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1.  Substance Use History in Behavioral-Variant Frontotemporal Dementia versus Primary Progressive Aphasia 
Journal of addictive diseases  2015;35(1):36-41.
Background
As older adults are prone to cognitive disorders, the interaction of the fields of substance use and misuse and cognitive neuroscience is an emerging area of research. Substance use has been reported in some subtypes of frontotemporal dementia (FTD), such as behavioral variant frontotemporal dementia (bvFTD). However, characterization of substance use in other subtypes of FTD, such as primary progressive aphasia (PPAPH), is unknown.
Objective
The objective of this baseline analysis was to explore whether any measures of substance use history differed significantly among bvFTD (n = 842) and PPAPH (n = 526) in a large national dataset.
Design/Methods
The National Alzheimer’s Coordinating Center’s (NACC) Uniform Data Set (UDS) study is a national dataset that collects data on patients with various cognitive disorders and includes some questions on substance use. We used each substance use variable as the outcome and the FTD subtype as the predictor.
Results
Total years smoked cigarettes, age when last smoked cigarettes, and average # of packs/day smoked when participants smoked, and any recent, remote, or combined recent/remote history of alcohol abuse or drug abuse did not significantly differ between the bvFTD and PPAPH subtypes (all p-values > 0.001). A significantly greater percentage of participants smoked in the last 30 days in the bvFTD subtype (10.4%, n = 834) compared to the PPAPH subtype (3.3%, n = 517) (p < 0.001).
Discussion
Clinical providers in both the dementia and substance use fields are encouraged to screen for and monitor substance use in all FTD subtypes.
doi:10.1080/10550887.2015.1102026
PMCID: PMC4720534  PMID: 26485480
frontotemporal; dementia; cigarette smoking; alcohol; substance use; drug
2.  A pooled analysis of reproductive factors, exogenous hormone use and risk of multiple myeloma among women in the International Multiple Myeloma Consortium 
Background
Female sex hormones are known to have immunomodulatory effects. Therefore, reproductive factors and exogenous hormone use could influence the risk of multiple myeloma in women. However, the role of hormonal factors in multiple myeloma etiology remains unclear because previous investigations were underpowered to detect modest associations.
Methods
We conducted a pooled analysis of seven case–control studies included in the International Multiple Myeloma Consortium, with individual data on reproductive factors and exogenous hormone use from 1,072 female cases and 3,541 female controls. Study-specific odd ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using logistic regression and pooled analyses were conducted using random effects meta-analyses.
Results
Multiple myeloma was not associated with reproductive factors, including ever parous (OR=0.92, 95%CI=0.68-1.25), or with hormonal contraception use (OR=1.04, 95%CI=0.80-1.36). Postmenopausal hormone therapy users had non-significantly reduced risks of multiple myeloma compared with never users, but this association differed across centers (OR=0.65, 95%CI=0.37-1.15, I2=76.0%, p-heterogeneity= 0.01).
Conclusions
These data do not support a role for reproductive factors or exogenous hormones in myelomagenesis.
Impact
Incidence rates of multiple myeloma are higher in men than in women, and sex hormones could influence this pattern. Associations with reproductive factors and exogenous hormone use were inconclusive despite our large sample size, suggesting that female sex hormones may not play a significant role in multiple myeloma etiology.
doi:10.1158/1055-9965.EPI-15-0953
PMCID: PMC4745255  PMID: 26464426
3.  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
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
doi:10.1093/jnci/djv279
PMCID: PMC4806328  PMID: 26464424
4.  Non-Hodgkin lymphoma, body mass index and cytokine polymorphisms: a pooled analysis from the InterLymph consortium 
Background
Excess adiposity has been associated with lymphomagenesis, possibly mediated by increased cytokine production causing a chronic inflammatory state. The relationship between obesity, cytokine polymorphisms and selected mature B-cell neoplasms is reported.
Method
Data on 4979 cases and 4752 controls from nine American/European studies from the InterLymph consortium (1988–2008) were pooled. For diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), joint associations of body mass index (from self-reported height and weight) and 12 polymorphisms in cytokines IL1A (rs1800587), IL1B (rs16944, rs1143627), IL1RN (rs454078), IL2 (rs2069762), IL6 (rs1800795, rs1800797), IL10 (rs1800890, rs1800896), TNF (rs1800629), LTA (rs909253), and CARD15 (rs2066847) were investigated using unconditional logistic regression. BMI-polymorphism interaction effects were estimated using the relative excess risk due to interaction (RERI).
Results
Obesity (BMI≥30kg m−2) was associated with DLBCL risk (OR=1.33, 95%CI 1.02–1.73), as was TNF-308GA+AA (OR=1.24, 95%CI 1.07–1.44). Together, being obese and TNF-308GA+AA increased DLBCL risk almost two-fold relative to those of normal weight and TNF-308GG (OR=1.93 95%CI 1.27–2.94), with a RERI of 0.41 (95%CI −0.05,0.84, P(interaction)=0.13). For FL and CLL/SLL, no associations with obesity or TNF-308GA+AA, either singly or jointly, were observed. No evidence of interactions between obesity and the other polymorphisms were detected.
Conclusions
Our results suggest that cytokine polymorphisms do not generally interact with BMI to increase lymphoma risk but obesity and TNF-308GA+AA may interact to increase DLBCL risk.
Impact
Studies using better measures of adiposity are needed to further investigate the interactions between obesity and TNF-308G>A in the pathogenesis of lymphoma.
doi:10.1158/1055-9965.EPI-14-1355
PMCID: PMC4490950  PMID: 25962811
Body mass index; genotype; polymorphism; non-Hodgkin lymphoma
5.  Recreational physical activity and risk of triple negative breast cancer in the California Teachers Study 
Background
Evidence has accumulated showing that recreational physical activity reduces breast cancer risk. However, it is unclear whether risk reduction pertains to specific receptor-defined subtypes. Moreover, few studies have examined whether changes in the amount of recreational physical activity during adulthood influence breast cancer risk.
