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1.  Occupational sun exposure and risk of melanoma according to anatomical site 
Although sunburn and intermittent sun exposures are associated with increased melanoma risk, most studies have found null or inverse associations between occupational (more continuous pattern) sun exposure and melanoma risk. The association of melanoma with occupational sun exposure may differ according to anatomical site, with some studies finding a positive association with melanoma on the head and neck. We examined the association between occupational sun exposure (self-reported weekday sun exposure) and melanoma risk according to anatomical site, using data from two multi-centre population-based case-control studies: the Australian Melanoma Family Study (588 cases, 472 controls) and the Genes, Environment and Melanoma study (GEM; 1079 cases, 2181 controls). Unconditional logistic regression was used to estimate odds ratios (OR) and their 95% confidence intervals, adjusting for potential confounders. Occupational sun exposure was not positively associated with melanoma risk overall or at different body sites in both studies. The GEM study found inverse associations between occupational sun exposure and melanoma on the head and neck (OR for highest vs. lowest quartile: 0.56, 95% CI 0.36-0.86, Ptrend 0.02), and between the proportion of total sun exposure occurring on weekdays and melanoma on the upper limbs (OR for highest vs. lowest quartile: 0.66, 95% CI 0.42-1.02, Ptrend 0.03). Our results suggest that occupational sun exposure does not increase risk of melanoma, even of melanomas situated on the head and neck. This finding appeared not to be due to negative confounding of occupational sun exposure by weekend sun.
PMCID: PMC3960350  PMID: 24288300
Melanoma; risk factors; sunlight; case-control studies
2.  Tumor-Infiltrating Lymphocyte Grade in Primary Melanomas Is Independently Associated With Melanoma-Specific Survival in the Population-Based Genes, Environment and Melanoma Study 
Journal of Clinical Oncology  2013;31(33):4252-4259.
Although most hospital-based studies suggest more favorable survival with tumor-infiltrating lymphocytes (TILs) present in primary melanomas, it is uncertain whether TILs provide prognostic information beyond existing melanoma staging definitions. We addressed the issue in an international population-based study of patients with single and multiple primary melanomas.
Patients and Methods
On the basis of the Genes, Environment and Melanoma (GEM) study, we conducted follow-up of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). The odds of TIL grades associated with clinicopathologic features and survival by TIL grade were examined.
Independent predictors (P < .05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade, they were age, site, Breslow thickness, and radial growth phase. Nonbrisk and brisk TIL grades were each associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (Ptrend < .001). Death as a result of melanoma was 30% less with nonbrisk TIL grade (hazard ratio [HR], 0.7; 95% CI, 0.5 to 1.0) and 50% less with brisk TIL grade (HR, 0.5; 95% CI, 0.3 to 0.9) relative to TIL absence, adjusted for age, sex, site, and AJCC tumor stage.
At the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independently of tumor characteristics currently used for AJCC tumor stage. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions.
PMCID: PMC3821014  PMID: 24127443
3.  Identification of a melanoma susceptibility locus and somatic mutation in TET2  
Carcinogenesis  2014;35(9):2097-2101.
We performed a genome-wide association study and identified single-nucleotide polymorphism rs4698934 located in the intron of the TET2 gene on chromosome 4q24 nominally significantly associated with melanoma risk, and a novel somatic mutation of TET2 was identified in melanoma case.
Although genetic studies have reported a number of loci associated with melanoma risk, the complex genetic architecture of the disease is not yet fully understood. We sought to identify common genetic variants associated with melanoma risk in a genome-wide association study (GWAS) of 2298 cases and 6654 controls. Thirteen of 15 known loci were replicated with nominal significance. A total of 69 single-nucleotide polymorphisms (SNPs) were selected for in silico replication in two independent melanoma GWAS datasets (a total of 5149 cases and 12 795 controls). Seven novel loci were nominally significantly associated with melanoma risk. These seven SNPs were further genotyped in 234 melanoma cases and 238 controls. The SNP rs4698934 was nominally significantly associated with melanoma risk. The combined odds ratio per T allele = 1.18; 95% confidence interval (1.10–1.25); combined P = 7.70 × 10− 7. This SNP is located in the intron of the TET2 gene on chromosome 4q24. In addition, a novel somatic mutation of TET2 was identified by next-generation sequencing in 1 of 22 sporadic melanoma cases. TET2 encodes a member of TET family enzymes that oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). It is a putative epigenetic biomarker of melanoma as we previously reported, with observation of reduced TET2 transcriptional expression. This study is the first to implicate TET2 genetic variation and mutation in melanoma.
PMCID: PMC4146422  PMID: 24980573
4.  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.
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.
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).
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.
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.
PMCID: PMC4155467  PMID: 25174034
5.  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.
