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1.  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
2.  Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells 
AKT is a central protein in many cellular pathways such as cell survival, proliferation, glucose uptake, metabolism, angiogenesis, as well as radiation and drug response. The three isoforms of AKT (AKT1, AKT2 and AKT3) are proposed to have different physiological functions, properties and expression patterns in a cell type-dependent manner. As of yet, not much is known about the influence of the different AKT isoforms in the genome and their effects in the metabolism of colorectal cancer cells. In the present study, DLD-1 isogenic AKT1, AKT2 and AKT1/2 knockout colon cancer cell lines were used as a model system in conjunction with the parental cell line in order to further elucidate the differences between the AKT isoforms and how they are involved in various cellular pathways. This was done using genome wide expression analyses, metabolic profiling and cell migration assays. In conclusion, downregulation of genes in the cell adhesion, extracellular matrix and Notch-pathways and upregulation of apoptosis and metastasis inhibitory genes in the p53-pathway, confirm that the knockout of both AKT1 and AKT2 will attenuate metastasis and tumor cell growth. This was verified with a reduction in migration rate in the AKT1 KO and AKT2 KO and most explicitly in the AKT1/2 KO. Furthermore, the knockout of AKT1, AKT2 or both, resulted in a reduction in lactate and alanine, suggesting that the metabolism of carbohydrates and glutathione was impaired. This was further verified in gene expression analyses, showing downregulation of genes involved in glucose metabolism. Additionally, both AKT1 KO and AKT2 KO demonstrated an impaired fatty acid metabolism. However, genes were upregulated in the Wnt and cell proliferation pathways, which could oppose this effect. AKT inhibition should therefore be combined with other effectors to attain the best effect.
doi:10.3892/ijo.2016.3771
PMCID: PMC5182003  PMID: 27878243
microarray; metabolism; cell migration AKT1; AKT2; AKT; PKB; gene expression; colon cancer; DLD-1; metabolic profiling; CD44; CD133
3.  Image analysis-derived metrics of histomorphological complexity predicts prognosis and treatment response in stage II-III colon cancer 
Scientific Reports  2016;6:36149.
The complexity of tumor histomorphology reflects underlying tumor biology impacting on natural course and response to treatment. This study presents a method of computer-aided analysis of tissue sections, relying on multifractal (MF) analyses, of cytokeratin-stained tumor sections which quantitatively evaluates of the morphological complexity of the tumor-stroma interface. This approach was applied to colon cancer collection, from an adjuvant treatment randomized study. Metrics obtained with the method acted as independent markers for natural course of the disease, and for benefit of adjuvant treatment. Comparative analyses demonstrated that MF metrics out-performed standard histomorphological features such as tumor grade, budding and configuration of invasive front. Notably, the MF analyses-derived “αmax” –metric constitutes the first response-predictive biomarker in stage II-III colon cancer showing significant interactions with treatment in analyses using a randomized trial-derived study population. Based on these results the method appears as an attractive and easy-to-implement tool for biomarker identification.
doi:10.1038/srep36149
PMCID: PMC5095346  PMID: 27805003
4.  Autoimmune and Atopic Disorders and Risk of Classical Hodgkin Lymphoma 
American Journal of Epidemiology  2015;182(7):624-632.
Results from previous investigations have shown associations between the risk of Hodgkin lymphoma (HL) and a history of autoimmune and atopic diseases, but it remains unknown whether these associations apply to all types of HL or only to specific subtypes. We investigated immune diseases and the risk of classical HL in a population-based case-control study that included 585 patients and 3,187 controls recruited from October 1999 through August 2002. We collected information on immune diseases through telephone interviews and performed serological analyses of specific immunoglobulin E reactivity. Tumor Epstein-Barr virus (EBV) status was determined for 498 patients. Odds ratios with 95% confidence intervals were calculated using logistic regression analysis. Rheumatoid arthritis was associated with a higher risk of HL (odds ratio (OR) = 2.63; 95% confidence interval (CI): 1.47, 4.70), especially EBV-positive HL (OR = 3.18; 95% CI: 1.23, 8.17), and with mixed-cellularity HL (OR = 4.25; 95% CI: 1.66, 10.90). HL risk was higher when we used proxies of severe rheumatoid arthritis, such as ever having received daily rheumatoid arthritis medication (OR = 3.98; 95% CI: 2.08, 7.62), rheumatoid arthritis duration of 6–20 years (OR = 3.80; 95% CI: 1.72, 8.41), or ever having been hospitalized for rheumatoid arthritis (OR = 7.36; 95% CI: 2.95, 18.38). Atopic diseases were not associated with the risk of HL. EBV replication induced by chronic inflammation in patients with autoimmune diseases might explain the higher risk of EBV-positive HL.
doi:10.1093/aje/kwv081
PMCID: PMC4581588  PMID: 26346543
atopic hypersensitivity; Epstein-Barr virus; Hodgkin lymphoma; primary Sjögren's syndrome; rheumatoid arthritis; systemic lupus erythematosus
5.  Sequence variation in mature microRNA-608 and benefit from neo-adjuvant treatment in locally advanced rectal cancer patients 
Carcinogenesis  2016;37(9):852-857.