Methods
A total of 108,907 women, ages 22 to 79 years with no history of breast cancer when joining the California Teachers Study in 1995–1996, completed a baseline questionnaire and were eligible for the study. Through 2012, 5882 women were diagnosed with invasive breast cancer. Breast cancer subtypes were defined by the expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Multivariable Cox proportional hazards models provided adjusted hazard ratios (HRs) and 95 % confidence intervals (CIs) for breast cancer overall and ER/PR/HER2-defined subtypes associated with long-term (from high school through age 54 or age at cohort entry, whichever was younger) and baseline (during 3 years prior to baseline) recreational physical activity. Among women who also completed a follow-up questionnaire at 10 years after baseline in 2005–2008 (54,686 women, 1406 with invasive breast cancer), risk associated with changes in the amount of recreational physical activity from baseline to the 10-year follow-up (during 3 years prior to the 10-year follow-up) was determined.
Results
Both long-term and baseline strenuous recreational physical activity were inversely associated with risk of invasive breast cancer (Ptrend ≤0.03). The observed associations were mainly confined to women with triple negative breast cancer (TNBC, ER–/PR–/HER2–, Ptrend ≤0.02) or luminal A-like subtype (ER+ or PR+ plus HER2–) who were former users of menopausal hormone therapy at baseline (Ptrend = 0.02, Phomogeneity of trends ≤0.03). Moreover, women who consistently engaged in the highest level (≥3.51 h/wk/y) of strenuous recreational physical activity between baseline and 10-year follow-up had the lowest risk of breast cancer (HR = 0.71, 95 % CI = 0.52–0.98) when compared to those who were consistently low (≤0.50 h/wk/y).
Conclusions
Strenuous recreational physical activity is associated with lower breast cancer risk, especially TNBC. The benefit may be maximized by consistently engaging in high-intensity recreational physical activity during adulthood.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0723-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-016-0723-3
PMCID: PMC4912767  PMID: 27317095
Physical activity; Breast cancer; Triple negative breast cancer; Luminal; Estrogen receptor; Progesterone receptor; HER2; Risk factors; BMI; Menopausal hormone therapy
6.  The Ninth Annual American Association for Cancer Research International Conference on Frontiers in Cancer Prevention Research 
The Ninth Annual AACR Frontiers in Cancer Prevention Research conference was held in Philadelphia in November 7–10, 2010. Its thematic focus was “Prevention: From Basic Science to Public Health Benefit.” Telomere plasticity, the microenvironment, inflammation, transformation to the metastatic phenotype, and pathways to obesity were highlighted as important elements of carcinogenesis amenable to intervention. The integration of information from novel technologies related to physical biology, molecular and genetic profiles, and imaging along with behavioral and clinical parameters have advanced risk stratification and early detection. Cancer prevention represents a powerful testing ground for the development of individually tailored intervention and for increasing the efficiency of drug discovery. Advances in clinical trials relate to more efficient design strategies, have shown first-in-human targeting capabilities, and have developed powerful strategies to overcome accrual barriers. Tailored intervention strategies now show high efficacy on large cohorts across several cancer types. These successes are expected to increase.
doi:10.1158/1940-6207.CAPR-11-0018
PMCID: PMC4827425  PMID: 21464034
7.  Associations of Non-Hodgkin Lymphoma (NHL) Risk With Autoimmune Conditions According to Putative NHL Loci 
American Journal of Epidemiology  2015;181(6):406-421.
Autoimmune conditions and immune system–related genetic variations are associated with risk of non-Hodgkin lymphoma (NHL). In a pooled analysis of 8,692 NHL cases and 9,260 controls from 14 studies (1988–2007) within the International Lymphoma Epidemiology Consortium, we evaluated the interaction between immune system genetic variants and autoimmune conditions in NHL risk. We evaluated the immunity-related single nucleotide polymorphisms rs1800629 (tumor necrosis factor gene (TNF) G308A), rs1800890 (interleukin-10 gene (IL10) T3575A), rs6457327 (human leukocyte antigen gene (HLA) class I), rs10484561 (HLA class II), and rs2647012 (HLA class II)) and categorized autoimmune conditions as primarily mediated by B-cell or T-cell responses. We constructed unconditional logistic regression models to measure associations between autoimmune conditions and NHL with stratification by genotype. Autoimmune conditions mediated by B-cell responses were associated with increased NHL risk, specifically diffuse large B-cell lymphoma (odds ratio (OR) = 3.11, 95% confidence interval (CI): 2.25, 4.30) and marginal zone lymphoma (OR = 5.80, 95% CI: 3.82, 8.80); those mediated by T-cell responses were associated with peripheral T-cell lymphoma (OR = 2.14, 95% CI: 1.35, 3.38). In the presence of the rs1800629 AG/AA genotype, B-cell-mediated autoimmune conditions increased NHL risk (OR = 3.27, 95% CI: 2.07, 5.16; P-interaction = 0.03) in comparison with the GG genotype (OR = 1.82, 95% CI: 1.31, 2.53). This interaction was consistent across major B-cell NHL subtypes, including marginal zone lymphoma (P-interaction = 0.02) and follicular lymphoma (P-interaction = 0.04).
doi:10.1093/aje/kwu290
PMCID: PMC4402340  PMID: 25713336
autoimmune conditions; environment; genetics; interaction; human leukocyte antigen; lymphoma, non-Hodgkin; tumor necrosis factor
8.  Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia 
Berndt, Sonja I. | Camp, Nicola J. | Skibola, Christine F. | Vijai, Joseph | Wang, Zhaoming | Gu, Jian | Nieters, Alexandra | Kelly, Rachel S. | Smedby, Karin E. | Monnereau, Alain | Cozen, Wendy | Cox, Angela | Wang, Sophia S. | Lan, Qing | Teras, Lauren R. | Machado, Moara | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Vajdic, Claire M. | Cocco, Pierluigi | Zhang, Yawei | Giles, Graham G. | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Montalvan, Rebecca | Burdett, Laurie | Hutchinson, Amy | Ye, Yuanqing | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Cunningham, Julie M. | Allmer, Cristine | Hjalgrim, Henrik | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Diver, W Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Arnett, Donna K. | Zhi, Degui | Leach, Justin M. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Sala, Núria | Casabonne, Delphine | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Chaffee, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R. | Strom, Sara S. | Leis, Jose F. | Weinberg, J. Brice | Caporaso, Neil E. | Norman, Aaron D. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María- Dolores | Vermeulen, Roel C. H. | Travis, Ruth C. | Southey, Melissa C. | Milne, Roger L. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R. | Villano, Danylo J. | Maria, Ann | Spinelli, John J. | Gascoyne, Randy D. | Connors, Joseph M. | Bertrand, Kimberly A. | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Ma, Baoshan | Huang, Jinyan | Crouch, Simon | Park, Ju-Hyun | Chatterjee, Nilanjan | North, Kari E. | Snowden, John A. | Wright, Josh | Fraumeni, Joseph F. | Offit, Kenneth | Wu, Xifeng | de Sanjose, Silvia | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature Communications  2016;7:10933.
Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P<5 × 10−7) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10−8) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10−7). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.
Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPP associated with risk of this disease.
doi:10.1038/ncomms10933
PMCID: PMC4786871  PMID: 26956414
9.  Hospitalization after Cataract Surgery in a Nationwide Managed-Care Population 
PLoS ONE  2016;11(2):e0149819.
Purpose
Little is known regarding the extent by which patients undergoing outpatient cataract surgery are at risk for postoperative hospitalization. We sought to determine the percentage of patients undergoing cataract surgery who were subsequently hospitalized, the patient characteristics associated with postoperative hospitalization, and the reasons for hospitalization.
Methods
We identified all beneficiaries of a large U.S. managed care network age ≥40 years old who underwent ≥1 cataract surgery from 2001–2011. All enrollees who required inpatient hospitalization within 7, 14, 30, and 90 days following initial cataract surgery and the reasons for hospitalization were determined. Logistic regression was performed to assess factors that significantly impacted the odds of requiring postoperative hospitalization.
Results
Among the 64,981 patients who underwent cataract surgery, rates of hospitalization within 7, 14, 30, and 90 days were 0.3%, 0.5%, 1.3% and 4.2%, respectively. Among the 10,674 patients who had no major preexisting medical comorbidities, 0.1% were hospitalized within 7 days. The odds of hospitalization increased by 35% (OR = 1.35 [CI, 1.23–1.48]) with the presence of each additional comorbidity and by 14% with each additional hospitalization in the 3 years prior to cataract surgery (OR = 1.14 [CI, 1.10–1,18]). Those who were hospitalized in the 30 days prior to cataract surgery had 524% increased odds of being hospitalized within 7 days after cataract surgery (OR = 6.24, [CI, 3.37–11.57]) compared to those with no record of preoperative hospitalization. Postoperative hospitalizations were most commonly due to cardiovascular conditions, comprising over 25% of primary diagnoses associated with hospitalization.
Conclusions
The risk of hospitalization after cataract surgery is low, and is very low among those with no major preexisting medical comorbidities. Opportunities may exist to limit comprehensive preoperative evaluation and testing to those who have serious pre-existing medical comorbidities.
doi:10.1371/journal.pone.0149819
PMCID: PMC4762614  PMID: 26901594
10.  Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data 
Human mutation  2015;36(7):684-688.
We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 × 10−11), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with ~3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma.
doi:10.1002/humu.22799
PMCID: PMC4750473  PMID: 25907361
glioma; TP53; rare SNP; TCGA
11.  Novel polymorphisms in caspase-8 are associated with breast cancer risk in the California Teachers Study 
BMC Cancer  2016;16:14.
Background
The ability of tamoxifen and raloxifene to decrease breast cancer risk varies among different breast cancer subtypes. It is important to determine one’s subtype-specific breast cancer risk when considering chemoprevention. A number of single nucleotide polymorphisms (SNPs), including one in caspase-8 (CASP8), have been previously associated with risk of developing breast cancer. Because caspase-8 is an important protein involved in receptor-mediated apoptosis whose activity is affected by estrogen, we hypothesized that additional SNPs in CASP8 could be associated with breast cancer risk, perhaps in a subtype-specific manner.
Methods
Twelve tagging SNPs of CASP8 were analyzed in a nested case control study (1,353 cases and 1,384 controls) of non-Hispanic white women participating in the California Teachers Study. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated for each SNP using all, estrogen receptor (ER)-positive, ER-negative, human epidermal growth factor receptor 2 (HER2)-positive, and HER2-negative breast cancers as separate outcomes.
Results
Several SNPs were associated with all, ER-positive, and HER2-positive breast cancers; however, after correcting for multiple comparisons (i.e., p < 0.0008), only rs2293554 was statistically significantly associated with HER2-positive breast cancer (OR = 1.98, 95 % CI 1.34-2.92, uncorrected p = 0.0005).
Conclusions
While our results for CASP8 SNPs should be validated in other cohorts with subtype-specific information, we conclude that some SNPs in CASP8 are associated with subtype-specific breast cancer risk. This study contributes to our understanding of CASP8 SNPs and breast cancer risk by subtype.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-2036-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-2036-9
PMCID: PMC4711015  PMID: 26758508
Breast cancer; Single nucleotide polymorphism; Caspase-8
12.  Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33 