PMCID: PMC4287989  PMID: 25569183
6.  IARC Monographs: 40 Years of Evaluating Carcinogenic Hazards to Humans 
Pearce, Neil | Blair, Aaron | Vineis, Paolo | Ahrens, Wolfgang | Andersen, Aage | Anto, Josep M. | Armstrong, Bruce K. | Baccarelli, Andrea A. | Beland, Frederick A. | Berrington, Amy | Bertazzi, Pier Alberto | Birnbaum, Linda S. | Brownson, Ross C. | Bucher, John R. | Cantor, Kenneth P. | Cardis, Elisabeth | Cherrie, John W. | Christiani, David C. | Cocco, Pierluigi | Coggon, David | Comba, Pietro | Demers, Paul A. | Dement, John M. | Douwes, Jeroen | Eisen, Ellen A. | Engel, Lawrence S. | Fenske, Richard A. | Fleming, Lora E. | Fletcher, Tony | Fontham, Elizabeth | Forastiere, Francesco | Frentzel-Beyme, Rainer | Fritschi, Lin | Gerin, Michel | Goldberg, Marcel | Grandjean, Philippe | Grimsrud, Tom K. | Gustavsson, Per | Haines, Andy | Hartge, Patricia | Hansen, Johnni | Hauptmann, Michael | Heederik, Dick | Hemminki, Kari | Hemon, Denis | Hertz-Picciotto, Irva | Hoppin, Jane A. | Huff, James | Jarvholm, Bengt | Kang, Daehee | Karagas, Margaret R. | Kjaerheim, Kristina | Kjuus, Helge | Kogevinas, Manolis | Kriebel, David | Kristensen, Petter | Kromhout, Hans | Laden, Francine | Lebailly, Pierre | LeMasters, Grace | Lubin, Jay H. | Lynch, Charles F. | Lynge, Elsebeth | ‘t Mannetje, Andrea | McMichael, Anthony J. | McLaughlin, John R. | Marrett, Loraine | Martuzzi, Marco | Merchant, James A. | Merler, Enzo | Merletti, Franco | Miller, Anthony | Mirer, Franklin E. | Monson, Richard | Nordby, Karl-Cristian | Olshan, Andrew F. | Parent, Marie-Elise | Perera, Frederica P. | Perry, Melissa J. | Pesatori, Angela Cecilia | Pirastu, Roberta | Porta, Miquel | Pukkala, Eero | Rice, Carol | Richardson, David B. | Ritter, Leonard | Ritz, Beate | Ronckers, Cecile M. | Rushton, Lesley | Rusiecki, Jennifer A. | Rusyn, Ivan | Samet, Jonathan M. | Sandler, Dale P. | de Sanjose, Silvia | Schernhammer, Eva | Costantini, Adele Seniori | Seixas, Noah | Shy, Carl | Siemiatycki, Jack | Silverman, Debra T. | Simonato, Lorenzo | Smith, Allan H. | Smith, Martyn T. | Spinelli, John J. | Spitz, Margaret R. | Stallones, Lorann | Stayner, Leslie T. | Steenland, Kyle | Stenzel, Mark | Stewart, Bernard W. | Stewart, Patricia A. | Symanski, Elaine | Terracini, Benedetto | Tolbert, Paige E. | Vainio, Harri | Vena, John | Vermeulen, Roel | Victora, Cesar G. | Ward, Elizabeth M. | Weinberg, Clarice R. | Weisenburger, Dennis | Wesseling, Catharina | Weiderpass, Elisabete | Zahm, Shelia Hoar
Environmental Health Perspectives  2015;123(6):507-514.
Background: Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans.
Objectives: The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process to determine the validity of these concerns. Here, we present the results of that examination, review the history of IARC evaluations, and describe how the IARC evaluations are performed.
Discussion: We concluded that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed.
Conclusions: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public’s health.
Citation: Pearce N, Blair A, Vineis P, Ahrens W, Andersen A, Anto JM, Armstrong BK, Baccarelli AA, Beland FA, Berrington A, Bertazzi PA, Birnbaum LS, Brownson RC, Bucher JR, Cantor KP, Cardis E, Cherrie JW, Christiani DC, Cocco P, Coggon D, Comba P, Demers PA, Dement JM, Douwes J, Eisen EA, Engel LS, Fenske RA, Fleming LE, Fletcher T, Fontham E, Forastiere F, Frentzel-Beyme R, Fritschi L, Gerin M, Goldberg M, Grandjean P, Grimsrud TK, Gustavsson P, Haines A, Hartge P, Hansen J, Hauptmann M, Heederik D, Hemminki K, Hemon D, Hertz-Picciotto I, Hoppin JA, Huff J, Jarvholm B, Kang D, Karagas MR, Kjaerheim K, Kjuus H, Kogevinas M, Kriebel D, Kristensen P, Kromhout H, Laden F, Lebailly P, LeMasters G, Lubin JH, Lynch CF, Lynge E, ‘t Mannetje A, McMichael AJ, McLaughlin JR, Marrett L, Martuzzi M, Merchant JA, Merler E, Merletti F, Miller A, Mirer FE, Monson R, Nordby KC, Olshan AF, Parent ME, Perera FP, Perry MJ, Pesatori AC, Pirastu R, Porta M, Pukkala E, Rice C, Richardson DB, Ritter L, Ritz B, Ronckers CM, Rushton L, Rusiecki JA, Rusyn I, Samet JM, Sandler DP, de Sanjose S, Schernhammer E, Seniori Costantini A, Seixas N, Shy C, Siemiatycki J, Silverman DT, Simonato L, Smith AH, Smith MT, Spinelli JJ, Spitz MR, Stallones L, Stayner LT, Steenland K, Stenzel M, Stewart BW, Stewart PA, Symanski E, Terracini B, Tolbert PE, Vainio H, Vena J, Vermeulen R, Victora CG, Ward EM, Weinberg CR, Weisenburger D, Wesseling C, Weiderpass E, Zahm SH. 2015. IARC Monographs: 40 years of evaluating carcinogenic hazards to humans. Environ Health Perspect 123:507–514;
PMCID: PMC4455595  PMID: 25712798
7.  MITF E318K’s effect on melanoma risk independent of, but modified by, other risk factors 
Pigment cell & melanoma research  2014;27(3):485-488.