Summary
Analysis of a polymorphism in mature microRNA-608 (rs4919510) in rectal cancer patients enrolled in a randomized phase II clinical trial identified patient subpopulations who might benefit from the use of an intensified neo-adjuvant treatment strategy with Cetuximab.
Single nucleotide polymorphisms (SNPs) in microRNA genes have been associated with colorectal cancer (CRC) risk, survival and response to treatment. Conflicting results are available on the association between rs4919510, a SNP in mature miR-608 and clinical outcome in CRC. Here, we analyzed the association between rs4919510 and benefit from perioperative treatment in a randomised phase II trial of neoadjuvant Capecitabine and Oxaliplatin (CAPOX) followed by chemo-radiotherapy, surgery and adjuvant CAPOX ± Cetuximab in high-risk locally advanced rectal cancer (LARC). A total of 155/164 (94.5%) patients were assessable. 95 (61.3%) were homozygous for CC, 55 (35.5%) heterozygous (CG) and 5 (3.2%) homozygous for GG. Median follow-up was 64.9 months. In the CAPOX arm the 5-year progression-free survival (PFS) and overall survival (OS) rates were 54.6% and 60.7% for CC and 82.0% and 82.1% for CG/GG, respectively (HR PFS 0.13, 95% CI: 0.12–0.83, P = 0.02; HR OS 0.38, 95% CI: 0.14–1.01, P = 0.05). In the CAPOX-C arm PFS and OS were 73.2 and 82.2%, respectively for CC carriers and 64.6 and 73.1% for CG/GG carriers (HR PFS 1.38, 95% CI: 0.61–3.13, P = 0.44; HR OS 1.34, 95% CI: 0.52–3.48, P = 0.55). An interaction was found between study treatment and rs4919510 genotype for both PFS (P = 0.02) and OS (P = 0.07). This is the first study investigating rs4919510 in LARC. The CC genotype appeared to be associated with worse prognosis compared to the CG/GG genotype in patients treated with chemotherapy and chemo-radiotherapy alone. Addition of Cetuximab to chemotherapy and chemo-radiotherapy in CC carriers appeared to improve clinical outcome.
doi:10.1093/carcin/bgw073
PMCID: PMC5008250  PMID: 27381831
6.  Survival-associated heterogeneity of marker-defined perivascular cells in colorectal cancer 
Oncotarget  2016;7(27):41948-41958.
Perivascular cells (PC) were recently implied as regulators of metastasis and immune cell activity. Perivascular heterogeneity in clinical samples, and associations with other tumor features and outcome, remain largely unknown.
Here we report a novel method for digital quantitative analyses of vessel characteristics and PC, which was applied to two collections of human metastatic colorectal cancer (mCRC).
Initial analyses identified marker-defined subsets of PC, including cells expressing PDGFR-β or α-SMA or both markers. PC subsets were largely independently expressed in a manner unrelated to vessel density and size. Association studies implied specific oncogenic mutations in malignant cells as determinants of PC status. Semi-quantitative and digital-image-analyses-based scoring of the NORDIC-VII cohort identified significant associations between low expression of perivascular PDGFR-α and -β and shorter overall survival. Analyses of the SPCRC cohort confirmed these findings. Perivascular PDGFR-α and -β remained independent factors for survival in multivariate analyses.
Overall, our study identified host vasculature and oncogenic status as determinants of tumor perivascular features. Perivascular PDGFR-α and -β were identified as novel independent markers predicting survival in mCRC. The novel methodology should be suitable for similar analyses in other tumor collections.
doi:10.18632/oncotarget.9632
PMCID: PMC5173107  PMID: 27248825
PDGFR; perivascular cells; colorectal cancer; tumor stroma; cancer associated fibroblasts
7.  Detection of Biomarkers with Solid-Phase Proximity Ligation Assay in Patients with Colorectal Cancer 
Translational Oncology  2016;9(3):251-255.
BACKGROUND: In the search for prognostic biomarkers, a significant amount of precious biobanked blood samples is needed for conventional analyses. Solid-phase proximity ligation assay (SP-PLA) is an analytic method with the ability to analyze many proteins at the same time in small amounts of plasma. The aim of this study was to explore the potential use of SP-PLA for biomarker validation in patients with colorectal cancer (CRC). MATERIAL AND METHODS: Plasma samples from patients with stage I to IV CRC, with (n = 31) and without (n = 29) disease dissemination at diagnosis or later, were analyzed with SP-PLA using 35 antibodies targeting an equal number of proteins in 5-μl plasma samples. Carcinoembryonic antigen (CEA), analyzed earlier in this cohort using a different technology, was used as a reference. RESULTS: A total of 21 of the 35 investigated proteins were detectable with SP-PLA. Patients in stage II to III with disseminated disease had lower plasma concentrations of HCC-4 (P = .025). Low plasma levels of tissue inhibitor of metalloproteinases–1 were seen in patients with disseminated disease stage II (P = .003). The level of CEA was higher in patients with disease dissemination compared with those without (P = .007). CONCLUSION: SP-PLA has the ability to analyze many protein markers simultaneously in a small amount of blood. However, none of the markers selected for the present SP-PLA analyses gave better prognostic information than CEA.
doi:10.1016/j.tranon.2016.04.001
PMCID: PMC4907971  PMID: 27267845
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.  Is England closing the international gap in cancer survival? 