Wang, Zhaoming | Zhu, Bin | Zhang, Mingfeng | Parikh, Hemang | Jia, Jinping | Chung, Charles C. | Sampson, Joshua N. | Hoskins, Jason W. | Hutchinson, Amy | Burdette, Laurie | Ibrahim, Abdisamad | Hautman, Christopher | Raj, Preethi S. | Abnet, Christian C. | Adjei, Andrew A. | Ahlbom, Anders | Albanes, Demetrius | Allen, Naomi E. | Ambrosone, Christine B. | Aldrich, Melinda | Amiano, Pilar | Amos, Christopher | Andersson, Ulrika | Andriole, Gerald | Andrulis, Irene L. | Arici, Cecilia | Arslan, Alan A. | Austin, Melissa A. | Baris, Dalsu | Barkauskas, Donald A. | Bassig, Bryan A. | Beane Freeman, Laura E. | Berg, Christine D. | Berndt, Sonja I. | Bertazzi, Pier Alberto | Biritwum, Richard B. | Black, Amanda | Blot, William | Boeing, Heiner | Boffetta, Paolo | Bolton, Kelly | Boutron-Ruault, Marie-Christine | Bracci, Paige M. | Brennan, Paul | Brinton, Louise A. | Brotzman, Michelle | Bueno-de-Mesquita, H. Bas | Buring, Julie E. | Butler, Mary Ann | Cai, Qiuyin | Cancel-Tassin, Geraldine | Canzian, Federico | Cao, Guangwen | Caporaso, Neil E. | Carrato, Alfredo | Carreon, Tania | Carta, Angela | Chang, Gee-Chen | Chang, I-Shou | Chang-Claude, Jenny | Che, Xu | Chen, Chien-Jen | Chen, Chih-Yi | Chen, Chung-Hsing | Chen, Constance | Chen, Kuan-Yu | Chen, Yuh-Min | Chokkalingam, Anand P. | Chu, Lisa W. | Clavel-Chapelon, Francoise | Colditz, Graham A. | Colt, Joanne S. | Conti, David | Cook, Michael B. | Cortessis, Victoria K. | Crawford, E. David | Cussenot, Olivier | Davis, Faith G. | De Vivo, Immaculata | Deng, Xiang | Ding, Ti | Dinney, Colin P. | Di Stefano, Anna Luisa | Diver, W. Ryan | Duell, Eric J. | Elena, Joanne W. | Fan, Jin-Hu | Feigelson, Heather Spencer | Feychting, Maria | Figueroa, Jonine D. | Flanagan, Adrienne M. | Fraumeni, Joseph F. | Freedman, Neal D. | Fridley, Brooke L. | Fuchs, Charles S. | Gago-Dominguez, Manuela | Gallinger, Steven | Gao, Yu-Tang | Gapstur, Susan M. | Garcia-Closas, Montserrat | Garcia-Closas, Reina | Gastier-Foster, Julie M. | Gaziano, J. Michael | Gerhard, Daniela S. | Giffen, Carol A. | Giles, Graham G. | Gillanders, Elizabeth M. | Giovannucci, Edward L. | Goggins, Michael | Gokgoz, Nalan | Goldstein, Alisa M. | Gonzalez, Carlos | Gorlick, Richard | Greene, Mark H. | Gross, Myron | Grossman, H. Barton | Grubb, Robert | Gu, Jian | Guan, Peng | Haiman, Christopher A. | Hallmans, Goran | Hankinson, Susan E. | Harris, Curtis C. | Hartge, Patricia | Hattinger, Claudia | Hayes, Richard B. | He, Qincheng | Helman, Lee | Henderson, Brian E. | Henriksson, Roger | Hoffman-Bolton, Judith | Hohensee, Chancellor | Holly, Elizabeth A. | Hong, Yun-Chul | Hoover, Robert N. | Hosgood, H. Dean | Hsiao, Chin-Fu | Hsing, Ann W. | Hsiung, Chao Agnes | Hu, Nan | Hu, Wei | Hu, Zhibin | Huang, Ming-Shyan | Hunter, David J. | Inskip, Peter D. | Ito, Hidemi | Jacobs, Eric J. | Jacobs, Kevin B. | Jenab, Mazda | Ji, Bu-Tian | Johansen, Christoffer | Johansson, Mattias | Johnson, Alison | Kaaks, Rudolf | Kamat, Ashish M. | Kamineni, Aruna | Karagas, Margaret | Khanna, Chand | Khaw, Kay-Tee | Kim, Christopher | Kim, In-Sam | Kim, Jin Hee | Kim, Yeul Hong | Kim, Young-Chul | Kim, Young Tae | Kang, Chang Hyun | Jung, Yoo Jin | Kitahara, Cari M. | Klein, Alison P. | Klein, Robert | Kogevinas, Manolis | Koh, Woon-Puay | Kohno, Takashi | Kolonel, Laurence N. | Kooperberg, Charles | Kratz, Christian P. | Krogh, Vittorio | Kunitoh, Hideo | Kurtz, Robert C. | Kurucu, Nilgun | Lan, Qing | Lathrop, Mark | Lau, Ching C. | Lecanda, Fernando | Lee, Kyoung-Mu | Lee, Maxwell P. | Le Marchand, Loic | Lerner, Seth P. | Li, Donghui | Liao, Linda M. | Lim, Wei-Yen | Lin, Dongxin | Lin, Jie | Lindstrom, Sara | Linet, Martha S. | Lissowska, Jolanta | Liu, Jianjun | Ljungberg, Börje | Lloreta, Josep | Lu, Daru | Ma, Jing | Malats, Nuria | Mannisto, Satu | Marina, Neyssa | Mastrangelo, Giuseppe | Matsuo, Keitaro | McGlynn, Katherine A. | McKean-Cowdin, Roberta | McNeill, Lorna H. | McWilliams, Robert R. | Melin, Beatrice S. | Meltzer, Paul S. | Mensah, James E. | Miao, Xiaoping | Michaud, Dominique S. | Mondul, Alison M. | Moore, Lee E. | Muir, Kenneth | Niwa, Shelley | Olson, Sara H. | Orr, Nick | Panico, Salvatore | Park, Jae Yong | Patel, Alpa V. | Patino-Garcia, Ana | Pavanello, Sofia | Peeters, Petra H. M. | Peplonska, Beata | Peters, Ulrike | Petersen, Gloria M. | Picci, Piero | Pike, Malcolm C. | Porru, Stefano | Prescott, Jennifer | Pu, Xia | Purdue, Mark P. | Qiao, You-Lin | Rajaraman, Preetha | Riboli, Elio | Risch, Harvey A. | Rodabough, Rebecca J. | Rothman, Nathaniel | Ruder, Avima M. | Ryu, Jeong-Seon | Sanson, Marc | Schned, Alan | Schumacher, Fredrick R. | Schwartz, Ann G. | Schwartz, Kendra L. | Schwenn, Molly | Scotlandi, Katia | Seow, Adeline | Serra, Consol | Serra, Massimo | Sesso, Howard D. | Severi, Gianluca | Shen, Hongbing | Shen, Min | Shete, Sanjay | Shiraishi, Kouya | Shu, Xiao-Ou | Siddiq, Afshan | Sierrasesumaga, Luis | Sierri, Sabina | Loon Sihoe, Alan Dart | Silverman, Debra T. | Simon, Matthias | Southey, Melissa C. | Spector, Logan | Spitz, Margaret | Stampfer, Meir | Stattin, Par | Stern, Mariana C. | Stevens, Victoria L. | Stolzenberg-Solomon, Rachael Z. | Stram, Daniel O. | Strom, Sara S. | Su, Wu-Chou | Sund, Malin | Sung, Sook Whan | Swerdlow, Anthony | Tan, Wen | Tanaka, Hideo | Tang, Wei | Tang, Ze-Zhang | Tardon, Adonina | Tay, Evelyn | Taylor, Philip R. | Tettey, Yao | Thomas, David M. | Tirabosco, Roberto | Tjonneland, Anne | Tobias, Geoffrey S. | Toro, Jorge R. | Travis, Ruth C. | Trichopoulos, Dimitrios | Troisi, Rebecca | Truelove, Ann | Tsai, Ying-Huang | Tucker, Margaret A. | Tumino, Rosario | Van Den Berg, David | Van Den Eeden, Stephen K. | Vermeulen, Roel | Vineis, Paolo | Visvanathan, Kala | Vogel, Ulla | Wang, Chaoyu | Wang, Chengfeng | Wang, Junwen | Wang, Sophia S. | Weiderpass, Elisabete | Weinstein, Stephanie J. | Wentzensen, Nicolas | Wheeler, William | White, Emily | Wiencke, John K. | Wolk, Alicja | Wolpin, Brian M. | Wong, Maria Pik | Wrensch, Margaret | Wu, Chen | Wu, Tangchun | Wu, Xifeng | Wu, Yi-Long | Wunder, Jay S. | Xiang, Yong-Bing | Xu, Jun | Yang, Hannah P. | Yang, Pan-Chyr | Yatabe, Yasushi | Ye, Yuanqing | Yeboah, Edward D. | Yin, Zhihua | Ying, Chen | Yu, Chong-Jen | Yu, Kai | Yuan, Jian-Min | Zanetti, Krista A. | Zeleniuch-Jacquotte, Anne | Zheng, Wei | Zhou, Baosen | Mirabello, Lisa | Savage, Sharon A. | Kraft, Peter | Chanock, Stephen J. | Yeager, Meredith | Landi, Maria Terese | Shi, Jianxin | Chatterjee, Nilanjan | Amundadottir, Laufey T.