A rare germline variant in the MITF (microphthalmia-associated transcription factor) gene, E318K, has been reported as associated with melanoma. We confirmed its independent association with melanoma (odds ratio (OR) 1.7, 95% Confidence Interval (CI) = 1.1, 2.7, p = 0.03); adjusted for age, sex, center, age*sex interaction, pigmentation characteristics, family history of melanoma and nevus density). In stratified analyses, carriage of MITF E318K was associated with melanoma more strongly in people with dark hair than fair hair (p for interaction, 0.03) and in those with no moles than some or many moles (p for interaction, <0.01). There was no evidence of interaction between MC1R “red hair variants” and MITF E318K. Moreover, risk of melanoma among carriers with “low risk” phenotypes was as great or greater than among those with “at risk” phenotypes with few exceptions.
PMCID: PMC3988207  PMID: 24406078
MITF; melanoma; risk factors; single nucleotide polymorphism; case control study
8.  Prostate cancer mortality outcomes and patterns of primary treatment for Aboriginal men in New South Wales, Australia 
Bju International  2015;115(Suppl 5):16-23.
To compare prostate cancer mortality for Aboriginal and non-Aboriginal men and to describe prostate cancer treatments received by Aboriginal men.
Patients and methods
We analysed cancer registry records for all men diagnosed with prostate cancer in New South Wales (NSW) in 2001–2007 linked to hospital inpatient episodes and deaths. More detailed information on androgen-deprivation therapy and radiotherapy was obtained from medical records for 87 NSW Aboriginal men diagnosed in 2000–2011. The main outcomes were primary treatment for, and death from, prostate cancer. Analysis included Cox proportional hazards regression and logistic regression.
There were 259 Aboriginal men among 35 214 prostate cancer cases diagnosed in 2001–2007. Age and spread of disease at diagnosis were similar for Aboriginal and non-Aboriginal men. Prostate cancer mortality 5 years after diagnosis was higher for Aboriginal men (17.5%, 95% confidence interval (CI) 12.4–23.3) than non-Aboriginal men (11.4%, 95% CI 11.0–11.8). Aboriginal men were 49% more likely to die from prostate cancer (hazard ratio 1.49, 95% CI 1.07–1.99) after adjusting for differences in demographic factors, stage at diagnosis, health access and comorbidities. Aboriginal men were less likely to have a prostatectomy for localised or regional cancer than non-Aboriginal men (adjusted odds ratio 0.60, 95% CI 0.40–0.91). Of 87 Aboriginal men with full staging and treatment information, 60% were diagnosed with localised disease. Of these, 38% had a prostatectomy (± radiotherapy), 29% had radiotherapy only and 33% had neither.
More research is required to explain differences in treatment and mortality for Aboriginal men with prostate cancer compared with non-Aboriginal men. In the meantime, ongoing monitoring and efforts are needed to ensure Aboriginal men have equitable access to best care.
PMCID: PMC4409091  PMID: 25124107
Aboriginal men; patterns of care; prostate cancer; mortality; outcomes; indigenous
9.  MC1R genotypes and risk of melanoma before age 40 years: a population-based case-control-family study 
The contribution of melanocortin-1 receptor (MC1R) gene variants to the development of early-onset melanoma is unknown. Using an Australian population-based, case-control-family study, we sequenced MC1R for 565 cases with invasive cutaneous melanoma diagnosed between ages 18–39 years, 409 unrelated controls and 518 sibling controls. Variants were classified a priori into `R' variants (D84E, R142H, R151C, I155T, R160W, D294H) and `r' variants (all other nonsynonymous variants). We estimated odds ratios (OR) for melanoma using unconditional (unrelated controls) and conditional (sibling controls) logistic regression. The prevalence of having at least one R or r variant was 86% for cases, 73% for unrelated controls and 81% for sibling controls. R151C conferred the highest risk (per allele OR 2.57, 95% confidence interval 1.86–3.56 for the case-unrelated-control analysis and 1.70 (1.12–2.60) for the case-sibling-control analysis). When mutually adjusted, the ORs per R allele were 2.23 (1.77–2.80) and 2.06 (1.47–2.88), respectively from the two types of analysis, and the ORs per r allele were 1.69 (1.33–2.13) and 1.25 (0.88–1.79), respectively. The associations were stronger for men and those with none or few nevi or with high childhood sun exposure. Adjustment for phenotype, nevi and sun exposure attenuated the overall log OR for R variants by approximately 18%, but had lesser influence on r variant risk estimates. MC1R variants explained about 21% of the familial aggregation of melanoma. Some MC1R variants are important determinants of early-onset melanoma. The strength of association with melanoma differs according to the type and number of variants.