British Journal of Cancer  2015;113(5):848-860.
Background:
We provide an up-to-date international comparison of cancer survival, assessing whether England is ‘closing the gap' compared with other high-income countries.
Methods:
Net survival was estimated using national, population-based, cancer registrations for 1.9 million patients diagnosed with a cancer of the stomach, colon, rectum, lung, breast (women) or ovary in England during 1995–2012. Trends during 1995–2009 were compared with estimates for Australia, Canada, Denmark, Norway and Sweden. Clinicians were interviewed to help interpret trends.
Results:
Survival from all cancers remained lower in England than in Australia, Canada, Norway and Sweden by 2005–2009. For some cancers, survival improved more in England than in other countries between 1995–1999 and 2005–2009; for example, 1-year survival from stomach, rectal, lung, breast and ovarian cancers improved more than in Australia and Canada. There has been acceleration in lung cancer survival improvement in England recently, with average annual improvement in 1-year survival rising to 2% during 2010–2012. Survival improved more in Denmark than in England for rectal and lung cancers between 1995–1999 and 2005–2009.
Conclusions:
Survival has increased in England since the mid-1990s in the context of strategic reform in cancer control, however, survival remains lower than in comparable developed countries and continued investment is needed to close the international survival gap.
doi:10.1038/bjc.2015.265
PMCID: PMC4559829  PMID: 26241817
cancer survival; international comparison; population-based; cancer registries
10.  Medical History, Lifestyle, and Occupational Risk Factors for Hairy Cell Leukemia: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
Background
Little is known about the etiology of hairy cell leukemia (HCL), a rare B-cell lymphoproliferative disorder with marked male predominance. Our aim was to identify key risk factors for HCL.
Methods
A pooled analysis of individual-level data for 154 histologically confirmed HCL cases and 8834 controls from five case–control studies, conducted in Europe and Australia, was undertaken. Age-, race and/or ethnicity-, sex-, and study-adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression.
Results
The usual patterns for age and sex in HCL were observed, with a median age of 55 years and sex ratio of 3.7 males to females. Cigarette smoking was inversely associated with HCL (OR = 0.51, 95% CI = 0.37 to 0.71) with dose–response relationships observed for duration, frequency, and lifetime cigarette smoking (P trend < .001). In contrast, occupation as a farmer was positively associated with HCL (OR = 2.34, 95% CI = 1.36 to 4.01), with a dose–response relationship observed for duration (OR = 1.82, 95% CI = 0.85 to 3.88 for ≤10 years vs never; and OR = 2.98, 95% CI = 1.50 to 5.93 for >10 years vs never; P trend = .025). Adult height was also positively associated with HCL (OR = 2.69, 95% CI = 1.39 to 5.29 for upper vs lower quartile of height). The observed associations remained consistent in multivariate analysis.
Conclusions
Our observations of an increased risk of HCL from farming exposures and decreased risk from smoking exposures, independent of one another, support a multifactorial origin and an etiological specificity of HCL compared with other non-Hodgkin lymphoma subtypes. The positive association with height is a novel finding that needs replication.