Human Molecular Genetics  2014;23(24):6616-6633.
Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10−39; Region 3: rs2853677, P = 3.30 × 10−36 and PConditional = 2.36 × 10−8; Region 4: rs2736098, P = 3.87 × 10−12 and PConditional = 5.19 × 10−6, Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10−6; and Region 6: rs10069690, P = 7.49 × 10−15 and PConditional = 5.35 × 10−7) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10−18 and PConditional = 7.06 × 10−16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
doi:10.1093/hmg/ddu363
PMCID: PMC4240198  PMID: 25027329
13.  The impact of central corneal thickness on the risk for glaucoma in a large multiethnic population 
Journal of glaucoma  2014;23(9):606-612.
Purpose
To investigate the relationship between central corneal thickness (CCT) and demographics, and determine whether CCT may be a substantial mediator of the relationships between glaucoma and its demographic risk factors.
Methods
This cross-sectional study included patients in the Kaiser Permanente Northern California health plan from January 1, 2007 to December 31, 2011 who were 40 years and older and had a documented CCT measurement (N=81,082). Those with any cornea-related diagnoses or a history of corneal refractive surgery were excluded. Demographic characteristics, including age, sex, and race/ethnicity, as well as clinical information including glaucoma-related diagnosis, diabetic status, CCT, and intraocular pressure were gathered from the electronic medical record.
Results
Multivariate linear regression analysis indicated that female sex, increased age, and Black race were significantly associated with thinner corneas. A subgroup analysis among Asians revealed that Chinese, Japanese, and Koreans had corneas 6-13 μm thicker than South and Southeast Asians, Filipinos, and Pacific Islanders for each diagnosis (P<.001). In our population, 24.5% (N=19878) had some form of open-angle glaucoma; 21.9% (N=17779) did not have any glaucoma-related diagnosis. Variation in CCT accounted for only 6.68% (95% confidence interval [CI] 6.14-7.24%) of the increased risk of open-angle glaucoma seen with increasing age, but explained as much as 29.4% (95% CI 27.0%-32.6%) of the increased risk of glaucoma seen among Blacks, and 29.5% (95% CI 23.5%-37.0%) of the increased risk of glaucoma seen among Hispanics.
Conclusions
CCT appears to explain a substantial portion of the increased risk of glaucoma seen among Blacks and Hispanics.
doi:10.1097/IJG.0000000000000088
PMCID: PMC4250426  PMID: 25055208
14.  Detection of HPV DNA in paraffin-embedded cervical samples: a comparison of four genotyping methods 
BMC Infectious Diseases  2015;15:544.
Background
Identification of human papillomavirus (HPV) DNA in cervical tissue is important for understanding cervical carcinogenesis and for evaluating cervical cancer prevention approaches. However, HPV genotyping using formalin-fixed, paraffin-embedded (FFPE) tissues is technically challenging. We evaluated the performance of four commonly used genotyping methods on FFPE cervical specimens conducted in different laboratories and compared to genotyping results from cytological samples.
Methods
We included 60 pairs of exfoliated-cell and FFPE specimens from women with histologically confirmed cervical intraepithelial lesions grade 2 or 3. Cytology specimens were genotyped using the Linear Array assay. Four expert laboratories processed tissue specimens using different preparation methods and then genotyped the resultant sample preparations using four different HPV genotyping methods: SPF10-PCR DEIA LiPA25 (version 1), Inno-LiPA, Linear Array and the Onclarity assay. Percentage agreement, kappa statistics and McNemar’s chi-square were calculated for each comparison of different methods and specimen types.
Results
Overall agreement with respect to carcinogenic HPV status for FFPE samples between different methods was: 81.7, 86.7 and 91.7 % for Onclarity versus Inno-LiPA, Linear Array and SPF-LiPA25, respectively; 81.7 and 85.0 % for Linear Array versus Inno-LiPA and SPF-LiPA25, respectively; and 86.7 % for SPF-LiPA25 versus Inno-LiPA. Type-specific agreement was >88.3 % for all pair-wise comparisons. Comparisons with cytology specimens resulted in overall agreements from 80 to 95 % depending on the method and type-specific agreement was >90 % for most comparisons.
Conclusions
Our data demonstrate that the four genotyping methods run by expert laboratories reliably detect HPV DNA in FFPE specimens with some variation in genotype-specific detection.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-1281-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-015-1281-5
PMCID: PMC4660657  PMID: 26607224
Genotyping; Formalin-fixed paraffin-embedded tissues; Cervical intraepithelial lesions; Exfoliated-cell
15.  Physical Activity and Risk of Cognitive Impairment among Oldest Old Women 
Objective
Physical activity may reduce the risk of cognitive decline in the elderly, but its effects among the oldest old are not well known. Our study assessed the association between very late life physical activity and 5-year risk of mild cognitive impairment (MCI) or dementia and neuropsychological test performance among oldest old women.