PMCID: PMC4330189  PMID: 22095472
MC1R; melanoma; early-onset; phenotype; nevi; sun exposure
10.  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.
PMCID: PMC4287989  PMID: 25569183
11.  Fetal Growth and Childhood Acute Lymphoblastic Leukemia: Findings from the Childhood Leukemia International Consortium (CLIC) 
Positive associations have been reported between measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual-level data from 12 case-control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth – weight-for-gestational-age and proportion of optimal birth weight (POBW) – were analysed. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta-analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analyses were undertaken when possible. Data on weight for gestational age were available for 7,348 cases and 12,489 controls from all 12 studies and POBW data were available for 1,680 cases and 3,139 controls from three studies. The summary ORs from the meta-analyses were 1.24 (95% CI 1.13, 1.36) for children who were large for gestational age relative to appropriate for gestational age, and 1.16 (95% CI: 1.09, 1.24) for a one standard deviation increase in POBW. The pooled analyses produced similar results. The summary and pooled ORs for small-for-gestational-age children were 0.83 (95% CI: 0.75, 0.92) and 0.86 (95% CI 0.77, 0.95) respectively. Results were consistent across subgroups defined by sex, ethnicity and immunophenotype, and when the analysis was restricted to children who did not have high birth weight. The evidence that accelerated fetal growth is associated with a modest increased risk of childhood ALL is strong and consistent with known biological mechanisms involving insulin like growth factors.
PMCID: PMC3797193  PMID: 23754574
birth weight; fetal growth; leukemia; childhood; pooled analysis; meta-analysis
12.  Prevalence and predictors of germline CDKN2A mutations for melanoma cases from Australia, Spain and the United Kingdom 
Mutations in the CDKN2A and CDK4 genes predispose to melanoma. From three case-control studies of cutaneous melanoma, we estimated the prevalence and predictors of these mutations for people from regions with widely differing latitudes and melanoma incidence.
Population-based cases and controls from the United Kingdom (1586 cases, 499 controls) and Australia (596 early-onset cases, 476 controls), and a hospital-based series from Spain (747 cases, 109 controls), were screened for variants in all exons of CDKN2A and the p16INK4A binding domain of CDK4.
The prevalence of mutations for people with melanoma was similar across regions: 2.3%, 2.5% and 2.0% for Australia, Spain and the United Kingdom respectively. The strongest predictors of carrying a mutation were having multiple primaries (odds ratio (OR) = 5.4, 95% confidence interval (CI: 2.5, 11.6) for 2 primaries and OR = 32.4 (95% CI: 14.7, 71.2) for 3 or more compared with 1 primary only); and family history (OR = 3.8; 95% CI:1.89, 7.5) for 1 affected first- or second-degree relative and OR = 23.2 (95% CI: 11.3, 47.6) for 2 or more compared with no affected relatives). Only 1.1% of melanoma cases with neither a family history nor multiple primaries had mutations.
There is a low probability (<2%) of detecting a germline CDKN2A mutation in people with melanoma except for those with a strong family history of melanoma (≥2 affected relatives, 25%), three or more primary melanomas (29%), or more than one primary melanoma who also have other affected relatives (27%).
Electronic supplementary material
The online version of this article (doi:10.1186/1897-4287-12-20) contains supplementary material, which is available to authorized users.
PMCID: PMC4361137  PMID: 25780468
Family history; Multiple primaries; Population-based; Melanoma; CDKN2A
13.  Adjuvant therapy with high dose vitamin D following primary treatment of melanoma at high risk of recurrence: a placebo controlled randomised phase II trial (ANZMTG 02.09 Mel-D) 
BMC Cancer  2014;14:780.
Patients with primary cutaneous melanomas that are ulcerated and >2 mm in thickness, >4 mm in thickness and those with nodal micrometastases at diagnosis, have few options for adjuvant treatment. Recent studies have suggested a role for vitamin D to delay melanoma recurrence and improve overall prognosis.
This is a pilot placebo-controlled randomised phase II trial to assess the feasibility, safety and toxicity of an oral loading dose of Vitamin D (500,000 IU) followed by an oral dose of 50,000 IU of Vitamin D monthly for 2 years in patients who have been treated for cutaneous melanoma by wide excision of the primary. Patients aged 18 – 79 years who have completed primary surgical treatment and have Stage IIb, IIc, IIIa (N1a, N2a) or IIIb (N1a, N2a) disease are eligible for randomisation 2:1 to active treatment or placebo. The primary endpoints are sufficiency of dose, adherence to study medication and safety of the drug. The secondary endpoints are participation and progression free survival. The study has been approved by the Ethics Review Committee (RPAH Zone) of the Sydney Local Health District, protocol number X09-0138.
Effective, non-toxic adjuvant therapy for high risk primary melanoma is not currently available. Favorable outcomes of this phase II study will form the basis for a multi-centre phase III study to assess whether the addition of oral high-dose vitamin D therapy in patients who have completed primary treatment for melanoma and are at high risk of recurrence will:prolong time to recurrence within 5 yearsimprove overall survival at 5 years andbe both safe and tolerable.