doi:10.1093/jncimonographs/lgu004
PMCID: PMC4155459  PMID: 25174032
11.  Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
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
12.  Medical History, Lifestyle, Family History, and Occupational Risk Factors for Marginal Zone Lymphoma: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
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
13.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
Vijai, Joseph | Wang, Zhaoming | Berndt, Sonja I | Skibola, Christine F | Slager, Susan L | de Sanjose, Silvia | Melbye, Mads | Glimelius, Bengt | Bracci, Paige M | Conde, Lucia | Birmann, Brenda M | Wang, Sophia S | Brooks-Wilson, Angela R | Lan, Qing | de Bakker, Paul I W | Vermeulen, Roel C H | Portlock, Carol | Ansell, Stephen M | Link, Brian K | Riby, Jacques | North, Kari E | Gu, Jian | Hjalgrim, Henrik | Cozen, Wendy | Becker, Nikolaus | Teras, Lauren R | Spinelli, John J | Turner, Jenny | Zhang, Yawei | Purdue, Mark P | Giles, Graham G | Kelly, Rachel S | Zeleniuch-Jacquotte, Anne | Ennas, Maria Grazia | Monnereau, Alain | Bertrand, Kimberly A | Albanes, Demetrius | Lightfoot, Tracy | Yeager, Meredith | Chung, Charles C | Burdett, Laurie | Hutchinson, Amy | Lawrence, Charles | Montalvan, Rebecca | Liang, Liming | Huang, Jinyan | Ma, Baoshan | Villano, Danylo J | Maria, Ann | Corines, Marina | Thomas, Tinu | Novak, Anne J | Dogan, Ahmet | Liebow, Mark | Thompson, Carrie A | Witzig, Thomas E | Habermann, Thomas M | Weiner, George J | Smith, Martyn T | Holly, Elizabeth A | Jackson, Rebecca D | Tinker, Lesley F | Ye, Yuanqing | Adami, Hans-Olov | Smedby, Karin E | De Roos, Anneclaire J | Hartge, Patricia | Morton, Lindsay M | Severson, Richard K | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Diver, W Ryan | Vajdic, Claire M | Armstrong, Bruce K | Kricker, Anne | Zheng, Tongzhang | Holford, Theodore R | Severi, Gianluca | Vineis, Paolo | Ferri, Giovanni M | Ricco, Rosalia | Miligi, Lucia | Clavel, Jacqueline | Giovannucci, Edward | Kraft, Peter | Virtamo, Jarmo | Smith, Alex | Kane, Eleanor | Roman, Eve | Chiu, Brian C H | Fraumeni, Joseph F | Wu, Xifeng | Cerhan, James R | Offit, Kenneth | Chanock, Stephen J | Rothman, Nathaniel | Nieters, Alexandra
Nature communications  2015;6:5751.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95×10−15) and HLA-B (rs2922994, P=2.43×10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
doi:10.1038/ncomms6751
PMCID: PMC4287989  PMID: 25569183
14.  High BRAF Mutation Frequency and Marked Survival Differences in Subgroups According to KRAS/BRAF Mutation Status and Tumor Tissue Availability in a Prospective Population-Based Metastatic Colorectal Cancer Cohort 
PLoS ONE  2015;10(6):e0131046.
RAS and BRAF mutations impact treatment and prognosis of metastatic colorectal cancer patients (mCRC), but the knowledge is based on trial patients usually not representative for the general cancer population. Patient characteristics, treatment and efficacy according to KRAS, BRAF and MSI status were analyzed in a prospectively collected unselected population-based cohort of 798 non-resectable mCRC patients. The cohort contained many patients with poor performance status (39% PS 2-4) and elderly (37% age>75), groups usually not included in clinical trials. Patients without available tissue micro array (TMA) (42%) had worse prognostic factors and inferior survival (all patients; 7m vs 11m, chemotherapy-treated;12m vs 17m). The 92 patients (21%) with BRAF mutation had a poor prognosis regardless of microsatellite instability, but receipt of 1-2nd chemotherapy was similar to wildtype BRAF patients. Median survival in this cohort varied from 1 month in BRAF mutated patients not given chemotherapy to 26 months in wildtype KRAS/BRAF patients <75 years in good PS. TMA availability, BRAF mutation and KRAS mutation were all independent prognostic factors for survival. The observed 21% BRAF mutation incidence is higher than the previously and repeatedly reported incidence of 5-12% in mCRC. Screening for BRAF mutations before selection of treatment is relevant for many patients, especially outside clinical trials. A BRAF mutation only partly explained the very poor prognosis of many mCRC patients. Survival in unselected metastatic colorectal cancer patients is extremely variable and subgroups have an extremely short survival compared to trial patients. Patients without available TMA had worse prognostic factors and shorter survival, which questions the total generalizability of present TMA studies and implies that we lack information on the biologically worst mCRC cases. Lack of available tissue is an important underexposed issue which introduces sample bias, and this should be recognized more clearly when conclusions are made from translational mCRC studies.