Design
Prospective.
Setting
Three study sites.
Participants
1249 women (mean age 83.3 ± 2.8).
Measurements
Baseline physical activity was measured by self-reported blocks walked per week and analyzed by tertile. Five years later, surviving participants who were 85 and older (oldest old) completed neuropsychological testing and underwent adjudication of clinical cognitive status (normal, MCI, or dementia). All analyses were adjusted for baseline age, education, cognition, depression, body mass index, hypertension, smoking, and coronary artery disease.
Results
Comparedto women in the lowest tertile, women in the highest tertile were less likely to develop dementia compared to those in the lowest tertile (13.0% vs 23.2%, multivariate adjusted odds ratio, 0.54; 95% confidence interval, 0.36–0.82). However, risk of MCI was not associated with physical activity. Physical activity was also associated with higher performance 5 years later on tests of global cognition, category fluency, and executive function but not phonemic fluency, memory, or attention.
Conclusions
Higher level of very late-life physical activity was associated with a lower risk of subsequent dementia in oldest old women. These findings support future studies for late-life physical activity interventions for the prevention of dementia among oldest old women.
doi:10.1016/j.jagp.2013.03.002
PMCID: PMC3864545  PMID: 23831179
Cognitive aging; physical activity; cohort studies; dementia; oldest old
16.  The role of co-factors in the progression from human papillomavirus infection to cervical cancer 
Gynecologic oncology  2012;128(2):265-270.
Objective
Co-factors for cervical cancer, including oral contraceptive (OC) use, smoking and multiparity have been identified; however, the stage at which they act in cervical carcinogenesis is not clear. We compared established risk factors among women with CIN2 and CIN3 to evaluate the heterogeneity of these factors in precancer and also assessed their role during cervical carcinogenesis.
Methods
The current analysis included 2783 women with various stages of cervical disease who were enrolled in the Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED) and the Biopsy Study. Associations of co-factors within cervical precancer and at different stages of cervical carcinogenesis were estimated using logistic regression.
Results
Long-term OC use (10+ years vs. never: OR=2.42, 95% CI: [1.13–5.15]), multiparity (3+ births vs. nulliparous: OR=1.54 [1.04–2.28]), smoking (ever vs. never: OR=1.95 [1.48–2.58]), and no Pap test in the previous five years (2.05 [1.32–3.17]) were positively associated with CIN3 compared to CIN2. We observed that long-term OC use, parity and smoking were associated with an increased risk of CIN3 compared to
Conclusions
Differences in established risk factors suggest that CIN3 is a more specific definition of precancer than CIN2. Hormonally-related factors and smoking play a role in the transition from human papillomavirus infection to precancer.
doi:10.1016/j.ygyno.2012.11.003
PMCID: PMC4627848  PMID: 23146688
British journal of haematology  2014;166(5):667-676.
SUMMARY
Multiple myeloma (MM) is a rare but highly fatal malignancy. High body weight is associated with this cancer, but several questions remain regarding the aetiological relevance of timing and location of body weight. To address these questions, we conducted a pooled analysis of MM mortality using 1.5 million participants (including 1,388 MM deaths) from 20 prospective cohorts in the National Cancer Institute Cohort Consortium. Proportional hazards regression was used to calculate pooled multivariate hazard ratios (HRs) and 95% confidence intervals (CIs). Associations with elevated MM mortality were observed for higher early-adult body mass index (BMI; HR=1.22, 95% CI: 1.09–1.35 per 5 kg/m2) and for higher cohort-entry BMI (HR 1.09, 95% CI: 1.03–1.16 per 5 kg/m2) and waist circumference (HR= 1.06, 95% CI: 1.02–1.10 per 5 cm). Women who were the heaviest, both in early adulthood (BMI 25+) and at cohort entry (BMI 30+) were at greater risk compared to those with BMI 18.5–<25 at both time points (HR=1.95, 95% CI: 1.33–2.86). Waist-to-hip ratio and height were not associated with MM mortality. These observations suggest that overall, and possibly also central, obesity influence myeloma mortality, and women have the highest risk of death from this cancer if they remain heavy throughout adulthood.
doi:10.1111/bjh.12935
PMCID: PMC4134758  PMID: 24861847
multiple myeloma; prospective cohort study; pooled analysis; body mass index; anthropometry
Cancer causes & control : CCC  2014;25(9):1233-1237.
Background
The role of medication use in multiple myeloma (MM) risk remains unclear.
Methods
The Los Angeles County Multiple Myeloma Case-Control Study, comprising 278 MM cases and individually-matched neighborhood controls, provided data to assess associations between medication use and MM risk. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression.
Results
Erythromycin (ever) use was associated with increased MM risk (OR=1.85, 95% CI=1.13–3.03). This association was restricted to men (OR=3.77, 95% CI=1.72–8.29) and was especially apparent among men who took two or more courses of erythromycin (OR=4.68, 95% CI = 1.70– 12.87).
Conclusions
Compared to females, males have lower levels of CYP3A4, for which erythromycin is both a substrate and inhibitor. Use of CYP3A4-inhibiting drugs such as erythromycin in men may thus result in even lower levels of CYP3A4 and, consequently, higher levels of CYP3A4-metabolized substances. These results could potentially provide clues to explain discrepancies in MM incidence by sex. Consortial efforts to confirm these associations are warranted.
doi:10.1007/s10552-014-0424-0
PMCID: PMC4156901  PMID: 24981100
Background
Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design.
Methods
We pooled individual-level data from 20 case-control studies (17471 NHL cases, 23096 controls) from North America, Europe, and Australia. Centralized data harmonization and analysis ensured standardized definitions and approaches, with rigorous quality control.
Results
The pooled study population included 11 specified NHL subtypes with more than 100 cases: diffuse large B-cell lymphoma (N = 4667), follicular lymphoma (N = 3530), chronic lymphocytic leukemia/small lymphocytic lymphoma (N = 2440), marginal zone lymphoma (N = 1052), peripheral T-cell lymphoma (N = 584), mantle cell lymphoma (N = 557), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (N = 374), mycosis fungoides/Sézary syndrome (N = 324), Burkitt/Burkitt-like lymphoma/leukemia (N = 295), hairy cell leukemia (N = 154), and acute lymphoblastic leukemia/lymphoma (N = 152). Associations with medical history, family history, lifestyle factors, and occupation for each of these 11 subtypes are presented in separate articles in this issue, with a final article quantitatively comparing risk factor patterns among subtypes.