62 patients have been randomised since the study commenced in December 2010. Target accrual for the study has been met with 75 patients randomised between December 2010 and August 2014.
The Mel-D trial is conducted by the Australia and New Zealand Melanoma Trials Group (ANZMTG 02.09)
Trial registration
Australia and New Zealand Clinical Trials Registry (ANZCTR) ACTRN12609000351213
PMCID: PMC4221702  PMID: 25343963
Melanoma; Vitamin D; Randomised trial; Safety; Toxicity; Recurrence; Recruitment
14.  Ambient UV, personal sun exposure and risk of multiple primary melanomas 
Cancer causes & control : CCC  2007;18(3):295-304.
Sun exposure is the main cause of melanoma in populations of European origin. No previous study has examined the effect of sun exposure on risk of multiple primary melanomas compared with people who have one melanoma.
We identified and enrolled 2,023 people with a first primary melanoma (controls) and 1,125 with multiple primary melanomas (cases) in seven centers in four countries, recorded their residential history to assign ambient UV and interviewed them about their sun exposure.
Risk of multiple primary melanomas increased significantly (P < 0.05) to OR = 2.10 for the highest exposure quarter of ambient UV irradiance at birth and 10 years of age, to OR = 1.38 for lifetime recreational sun exposure, to OR = 1.85 for beach and waterside activities, to OR = 1.57 for vacations in a sunnier climate, to OR = 1.50 for sunburns. Occupational sun exposure did not increase risk (OR = 1.03 for highest exposure). Recreational exposure at any age increased risk and appeared to add to risk from ambient UV in early life.
People who have had a melanoma can expect to reduce their risk of a further melanoma by reducing recreational sun exposure whatever their age. The same is probably true for a person who has never had a melanoma.
PMCID: PMC4206211  PMID: 17206532
Melanoma; Multiple primary neoplasms; Sunlight; Case-control studies
15.  Confirmation of Childhood Acute Lymphoblastic Leukemia Variants, ARID5B and IKZF1, and Interaction with Parental Environmental Exposures 
PLoS ONE  2014;9(10):e110255.
Genome wide association studies (GWAS) have established association of ARID5B and IKZF1 variants with childhood acute lymphoblastic leukemia (ALL). Epidemiological studies suggest that environmental factors alone appear to make a relatively minor contribution to disease risk. The polygenic nature of childhood ALL predisposition together with the timing of environmental triggers may hold vital clues for disease etiology. This study presents results from an Australian GWAS of childhood ALL cases (n = 358) and population controls (n = 1192). Furthermore, we utilised family trio (n = 204) genotypes to extend our investigation to gene-environment interaction of significant loci with parental exposures before conception, and child’s sex and age. Thirteen SNPs achieved genome wide significance in the population based case/control analysis; ten annotated to ARID5B and three to IKZF1. The most significant SNPs in these regions were ARID5B rs4245595 (OR 1.63, CI 1.38–1.93, P = 2.13×10−9), and IKZF1 rs1110701 (OR 1.69, CI 1.42–2.02, p = 7.26×10−9). There was evidence of gene-environment interaction for risk genotype at IKZF1, whereby an apparently stronger genetic effect was observed if the mother took folic acid or if the father did not smoke prior to pregnancy (respective interaction P-values: 0.04, 0.05). There were no interactions of risk genotypes with age or sex (P-values >0.2). Our results evidence that interaction of genetic variants and environmental exposures may further alter risk of childhood ALL however, investigation in a larger population is required. If interaction of folic acid supplementation and IKZF1 variants holds, it may be useful to quantify folate levels prior to initiating use of folic acid supplements.
PMCID: PMC4195717  PMID: 25310577
16.  Feasibility of a GP delivered skin cancer prevention intervention in Australia 
BMC Family Practice  2014;15:137.
Despite years of public education, sun-related behaviours are difficult to change and a recent survey showed low levels of sun protection. In this study we evaluated the feasibility and acceptability of an opportunistic skin cancer prevention intervention in general practice.
We used a controlled pre-and-post intervention design. Participants (n = 100) were recruited sequentially from patients attending two general practices in Sydney, Australia, from November to December 2010. Participants in the intervention practice (n = 50) received general practitioner delivered sun protection advice after completing a skin cancer risk assessment tool, and a sun protection pamphlet, in addition to routine care, at a single attendance. The skin cancer risk assessment tool provided three levels of risk. The general practitioner (GP) reinforced the level of risk and discussed sun protection. Participants in the control practice (n = 50) received routine care. We measured feasibility by patients’ and GPs’ participation in the intervention and time taken, and acceptability by intervention participants and GPs ratings of the intervention. We measured reported sun-related knowledge, attitudes and behaviour between the two groups at 1 and 13 months.
The intervention was found to be feasible within existing primary care team arrangements. Participation at baseline was 81% (108/134), and repeated participation was 88% (88/100) at 1 month and 70% (70/100) at 13 months. Participants and practitioners found the intervention acceptable. At 1 month, sun-related knowledge had increased in both patient groups, with a greater increase in the intervention group (adjusted mean difference 0.48, p = 0.034). There were no differences between groups in sun-related knowledge, attitudes and behaviour at 13 months.