doi:10.1371/journal.pone.0131046
PMCID: PMC4484806  PMID: 26121270
15.  Genome-wide association study identifies multiple susceptibility loci for diffuse large B-cell lymphoma 
Cerhan, James R | Berndt, Sonja I | Vijai, Joseph | Ghesquières, Hervé | McKay, James | Wang, Sophia S | Wang, Zhaoming | Yeager, Meredith | Conde, Lucia | de Bakker, Paul I W | Nieters, Alexandra | Cox, David | Burdett, Laurie | Monnereau, Alain | Flowers, Christopher R | De Roos, Anneclaire J | Brooks-Wilson, Angela R | Lan, Qing | Severi, Gianluca | Melbye, Mads | Gu, Jian | Jackson, Rebecca D | Kane, Eleanor | Teras, Lauren R | Purdue, Mark P | Vajdic, Claire M | Spinelli, John J | Giles, Graham G | Albanes, Demetrius | Kelly, Rachel S | Zucca, Mariagrazia | Bertrand, Kimberly A | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Hutchinson, Amy | Zhi, Degui | Habermann, Thomas M | Link, Brian K | Novak, Anne J | Dogan, Ahmet | Asmann, Yan W | Liebow, Mark | Thompson, Carrie A | Ansell, Stephen M | Witzig, Thomas E | Weiner, George J | Veron, Amelie S | Zelenika, Diana | Tilly, Hervé | Haioun, Corinne | Molina, Thierry Jo | Hjalgrim, Henrik | Glimelius, Bengt | Adami, Hans-Olov | Bracci, Paige M | Riby, Jacques | Smith, Martyn T | Holly, Elizabeth A | Cozen, Wendy | Hartge, Patricia | Morton, Lindsay M | Severson, Richard K | Tinker, Lesley F | North, Kari E | Becker, Nikolaus | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | Staines, Anthony | Lightfoot, Tracy | Crouch, Simon | Smith, Alex | Roman, Eve | Diver, W Ryan | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J | Villano, Danylo J | Zheng, Tongzhang | Zhang, Yawei | Holford, Theodore R | Kricker, Anne | Turner, Jenny | Southey, Melissa C | Clavel, Jacqueline | Virtamo, Jarmo | Weinstein, Stephanie | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Vermeulen, Roel C H | Boeing, Heiner | Tjonneland, Anne | Angelucci, Emanuele | Di Lollo, Simonetta | Rais, Marco | Birmann, Brenda M | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Huang, Jinyan | Ma, Baoshan | Ye, Yuanqing | Chiu, Brian C H | Sampson, Joshua | Liang, Liming | Park, Ju-Hyun | Chung, Charles C | Weisenburger, Dennis D | Chatterjee, Nilanjan | Fraumeni, Joseph F | Slager, Susan L | Wu, Xifeng | de Sanjose, Silvia | Smedby, Karin E | Salles, Gilles | Skibola, Christine F | Rothman, Nathaniel | Chanock, Stephen J
Nature genetics  2014;46(11):1233-1238.
doi:10.1038/ng.3105
PMCID: PMC4213349  PMID: 25261932
16.  Microsatellite instability and mutations in BRAF and KRAS are significant predictors of disseminated disease in colon cancer 
BMC Cancer  2015;15:125.
Background
Molecular alterations are well studied in colon cancer, however there is still need for an improved understanding of their prognostic impact. This study aims to characterize colon cancer with regard to KRAS, BRAF, and PIK3CA mutations, microsatellite instability (MSI), and average DNA copy number, in connection with tumour dissemination and recurrence in patients with colon cancer.
Methods
Disease stage II-IV colon cancer patients (n = 121) were selected. KRAS, BRAF, and PIK3CA mutation status was assessed by pyrosequencing and MSI was determined by analysis of mononucleotide repeat markers. Genome-wide average DNA copy number and allelic imbalance was evaluated by SNP array analysis.
Results
Patients with mutated KRAS were more likely to experience disease dissemination (OR 2.75; 95% CI 1.28-6.04), whereas the opposite was observed for patients with BRAF mutation (OR 0.34; 95% 0.14-0.81) or MSI (OR 0.24; 95% 0.09-0.64). Also in the subset of patients with stage II-III disease, both MSI (OR 0.29; 95% 0.10-0.86) and BRAF mutation (OR 0.32; 95% 0.16-0.91) were related to lower risk of distant recurrence. However, average DNA copy number and PIK3CA mutations were not associated with disease dissemination.
Conclusions
The present study revealed that tumour dissemination is less likely to occur in colon cancer patients with MSI and BRAF mutation, whereas the presence of a KRAS mutation increases the likelihood of disseminated disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1144-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1144-x
PMCID: PMC4364587  PMID: 25884297
Colon cancer; MSI; BRAF; KRAS; PIK3CA; DNA copy number; Prognosis
17.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
Vijai, Joseph | Wang, Zhaoming | Berndt, Sonja I. | Skibola, Christine F. | Slager, Susan L. | de Sanjose, Silvia | Melbye, Mads | Glimelius, Bengt | Bracci, Paige M. | Conde, Lucia | Birmann, Brenda M. | Wang, Sophia S. | Brooks-Wilson, Angela R. | Lan, Qing | de Bakker, Paul I. W. | Vermeulen, Roel C. H. | Portlock, Carol | Ansell, Stephen M. | Link, Brian K. | Riby, Jacques | North, Kari E. | Gu, Jian | Hjalgrim, Henrik | Cozen, Wendy | Becker, Nikolaus | Teras, Lauren R. | Spinelli, John J. | Turner, Jenny | Zhang, Yawei | Purdue, Mark P. | Giles, Graham G. | Kelly, Rachel S. | Zeleniuch-Jacquotte, Anne | Ennas, Maria Grazia | Monnereau, Alain | Bertrand, Kimberly A. | Albanes, Demetrius | Lightfoot, Tracy | Yeager, Meredith | Chung, Charles C. | Burdett, Laurie | Hutchinson, Amy | Lawrence, Charles | Montalvan, Rebecca | Liang, Liming | Huang, Jinyan | Ma, Baoshan | Villano, Danylo J. | Maria, Ann | Corines, Marina | Thomas, Tinu | Novak, Anne J. | Dogan, Ahmet | Liebow, Mark | Thompson, Carrie A. | Witzig, Thomas E. | Habermann, Thomas M. | Weiner, George J. | Smith, Martyn T. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Ye, Yuanqing | Adami, Hans-Olov | Smedby, Karin E. | De Roos, Anneclaire J. | Hartge, Patricia | Morton, Lindsay M. | Severson, Richard K. | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Diver, W. Ryan | Vajdic, Claire M. | Armstrong, Bruce K. | Kricker, Anne | Zheng, Tongzhang | Holford, Theodore R. | Severi, Gianluca | Vineis, Paolo | Ferri, Giovanni M. | Ricco, Rosalia | Miligi, Lucia | Clavel, Jacqueline | Giovannucci, Edward | Kraft, Peter | Virtamo, Jarmo | Smith, Alex | Kane, Eleanor | Roman, Eve | Chiu, Brian C. H. | Fraumeni, Joseph F. | Wu, Xifeng | Cerhan, James R. | Offit, Kenneth | Chanock, Stephen J. | Rothman, Nathaniel | Nieters, Alexandra
Nature Communications  2015;6:5751.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
doi:10.1038/ncomms6751
PMCID: PMC4287989  PMID: 25569183
18.  A genome-wide association study of Hodgkin Lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21, and 10p14 (GATA3) 
Nature genetics  2010;42(12):1126-1130.
