peplonska, Beata | Peters, Ulrike | Petersen, Gloria M. | Pooler, Loreall | Prescott, Jennifer | Prokunina-Olsson, Ludmila | Purdue, Mark P. | Qiao, You-Lin | Rajaraman, Preetha | Real, Francisco X. | Riboli, Elio | Risch, Harvey A. | Rodriguez-Santiago, Benjamin | Ruder, Avima M. | Savage, Sharon A. | Schumacher, Fredrick | Schwartz, Ann G. | Schwartz, Kendra L. | Seow, Adeline | Wendy Setiawan, Veronica | Severi, Gianluca | Shen, Hongbing | Sheng, Xin | Shin, Min-Ho | Shu, Xiao-Ou | Silverman, Debra T. | Spitz, Margaret R. | Stevens, Victoria L. | Stolzenberg-Solomon, Rachael | Stram, Daniel | Tang, Ze-Zhong | Taylor, Philip R. | Teras, Lauren R. | Tobias, Geoffrey S. | Van Den Berg, David | Visvanathan, Kala | Wacholder, Sholom | Wang, Jiu-Cun | Wang, Zhaoming | Wentzensen, Nicolas | Wheeler, William | White, Emily | Wiencke, John K. | Wolpin, Brian M. | Wong, Maria Pik | Wu, Chen | Wu, Tangchun | Wu, Xifeng | Wu, Yi-Long | Wunder, Jay S. | Xia, Lucy | Yang, Hannah P. | Yang, Pan-Chyr | Yu, Kai | Zanetti, Krista A. | Zeleniuch-Jacquotte, Anne | Zheng, Wei | Zhou, Baosen | Ziegler, Regina G. | Perez-Jurado, Luis A. | Caporaso, Neil E. | Rothman, Nathaniel | Tucker, Margaret | Dean, Michael C. | Yeager, Meredith | Chanock, Stephen J.
Nature Communications  2016;7:11843.
To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
It is unclear how often genetic mosaicism of chromosome X arises. Here, the authors examine women with cancer and cancer-free controls and show that X chromosome mosaicism occurs more frequently than on autosomes, especially on the inactive X chromosome, but is not linked to non-haematologic cancer risk
PMCID: PMC4909985  PMID: 27291797
22.  Nutritional Factors and Non-Hodgkin Lymphoma Survival in an Ethnically Diverse Population: The Multiethnic Cohort Study 
To understand the possible effect of modifiable health behaviors on the prognosis of the increasing number of non-Hodgkin lymphoma (NHL) survivors, we examined the pre-diagnostic intake of major food groups with all-cause and NHL-specific survival in the Multiethnic Cohort (MEC).
This analysis included 2,339 participants free of NHL at cohort entry and diagnosed with NHL as identified b cancer registries during follow-up. Deaths were ascertained through routine linkages to state and national death registries. Cox proportional hazards regression was applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for overall and NHL-specific mortality according to prediagnostic intake of vegetables, fruits, red meat, processed meat, fish, legumes, dietary fiber, dairy products, and soy foods assessed by food frequency questionnaire.
The mean age at diagnosis was 71.8±8.5 years. During 4.5±4.1 years of follow-up, 1,348 deaths, including 903 NHL-specific deaths, occurred. In multivariable models, dairy intake was associated with higher all-cause mortality (highest vs. lowest tertile: HR=1.14, 95% CI 1.00–1.31, ptrend=0.03) and NHL-specific (HR=1.16, 95% CI 0.98–1.37) mortality. Legume intake above the lowest tertile was related to significant 13–16% lower all-cause and NHL-specific mortality, while red meat and fish intake in the intermediate tertiles was associated with lower NHL-specific mortality. No association with survival was detected for the other food groups.
These data suggest that pre-diagnostic dietary intake may not appreciably contribute to NHL survival although the higher mortality for dairy products and the better prognosis associated with legumes agree with known biologic effects of these foods.
PMCID: PMC4562319  PMID: 26330148
Non-Hodgkin Lymphoma; Ethnicity; Nutrition; Survival; Prognosis
23.  Associations between unprocessed red and processed meat, poultry, seafood and egg intake and the risk of prostate cancer: A pooled analysis of 15 prospective cohort studies 
International journal of cancer  2016;138(10):2368-2382.
Reports relating meat intake to prostate cancer risk are inconsistent. Associations between these dietary factors and prostate cancer were examined in a consortium of 15 cohort studies. During follow-up, 52, 683 incident prostate cancer cases, including 4,924 advanced cases, were identified among 842, 149 men. Cox proportional hazard models were used to calculate study-specific relative risks (RR) and then pooled using random effects models. Results do not support a substantial effect of total red, unprocessed red and processed meat for all prostate cancer outcomes, except for a modest positive association for tumors identified as advanced stage at diagnosis (advanced(r)). For seafood, no substantial effect was observed for prostate cancer regardless of stage or grade. Poultry intake was inversely associated with risk of advanced and fatal cancers (pooled multivariable RR [MVRR], 95% confidence interval, comparing ≥45 vs. <5 g/day: advanced 0.83, 0.70–0.99; trend test p value 0.29), fatal, 0.69, 0.59–0.82, trend test p value 0.16). Participants who ate ≥25 versus <5 g/day of eggs (1 egg ~ 50 g) had a significant 14% increased risk of advanced and fatal cancers (advanced 1.14, 1.01–1.28, trend test p value 0.01; fatal 1.14, 1.00–1.30, trend test p value 0.01). When associations were analyzed separately by geographical region (North America vs. other continents), positive associations between unprocessed red meat and egg intake, and inverse associations between poultry intake and advanced, advanced(r) and fatal cancers were limited to North American studies. However, differences were only statistically significant for eggs. Observed differences in associations by geographical region warrant further investigation.
PMCID: PMC4837898  PMID: 26685908
prostate cancer; diet; unprocessed red meat; processed meat; poultry; seafood; egg
24.  Disparity in Diabetes Risk across Native Hawaiians and Different Asian Groups: The Multiethnic Cohort 
We evaluated the impact of body mass index (BMI) and lifestyle risk factors on ethnic disparity in diabetes incidence among 89,198 Asian, Native Hawaiian, and white participants of the Multiethnic Cohort who completed multiple questionnaires. After 12 years of follow-up, 11,218 new cases were identified through self-report and health plan linkages. BMI was lowest in Chinese/Koreans, Japanese, and Filipinos (22.4, 23.5, 23.9 kg/m2). Using Cox regression, the unadjusted hazard ratios were 1.9 (Chinese/Korean), 2.1 (Japanese, Mixed-Asian), 2.2 (Filipino), 2.5 (Native Hawaiian), and 2.6 (Part-Asian) as compared to whites. With BMI added, the risk for Japanese, Filipinos, Chinese/Koreans, and Mixed-Asians increased (8–42%) but declined in Part-Asians and Native Hawaiians (17–31%). When lifestyle and dietary factors were also included, the risk was attenuated in all groups (6–14%). Despite their lower BMI, Asian Americans have a higher diabetes risk than whites, but dietary and lifestyle factors do not account for the excess risk.
PMCID: PMC4344420  PMID: 25164594
Type 2 diabetes mellitus; ethnicity; incidence; disparity; risk factors; Japanese; Filipinos; Native Hawaiians
25.  Type I and II Endometrial Cancers: Have They Different Risk Factors? 
Journal of Clinical Oncology  2013;31(20):2607-2618.
Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors.
Patients and Methods
Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors.
Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m2 increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (Pheterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar.
The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.
PMCID: PMC3699726  PMID: 23733771

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