A brief opportunistic skin cancer prevention intervention in general practice is feasible and acceptable. Further research in this setting with a more intensive intervention would be justified.
PMCID: PMC4128422  PMID: 25070692
Feasibility studies; Skin neoplasms; Preventive medicine; General practice; Health behaviour
17.  Colon and rectal cancer incidence and water trihalomethane concentrations in New South Wales, Australia 
BMC Cancer  2014;14:445.
There is evidence, although inconsistent, that long term exposure to disinfection by products (DBPs) increases the risk of bowel cancer. No study has been conducted in Australia to examine this association and due to difference in the methods of disinfection the risk can vary across geographical regions and. This study was conducted to analyse the association of trihalomethanes (THMs) in water with colon and rectal cancer in NSW Australia.
Average yearly concentrations of total and individual species of THMs were obtained for 50 local government areas (LGAs). Indirectly-standardized incidence rates of colon and rectal cancers in LGAs for the period 1995 to 2001 were regressed against mean THM concentrations lagged five years, adjusting for socioeconomic status, high risk drinking, smoking status, usual source of water and year of diagnosis, including local and global random effects within a Bayesian framework. The incidence rate ratios (IRRs) for an interquartile range (IQR) increase in THMs were estimated.
Using five year lag of exposure there was a positive association between bromoform concentration and CRC in men (IRR = 1.025, 95% CI 1.010, 1.040) but not in women (IRR = 1.003, 95% CI 0.987, 1.018). The association in men was mainly found in colon cancer with bromoform (IRR = 1.035, 95% CI 1.017, 1.053). There was no appreciable association of colorectal cancer with other species of THMs. Sensitivity analyses did not materially change the associations observed.
A positive association was observed between colon cancer and water bromoform concentrations in men. Given the potential population impact of such an association, further research into the relationship between THMs, particularly brominated species, and colorectal cancer is warranted.
PMCID: PMC4088985  PMID: 24938491
Cancer; Colon; Rectal; Disinfection by-products; Chlorination; Ecological studies
18.  The Childhood Leukemia International Consortium 
Cancer epidemiology  2013;37(3):336-347.
Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case–control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene–environment interactions.
The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene–environment interactions and subtype-specific associations through the pooling of data from independent studies.
By September 2012, CLIC included 22 studies (recruitment period: 1962–present) from 12 countries, totaling approximately 31 000 cases and 50 000 controls. Of these, 19 case–control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child–parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens.
CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene–environment interactions and associations among specific leukemia subtypes in different ethnic groups.
PMCID: PMC3652629  PMID: 23403126
Leukemia; Children; Consortium; Epidemiology; Genetics
19.  Identifying people at high risk of cutaneous malignant melanoma: results from a case-control study in Western Australia 
To assess whether screening people at high risk of malignant melanoma would be effective in reducing the mortality from the disease data from 400 case-control pairs in a study of cutaneous malignant melanoma conducted in Western Australia during 1980-1 were used to predict the risk of melanoma in the remaining 111 pairs. All variables previously shown to be associated with a decrease or increase in the incidence of melanoma were considered for inclusion in a single conditional logistic regression model of the incidence of melanoma in the randomly chosen subset of 400 case-control pairs. Five of these variables—number of raised naevi on the arms, arrival in Australia before 10 years of age, history of non-melanocytic skin cancer, time spent outdoors in summer from the age of 10 to 24, and family history of melanoma—provided good discrimination between patients and controls in this sample and the 111 other case-control pairs. Among the 222 subjects in these other case-control pairs a group defined as being at high risk of melanoma by a risk score derived from these five variables contained 60 (54%) of the patients with melanoma but only 18 (16%) of the controls.
These data suggest that in Western Australia more than half of all new patients with melanoma arise in an identifiable subpopulation constituting less than one fifth of the whole population. Identifying this subpopulation and screening it regularly for cutaneous malignant melanoma could be cost effective in reducing mortality from this disease.
PMCID: PMC2545764  PMID: 3133052
20.  Genome-wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia 
Berndt, Sonja I. | Skibola, Christine F. | Joseph, Vijai | Camp, Nicola J. | Nieters, Alexandra | Wang, Zhaoming | Cozen, Wendy | Monnereau, Alain | Wang, Sophia S. | Kelly, Rachel S. | Lan, Qing | Teras, Lauren R. | Chatterjee, Nilanjan | Chung, Charles C. | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Armstrong, Bruce K. | Cocco, Pierluigi | Zhang, Yawei | Severi, Gianluca | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Burdette, Laurie | Yuenger, Jeffrey | Hutchinson, Amy | Jacobs, Kevin B. | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Wang, Alice H. | Smedby, Karin E | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Jones, Brandt | Diver, W. Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Holly, Elizabeth A. | Smith, Martyn T. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Rabe, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R | Strom, Sara S. | Lanasa, Mark C. | Spector, Logan G. | Leis, Jose F. | Cunningham, Julie M. | Weinberg, J. Brice | Morrison, Vicki A. | Caporaso, Neil E. | Norman, Aaron D. | Linet, Martha S. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María-Dolores | Vermeulen, Roel C H | Travis, Ruth C. | Giles, Graham G. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J. | Spinelli, John J. | Bertrand, Kimberly A. | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Vajdic, Claire M. | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Sampson, Joshua | Crouch, Simon | Park, Ju-hyun | North, Kari E. | Cox, Angela | Snowden, John A. | Wright, Josh | Carracedo, Angel | Lopez-Otin, Carlos | Bea, Silvia | Salaverria, Itziar | Martin, David | Campo, Elias | Fraumeni, Joseph F. | de Sanjose, Silvia | Hjalgrim, Henrik | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature genetics  2013;45(8):868-876.