To identify predisposition loci for classical Hodgkin Lymphoma (cHL) we conducted a genome-wide association study of 589 cHL cases and 5,199 controls with validation in 4 independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL; odds ratio [OR]=1.22, Pcombined=1.91×10−8), 8q24.21 (rs2019960, PVT1; OR=1.33, Pcombined=1.26×10−13) and 10p14 (rs501764, GATA3; OR=1.25, Pcombined=7.05×10−8). Furthermore, we confirmed the role of the MHC in disease etiology by revealing a strong HLA association (rs6903608; OR=1.70, Pcombined=2.84×10−50). These data provide new insight into the pathogenesis of cHL.
doi:10.1038/ng.696
PMCID: PMC4268499  PMID: 21037568
19.  A population-based cohort study on adherence to practice guidelines for adjuvant chemotherapy in colorectal cancer 
BMC Cancer  2014;14:948.
Background
The value of adjuvant chemotherapy in colorectal cancer is well studied, and guidelines have been established. Little is known about how treatment guidelines are implemented in the everyday clinical setting.
Methods
This national population-based study on nearly 34,000 patients with colorectal cancer evaluates the adherence to present clinical guidelines for adjuvant chemotherapy. Virtually all patients with colorectal cancer in Sweden during the years 2007–2012 and data from the Swedish Colorectal Cancer Registry were included.
Results
In colon cancer stage III, adherence to national guidelines was associated with lower age, presence of multidisciplinary team (MDT) conference, low co-morbidity, and worse N stage. The MDT forum also affected whether or not high-risk stage II colon cancer patients were considered for adjuvant chemotherapy. Rectal cancer patients both in stage II and III were considered for adjuvant chemotherapy less often than colon cancer patients, but the same factors influenced the decision. Adjuvant chemotherapy was started later than eight weeks after surgery in 30% of colon cancer patients and in 38% of rectal cancer patients.
Conclusions
In Sweden, the adherence to national guidelines for adjuvant chemotherapy in colon cancer stage III is acceptable in younger and healthier patients. MDT conferences are of major importance and affect whether patients are recommended for adjuvant chemotherapy. Special consideration needs to be given to certain subgroups of patients, particularly older patients and patients with poorly differentiated tumors. There is a need to shorten the waiting time until start of chemotherapy.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-948) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-948
PMCID: PMC4301907  PMID: 25495897
Registries; Chemotherapy adjuvant; Colonic neoplasms; Rectal neoplasms; Practice guidelines
20.  1p36 deletion is a marker for tumour dissemination in microsatellite stable stage II-III colon cancer 
BMC Cancer  2014;14:872.
Background
The clinical behaviour of colon cancer is heterogeneous. Five-year overall survival is 50-65% with all stages included. Recurring somatic chromosomal alterations have been identified and some have shown potential as markers for dissemination of the tumour, which is responsible for most colon cancer deaths. We investigated 115 selected stage II-IV primary colon cancers for associations between chromosomal alterations and tumour dissemination.
Methods
Follow-up was at least 5 years for stage II-III patients without distant recurrence. Affymetrix SNP 6.0 microarrays and allele-specific copy number analysis were used to identify chromosomal alterations. Fisher’s exact test was used to associate alterations with tumour dissemination, detected at diagnosis (stage IV) or later as recurrent disease (stage II-III).