Conclusions
The International Lymphoma Epidemiology Consortium NHL Subtypes Project provides the largest and most comprehensive investigation of potential risk factors for a broad range of common and rare NHL subtypes to date. The analyses contribute to our understanding of the multifactorial nature of NHL subtype etiologies, motivate hypothesis-driven prospective investigations, provide clues for prevention, and exemplify the benefits of international consortial collaboration in cancer epidemiology.
doi:10.1093/jncimonographs/lgu005
PMCID: PMC4155460  PMID: 25174022
Background
Mycosis fungoides and Sézary syndrome (MF/SS) are rare cutaneous T-cell lymphomas. Their etiology is poorly understood.
Methods
A pooled analysis of 324 MF/SS cases and 17217 controls from 14 case–control studies from Europe, North America, and Australia, as part of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma (NHL) Subtypes Project, was carried out to investigate associations with lifestyle, medical history, family history, and occupational risk factors. Multivariate logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI).
Results
We found an increased risk of MF/SS associated with body mass index equal to or larger than 30kg/m2 (OR = 1.57, 95% CI = 1.03 to 2.40), cigarette smoking for 40 years or more (OR = 1.55, 95% CI = 1.04 to 2.31), eczema (OR = 2.38, 95% CI = 1.73 to 3.29), family history of multiple myeloma (OR = 8.49, 95% CI = 3.31 to 21.80), and occupation as crop and vegetable farmers (OR = 2.37, 95% CI = 1.14 to 4.92), painters (OR = 3.71, 95% CI = 1.94 to 7.07), woodworkers (OR = 2.20, 95% CI = 1.18 to 4.08), and general carpenters (OR = 4.07, 95% CI = 1.54 to 10.75). We also found a reduced risk of MF/SS associated with moderate leisure time physical activity (OR = 0.46, 95% CI = 0.22 to 0.97).
Conclusions
Our study provided the first detailed analysis of risk factors for MF/SS and further investigation is needed to confirm these findings in prospective data and in other populations.
doi:10.1093/jncimonographs/lgu008
PMCID: PMC4155463  PMID: 25174030
Background
Although risk factors for diffuse large B-cell lymphoma (DLBCL) have been suggested, their independent effects, modification by sex, and association with anatomical sites are largely unknown.
Methods
In a pooled analysis of 4667 cases and 22639 controls from 19 studies, we used stepwise logistic regression to identify the most parsimonious multivariate models for DLBCL overall, by sex, and for selected anatomical sites.
Results
DLBCL was associated with B-cell activating autoimmune diseases (odds ratio [OR] = 2.36, 95% confidence interval [CI] = 1.80 to 3.09), hepatitis C virus seropositivity (OR = 2.02, 95% CI = 1.47 to 2.76), family history of non-Hodgkin lymphoma (OR = 1.95, 95% CI = 1.54 to 2.47), higher young adult body mass index (OR = 1.58, 95% CI = 1.12 to 2.23, for 35+ vs 18.5 to 22.4 kg/m2), higher recreational sun exposure (OR = 0.78, 95% CI = 0.69 to 0.89), any atopic disorder (OR = 0.82, 95% CI = 0.76 to 0.89), and higher socioeconomic status (OR = 0.86, 95% CI = 0.79 to 0.94). Additional risk factors for women were occupation as field crop/vegetable farm worker (OR = 1.78, 95% CI = 1.22 to 2.60), hairdresser (OR = 1.65, 95% CI = 1.12 to 2.41), and seamstress/embroider (OR = 1.49, 95% CI = 1.13 to 1.97), low adult body mass index (OR = 0.46, 95% CI = 0.29 to 0.74, for <18.5 vs 18.5 to 22.4 kg/m2), hormone replacement therapy started age at least 50 years (OR = 0.68, 95% CI = 0.52 to 0.88), and oral contraceptive use before 1970 (OR = 0.78, 95% CI = 0.62 to 1.00); and for men were occupation as material handling equipment operator (OR = 1.58, 95% CI = 1.02 to 2.44), lifetime alcohol consumption (OR = 0.57, 95% CI = 0.44 to 0.75, for >400kg vs nondrinker), and previous blood transfusion (OR = 0.69, 95% CI = 0.57 to 0.83). Autoimmune disease, atopy, and family history of non-Hodgkin lymphoma showed similar associations across selected anatomical sites, whereas smoking was associated with central nervous system, testicular and cutaneous DLBCLs; inflammatory bowel disease was associated with gastrointestinal DLBCL; and farming and hair dye use were associated with mediastinal DLBCL.
Conclusion
Our results support a complex and multifactorial etiology for DLBCL with some variation in risk observed by sex and anatomical site.
doi:10.1093/jncimonographs/lgu010
PMCID: PMC4155465  PMID: 25174023
Background
Accounting for 10%–15% of all non-Hodgkin lymphomas in Western populations, peripheral T-cell lymphomas (PTCL) are the most common T-cell lymphoma but little is known about their etiology. Our aim was to identify etiologic risk factors for PTCL overall, and for specific PTCL subtypes, by analyzing data from 15 epidemiologic studies participating in the InterLymph Consortium.
Methods
A pooled analysis of individual-level data for 584 histologically confirmed PTCL cases and 15912 controls from 15 case–control studies conducted in Europe, North America, and Australia was undertaken. Data collected from questionnaires were harmonized to permit evaluation of a broad range of potential risk factors. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression.
Results
Risk factors associated with increased overall PTCL risk with a P value less than .05 included: a family history of hematologic malignancies (OR = 1.92, 95% CI = 1.30 to 2.84); celiac disease (OR = 17.8, 95% CI = 8.61 to 36.79); eczema (OR = 1.41, 95% CI = 1.07 to 1.85); psoriasis (OR = 1.97, 95% CI = 1.17 to 3.32); smoking 40 or more years (OR = 1.92, 95% CI = 1.41 to 2.62); and employment as a textile worker (ever) (OR = 1.58, 95% CI = 1.05 to 2.38) and electrical fitter (ever) (OR = 2.89, 95% CI = 1.41 to 5.95). Exposures associated with reduced overall PTCL risk included a personal history of allergies (OR = 0.69, 95% CI = 0.54 to 0.87), alcohol consumption (ever) (OR = 0.64, 95% CI = 0.49 to 0.82), and having ever lived or worked on a farm (OR = 0.72, 95% CI = 0.55% to 0.95%). We also observed the well-established risk elevation for enteropathy-type PTCL among those with celiac disease in our data.