PMCID: PMC3729927  PMID: 23770605
21.  Smoking, variation in N-acetyltransferase 1 (NAT1) and 2 (NAT2), and risk of non-Hodgkin lymphoma: a pooled analysis within the InterLymph consortium 
Cancer causes & control : CCC  2012;24(1):125-134.
Studies of smoking and risk of non-Hodgkin lymphoma (NHL) have yielded inconsistent results, possibly due to subtype heterogeneity and/or genetic variation impacting the metabolism of tobacco-derived carcinogens, including substrates of the N-acetyltransferase enzymes NAT1 and NAT2.
We conducted a pooled analysis of 5,026 NHL cases and 4,630 controls from seven case–control studies in the international lymphoma epidemiology consortium to examine associations between smoking, variation in the N-acetyltransferase genes NAT1 and NAT2, and risk of NHL subtypes. Smoking data were harmonized across studies, and genetic variants in NAT1 and NAT2 were used to infer acetylation phenotype of the NAT1 and NAT2 enzymes, respectively. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for risk of NHL and subtypes were calculated using joint fixed effects unconditional logistic regression models.
Current smoking was associated with a significant 30 % increased risk of follicular lymphoma (n = 1,176) but not NHL overall or other NHL subtypes. The association was similar among NAT2 slow (OR 1.36; 95 % CI 1.07–1.75) and intermediate/rapid (OR 1.27; 95 % CI 0.95–1.69) acetylators (pinteraction = 0.82) and also did not differ by NAT1*10 allelotype. Neither NAT2 phenotype nor NAT1*10 allelotype was associated with risk of NHL overall or NHL subtypes.
The current findings provide further evidence for a modest association between current smoking and follicular lymphoma risk and suggest that this association may not be influenced by variation in the N-acetyltransferase enzymes.
PMCID: PMC3529854  PMID: 23160945
Non-Hodgkin lymphoma; Gene environment interaction; Cigarette smoking; N-acetyltransferase; Follicular lymphoma
22.  Uptake of liquid-based cytology as an adjunct to conventional cytology for cervical screening in NSW, Australia: a cross-sectional and population-based cohort analysis 
BMC Public Health  2013;13:1196.
Cervical screening is currently recommended every two years in sexually active women aged 18-20 to 69 years in Australia. Direct replacement of conventional cytology with liquid-based cytology (LBC) for cervical screening was rejected for public funding on grounds of cost-effectiveness, first in 2002 and again in 2009, but LBC is performed as an adjunct to conventional cytology in women who elect to pay. The objective of this study was to describe prevalence and predictors of use of LBC in Australia’s most populous state, New South Wales (NSW).
We performed cross-sectional and population-based cohort analyses using data from the state Pap Test Register in NSW. We calculated the age-adjusted proportion of women aged 20-69 years electing to have adjunctive LBC over the period from 2006-2010. We also calculated the fully-adjusted odds ratios for the association between subsequent LBC use and age, socioeconomic status, place of residence, previous cytological history and provider type in a cohort of 360,247 women who had an index cervical cytology test in 2006–8.
Uptake of LBC varied between 29.7% (95% Confidence Interval (CI): 29.5-30.0%) in 2006/7 and 26.6% (95% CI: 26.4-26.9%) in 2009/10. LBC was more likely to be used in women aged 30-44 years, if it had been used previously (OR13.58, 95% CI: 13.33-13.84), if the previous test result was abnormal (OR2.62, 95% CI:2.53-2.72) or unsatisfactory (OR2.37, 95% CI:2.27-3.47), or if a gynaecologist requested the test (OR1.50, 95% CI:1.46-1.54). Uptake was least for women in remote/very remote areas (OR0.68; 95% CI:0.57-0.80 referenced to those in major cities) and in lower socioeconomic groups (OR 0.41, 95% CI:0.40-0.42 for lowest versus highest SES quintile).
In the current environment in NSW, Australia, in which public funding for LBC has not been available, adjunctive uptake of LBC depends strongly on a woman’s age, her screening history and socioeconomic factors. These findings provide important context for a current review of technologies used in the National Cervical Screening Program in Australia.
PMCID: PMC3890550  PMID: 24344646
Cervical screening; Cervical cytology; Pap smear; Liquid based cytology; Australia
23.  Survival for patients with single and multiple primary melanomas in the GEM study 
JAMA dermatology (Chicago, Ill.)  2013;149(8):10.1001/jamadermatol.2013.4581.
Little is known about survival after a diagnosis of a second or higher order (multiple) primary melanoma. We aimed to determine whether survival after diagnosis was better in patients with multiple primary melanomas (MPM) than with single primary melanomas (SPM), as suggested in a recent study.