Results
Loss of 1p36.11-21 was associated with tumour dissemination in microsatellite stable tumours of stage II-IV (odds ratio = 5.5). It was enriched to a similar extent in tumours with distant recurrence within stage II and stage III subgroups, and may therefore be used as a prognostic marker at diagnosis. Loss of 1p36.11-21 relative to average copy number of the genome showed similar prognostic value compared to absolute loss of copies. Therefore, the use of relative loss as a prognostic marker would benefit more patients by applying also to hyperploid cancer genomes. The association with tumour dissemination was supported by independent data from the The Cancer Genome Atlas.
Conclusion
Deletions on 1p36 may be used to guide adjuvant treatment decisions in microsatellite stable colon cancer of stages II and III.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-872) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-872
PMCID: PMC4251789  PMID: 25420937
Colon cancer; Prognostic marker; Allele-specific copy number analysis; Genome duplication; 1p36; Metastasis; Tumour dissemination
21.  Comparison of two instruments for measurement of quality of life in clinical practice - a qualitative study 
Background
The study aimed to investigate the meaning patients assign to two measures of quality of life: the Schedule for Evaluation of Individual Quality of Life Direct Weighting (SEIQoL-DW) and the SEIQoL-DW Disease Related (DR) version, in a clinical oncology setting. Even though the use of quality of life assessments has increased during the past decades, uncertainty regarding how to choose the most suitable measure remains. SEIQoL-DW versions assesses the individual’s perception of his or her present quality of life by allowing the individual to nominate the domains to be evaluated followed by a weighting procedure resulting in qualitative (domains) as well as quantitative outcomes (index score).
Methods
The study applied a cross-sectional design with a qualitative approach and collected data from a purposeful sample of 40 patients with gastrointestinal cancer. Patients were asked to complete two measures, SEIQoL-DW and the SEIQoL-DR, to assess quality of life. This included nomination of the areas in life considered most important and rating of these areas; after completion patients participated in cognitive interviews around their selections of areas. Interviews were audiotaped and transcribed verbatim which was followed by analysis using a phenomenographic approach.
Results
The analyses of nominated areas of the two measures resulted in 11 domains reflecting what patients perceived had greatest impact on their quality of life. Analysis of the cognitive interviews resulted in 16 thematic categories explaining the nominated domains. How patients reflected around their quality of life appeared to differ by version (DW vs. DR). The DW version more often related to positive aspects in life while the DR version more often related to negative changes in life due to having cancer.
Conclusions
The two SEIQoL versions tap into different concepts; health-related quality of life, addressing losses and problems related to having cancer and, quality of life, more associated with aspects perceived as positive in life. The SEIQoL-DR and the SEIQoL-DW are recommended in clinical practice to take both negative and positive aspects into account and acting on the problems of greatest importance to the patient.
doi:10.1186/1471-2288-14-115
PMCID: PMC4210549  PMID: 25300493
Cognitive interviews; Gastrointestinal cancer; Health-related quality of life; Measures; SEIQoL; Quality of life
22.  A comprehensive evaluation of the role of genetic variation in follicular lymphoma survival 
BMC Medical Genetics  2014;15:113.
Background
Survival in follicular lymphoma (FL) is highly variable, even within prognostic groups defined by tumor grade and the Follicular Lymphoma International Prognostic Index. Studies suggest that germline single nucleotide polymorphisms (SNPs) may hold prognostic information but further investigation is needed.
Methods
We explored the association between SNPs and FL outcome using two approaches: 1) Two independent genome-wide association studies (GWAS) of ~300.000 SNPs followed by a meta-analysis encompassing 586 FL patients diagnosed in Denmark/Sweden 1999–2002 and in the United States 2001–2006; and 2) Investigation of 22 candidate-gene variants previously associated with FL outcome in the Danish/Swedish cohort (N = 373). We estimated time to lymphoma-specific death (approach 1 and 2) and lymphoma progression (approach 2) with hazard ratios (HR) and 95% confidence intervals (CI) in a multivariable Cox regression model.
Results
In the GWAS meta-analysis, using a random effects model, no variants were associated with lymphoma-specific death at a genome-wide significant level (p < 5.0 ×10−8). The strongest association was observed for tightly linked SNPs on 17q24 near the ABCA10 and ABCA6 genes (rs10491178 HRrandom = 3.17, 95% CI 2.09-4.79, prandom = 5.24 ×10−8). The ABCA10 and ABCA6 genes belong to a family of genes encoding for ABC transporter proteins, implicated in multidrug resistance. In line with a previous study, rs2466571 in CD46 (HR = 0.73, 95% CI 0.58-0.91, p = 0.006) showed nominal association with lymphoma progression, as did two highly linked SNPs in IL8 (rs4073 HR = 0.78, 95% CI 0.62-0.97, p = 0.02; rs2227307 HR = 0.75, 95% CI 0.60-0.94, p = 0.01) previously associated with overall survival.
Conclusions
The results suggest a possible role for multidrug resistance in FL survival and add to the evidence that genetic variation in CD46 and IL8 may have prognostic implications in FL. Our findings need further confirmation in other independent populations or in a larger multicenter GWAS.