Conclusions Our pooled analyses identified a number of new potential risk factors for PTCL and require further validation in independent series.
doi:10.1093/jncimonographs/lgu012
PMCID: PMC4155466  PMID: 25174027
Morton, Lindsay M. | Slager, Susan L. | Cerhan, James R. | Wang, Sophia S. | Vajdic, Claire M. | Skibola, Christine F. | Bracci, Paige M. | de Sanjosé, Silvia | Smedby, Karin E. | Chiu, Brian C. H. | Zhang, Yawei | Mbulaiteye, Sam M. | Monnereau, Alain | Turner, Jennifer J. | Clavel, Jacqueline | Adami, Hans-Olov | Chang, Ellen T. | Glimelius, Bengt | Hjalgrim, Henrik | Melbye, Mads | Crosignani, Paolo | di Lollo, Simonetta | Miligi, Lucia | Nanni, Oriana | Ramazzotti, Valerio | Rodella, Stefania | Costantini, Adele Seniori | Stagnaro, Emanuele | Tumino, Rosario | Vindigni, Carla | Vineis, Paolo | Becker, Nikolaus | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Cocco, Pierluigi | Foretova, Lenka | Maynadié, Marc | Nieters, Alexandra | Staines, Anthony | Colt, Joanne S. | Cozen, Wendy | Davis, Scott | de Roos, Anneclaire J. | Hartge, Patricia | Rothman, Nathaniel | Severson, Richard K. | Holly, Elizabeth A. | Call, Timothy G. | Feldman, Andrew L. | Habermann, Thomas M. | Liebow, Mark | Blair, Aaron | Cantor, Kenneth P. | Kane, Eleanor V. | Lightfoot, Tracy | Roman, Eve | Smith, Alex | Brooks-Wilson, Angela | Connors, Joseph M. | Gascoyne, Randy D. | Spinelli, John J. | Armstrong, Bruce K. | Kricker, Anne | Holford, Theodore R. | Lan, Qing | Zheng, Tongzhang | Orsi, Laurent | Dal Maso, Luigino | Franceschi, Silvia | La Vecchia, Carlo | Negri, Eva | Serraino, Diego | Bernstein, Leslie | Levine, Alexandra | Friedberg, Jonathan W. | Kelly, Jennifer L. | Berndt, Sonja I. | Birmann, Brenda M. | Clarke, Christina A. | Flowers, Christopher R. | Foran, James M. | Kadin, Marshall E. | Paltiel, Ora | Weisenburger, Dennis D. | Linet, Martha S. | Sampson, Joshua N.
Background
Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.
Methods
We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case–control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE).
Results
Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10−4), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10−4). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.
Conclusions
Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.
doi:10.1093/jncimonographs/lgu013
PMCID: PMC4155467  PMID: 25174034
Open journal of epidemiology  2015;5(1):41-50.
Blood samples have traditionally been used as the main source of DNA for genetic analysis. However, this source can be difficult in terms of collection, transportation, and long-term storage. In this study, we investigated whether human nail clippings could be used as a source of DNA for SNP genotyping, null-allele detection, and whole-genome amplification. From extracted nail DNA, we achieved amplicons up to a length of ~400 bp and >96% concordance for SNP genotyping and 100% concordance for null-allele detection compared to DNA derived from matched blood samples. For whole-genome amplification, OmniPlex performed better than Multiple Displacement Amplification with a success rate of 89.3% and 76.8% for SNP genotyping and null-allele detection, respectively. Concordance was ~98% for both methods. When combined with OmniPlex whole-genome amplification, human nail clippings could potentially be used as an alternative to whole blood as a less invasive and more convenient source of DNA for genotyping studies.
doi:10.4236/ojepi.2015.51006
PMCID: PMC4499506  PMID: 26180661
Single Nucleotide Polymorphism (SNP); Nail Clippings; Genotyping; Whole Genome Amplification (WGA)
Background
Marginal zone lymphoma (MZL), comprised of nodal, extranodal, and splenic subtypes, accounts for 5%–10% of non-Hodgkin lymphoma cases. A detailed evaluation of the independent effects of risk factors for MZL and its subtypes has not been conducted.
Methods
Data were pooled from 1052 MZL cases (extranodal [EMZL] = 633, nodal [NMZL] = 157, splenic [SMZL] = 140) and 13766 controls from 12 case–control studies. Adjusted unconditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs).
Results
Novel findings for MZL subtypes include increased risk for B-cell activating autoimmune conditions (EMZL OR = 6.40, 95% CI = 4.24 to 9.68; NMZL OR = 7.80, 95% CI = 3.32 to 18.33; SMZL OR = 4.25, 95% CI = 1.49 to 12.14), hepatitis C virus seropositivity (EMZL OR = 5.29, 95% CI = 2.48 to 11.28), self-reported peptic ulcers (EMZL OR = 1.83, 95% CI = 1.35 to 2.49), asthma without other atopy (SMZL OR = 2.28, 95% CI = 1.23 to 4.23), family history of hematologic cancer (EMZL OR = 1.90, 95% CI = 1.37 to 2.62) and of non-Hodgkin lymphoma (NMZL OR = 2.82, 95% CI = 1.33 to 5.98), permanent hairdye use (SMZL OR = 6.59, 95% CI = 1.54 to 28.17), and occupation as a metalworker (NMZL OR = 3.56, 95% CI = 1.67 to 7.58). Reduced risks were observed with consumption of any alcohol (EMZL fourth quartile OR = 0.48, 95% CI = 0.28 to 0.82) and lower consumption of wine (NMZL first to third quartile ORs < 0.45) compared with nondrinkers, and occupation as a teacher (EMZL OR = 0.58, 95% CI = 0.37 to 0.88).
Conclusion
Our results provide new data suggesting etiologic heterogeneity across MZL subtypes although a common risk of MZL associated with B-cell activating autoimmune conditions was found.
doi:10.1093/jncimonographs/lgu011
PMCID: PMC4207869  PMID: 25174026

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