Survival analysis with median follow-up of 7.6 years (range 0.4-10.6).
The Genes, Environment and Melanoma (GEM) study enrolled incident cases of melanoma notified to population-based cancer registries in Australia, Canada, Italy and the USA. MPM were ascertained over a longer period than SPM.
2372 patients with SPM and 1206 with MPM.
Main outcome measures
Melanoma-specific fatality hazard ratios (HR) and confidence intervals (CI) associated with clinical and pathologic characteristics of SPM, MPM and both together in Cox regression models.
Thickness was the main determinant of fatality (HR for >4mm=7.68, 95% CI 4.46 to 13.23); other independent predictors were ulceration, mitoses and scalp location. After adjustment for these other predictors, there was little difference in fatality between MPM and SPM (HR for MPM relative to SPM=1.24, 95% CI 0.91 to 1.69; P = .18). Thicker SPM, however, had higher fatality (HR for >4mm=13.56, 95% CI 6.47-28.40) than thicker MPM (HR for >4mm=2.93, 95% CI 1.17-7.30).
While overall fatalities from SPM and MPM were similar, relative fatality for thick SPM was greater than for thick MPM. This finding may offer support for a difference in outcome between patients with SPM and MPM that is worth further exploration.
PMCID: PMC3815536  PMID: 23784017
GEM; MPM; SPM; pathology characteristics; fatality; survival
24.  Cancer burden in China: a Bayesian approach 
BMC Cancer  2013;13:458.
Cancer is a serious health issue in China, but accurate national counts for cancer incidence are not currently available. Knowledge of the cancer burden is necessary for national cancer control planning. In this study, national death survey data and cancer registration data were used to calculate the cancer burden in China using a Bayesian approach.
Cancer mortality and incidence rates for 2004–2005 were obtained from the National Cancer Registration database. The third National Death Survey (NDS), 2004–2005 database provided nationally representative cancer mortality rates. Bayesian modeling methods were used to estimate mortality to incidence (MI) ratios from the registry data and national incidence from the NDS for specific cancer types by age, sex and urban or rural location.
The total estimated incident cancer cases in 2005 were 2,956,300 (1,762,000 males, 1,194,300 females). World age standardized incidence rates were 236.2 per 100,000 in males and 168.9 per 100,000 in females in urban areas and 203.7 per 100,000 and 121.8 per 100,000 in rural areas.
MI ratios are useful for estimating national cancer incidence in the absence of representative incidence or survival data. Bayesian methods provide a flexible framework for smoothing rates and representing statistical uncertainty in the MI ratios. Expansion of China’s cancer registration network to be more representative of the country would improve the accuracy of cancer burden estimates.
PMCID: PMC3850959  PMID: 24093796
Bayes Theorem; China; Incidence; Mortality; Neoplasm
25.  MC1R genotype as a predictor of early-onset melanoma, compared with self-reported and physician-measured traditional risk factors: an Australian case-control-family study 
BMC Cancer  2013;13:406.
Melanocortin-1 receptor (MC1R) gene variants are very common and are associated with melanoma risk, but their contribution to melanoma risk prediction compared with traditional risk factors is unknown. We aimed to 1) evaluate the separate and incremental contribution of MC1R genotype to prediction of early-onset melanoma, and compare this with the contributions of physician-measured and self-reported traditional risk factors, and 2) develop risk prediction models that include MC1R, and externally validate these models using an independent dataset from a genetically similar melanoma population.
Using data from an Australian population-based, case-control-family study, we included 413 case and 263 control participants with sequenced MC1R genotype, clinical skin examination and detailed questionnaire. We used unconditional logistic regression to estimate predicted probabilities of melanoma. Results were externally validated using data from a similar study in England.
When added to a base multivariate model containing only demographic factors, MC1R genotype improved the area under the receiver operating characteristic curve (AUC) by 6% (from 0.67 to 0.73; P < 0.001) and improved the quartile classification by a net 26% of participants. In a more extensive multivariate model, the factors that contributed significantly to the AUC were MC1R genotype, number of nevi and previous non-melanoma skin cancer; the AUC was 0.78 (95% CI 0.75-0.82) for the model with self-reported nevi and 0.83 (95% CI 0.80-0.86) for the model with physician-counted nevi. Factors that did not further contribute were sun and sunbed exposure and pigmentation characteristics. Adding MC1R to a model containing pigmentation characteristics and other self-reported risk factors increased the AUC by 2.1% (P = 0.01) and improved the quartile classification by a net 10% (95% CI 1-18%, P = 0.03).
Although MC1R genotype is strongly associated with skin and hair phenotype, it was a better predictor of early-onset melanoma than was pigmentation characteristics. Physician-measured nevi and previous non-melanoma skin cancer were also strong predictors. There might be modest benefit to measuring MC1R genotype for risk prediction even if information about traditional self-reported or clinically measured pigmentation characteristics and nevi is already available.
PMCID: PMC3766240  PMID: 24134749
MC1R; Risk prediction; Accuracy; Melanoma; Sun exposure; Early-onset; Pigmentation; Nevi

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