Electronic supplementary material
The online version of this article (doi:10.1186/s12881-014-0113-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12881-014-0113-6
PMCID: PMC4411784  PMID: 25294155
Follicular lymphoma; Prognosis; Single nucleotide polymorphism; Genome-wide association study; Candidate gene study
23.  Evaluation of Cancer Stem Cell Markers CD133, CD44, CD24: Association with AKT Isoforms and Radiation Resistance in Colon Cancer Cells 
PLoS ONE  2014;9(4):e94621.
The cell surface proteins CD133, CD24 and CD44 are putative markers for cancer stem cell populations in colon cancer, associated with aggressive cancer types and poor prognosis. It is important to understand how these markers may predict treatment outcomes, determined by factors such as radioresistance. The scope of this study was to assess the connection between EGFR, CD133, CD24, and CD44 (including isoforms) expression levels and radiation sensitivity, and furthermore analyze the influence of AKT isoforms on the expression patterns of these markers, to better understand the underlying molecular mechanisms in the cell. Three colon cancer cell-lines were used, HT-29, DLD-1, and HCT116, together with DLD-1 isogenic AKT knock-out cell-lines. All three cell-lines (HT-29, HCT116 and DLD-1) expressed varying amounts of CD133, CD24 and CD44 and the top ten percent of CD133 and CD44 expressing cells (CD133high/CD44high) were more resistant to gamma radiation than the ten percent with lowest expression (CD133low/CD44low). The AKT expression was lower in the fraction of cells with low CD133/CD44. Depletion of AKT1 or AKT2 using knock out cells showed for the first time that CD133 expression was associated with AKT1 but not AKT2, whereas the CD44 expression was influenced by the presence of either AKT1 or AKT2. There were several genes in the cell adhesion pathway which had significantly higher expression in the AKT2 KO cell-line compared to the AKT1 KO cell-line; however important genes in the epithelial to mesenchymal transition pathway (CDH1, VIM, TWIST1, SNAI1, SNAI2, ZEB1, ZEB2, FN1, FOXC2 and CDH2) did not differ. Our results demonstrate that CD133high/CD44high expressing colon cancer cells are associated with AKT and increased radiation resistance, and that different AKT isoforms have varying effects on the expression of cancer stem cell markers, which is an important consideration when targeting AKT in a clinical setting.
doi:10.1371/journal.pone.0094621
PMCID: PMC3997403  PMID: 24760019
24.  Genetic Markers of Toxicity From Capecitabine and Other Fluorouracil-Based Regimens: Investigation in the QUASAR2 Study, Systematic Review, and Meta-Analysis 
Journal of Clinical Oncology  2014;32(10):1031-1039.
Purpose
Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain.
Patients and Methods
We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens.
Results
Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and *2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5′VNTR2R/3R and 3′UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10−6). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens.
Conclusion
A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value—better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to *2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.
doi:10.1200/JCO.2013.51.1857
PMCID: PMC4879695  PMID: 24590654
25.  Plasma YKL-40 in Patients with Metastatic Colorectal Cancer Treated with First Line Oxaliplatin-Based Regimen with or without Cetuximab: RESULTS from the NORDIC VII Study 
PLoS ONE  2014;9(2):e87746.
Background
We aim to test the hypothesis that high plasma YKL-40 is associated with short progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated with first-line oxaliplatin and 5-flourouracil with or without cetuximab.
Patients and Methods
A total of 566 patients in the NORDIC VII Study were randomized 1∶1∶1 to arm A (Nordic FLOX), arm B (Nordic FLOX + cetuximab), or arm C (Nordic FLOX + cetuximab for 16 weeks followed by cetuximab alone as maintenance therapy). Pretreatment plasma samples were available from 510 patients. Plasma YKL-40 was determined by ELISA and dichotomized according to the age-corrected 95% YKL-40 level in 3130 healthy subjects.
Results
Pretreatment plasma YKL-40 was elevated in 204 patients (40%), and median YKL-40 was higher in patients with mCRC than in healthy subjects (age adjusted, P<0.001). Patients with elevated YKL-40 had shorter PFS than patients with normal YKL-40 (7.5 vs. 8.2 months; hazard ratio (HR)  = 1.27 95% confidence interval (CI) 1.05–1.53 P = 0.013) and shorter OS (16.8 vs. 23.9 months; HR = 1.33, 1.04–1.69, P = 0.024). Multivariate Cox analysis demonstrated that elevated pretreatment YKL-40 was an independent biomarker of short OS (HR = 1.12, 1.01–1.25, P = 0.033). The ratio of the updated plasma YKL-40 (i.e. level after 1, 2, 8 weeks of treatment, and at end of treatment compared to the baseline level) was associated with OS (HR = 1.27, 1.06–1.52, P = 0.011).
Conclusions
Plasma YKL-40 is an independent prognostic biomarker in patients with mCRC treated with first-line oxaliplatin-based therapy alone or combined with cetuximab.
doi:10.1371/journal.pone.0087746
PMCID: PMC3912025  PMID: 24498368

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