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1.  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.
doi:10.1002/ijc.27357
PMCID: PMC4330189  PMID: 22095472
MC1R; melanoma; early-onset; phenotype; nevi; sun exposure
2.  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
3.  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.
doi:10.1002/ijc.28314
PMCID: PMC3797193  PMID: 23754574
birth weight; fetal growth; leukemia; childhood; pooled analysis; meta-analysis
4.  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.
Purpose
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.
Results
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.
Conclusion
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.
doi:10.1200/JCO.2013.51.3002
PMCID: PMC3821014  PMID: 24127443
5.  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(1):780.
Background
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.
Methods/Design
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.
Discussion
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
doi:10.1186/1471-2407-14-780
PMCID: PMC4221702  PMID: 25343963
Melanoma; Vitamin D; Randomised trial; Safety; Toxicity; Recurrence; Recruitment
6.  Ambient UV, personal sun exposure and risk of multiple primary melanomas 
Cancer causes & control : CCC  2007;18(3):295-304.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s10552-006-0091-x
PMCID: PMC4206211  PMID: 17206532
Melanoma; Multiple primary neoplasms; Sunlight; Case-control studies
7.  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.
doi:10.1371/journal.pone.0110255
PMCID: PMC4195717  PMID: 25310577
8.  The MOBI-Kids Study Protocol: Challenges in Assessing Childhood and Adolescent Exposure to Electromagnetic Fields from Wireless Telecommunication Technologies and Possible Association with Brain Tumor Risk 
The rapid increase in mobile phone use in young people has generated concern about possible health effects of exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF). MOBI-Kids, a multinational case–control study, investigates the potential effects of childhood and adolescent exposure to EMF from mobile communications technologies on brain tumor risk in 14 countries. The study, which aims to include approximately 1,000 brain tumor cases aged 10–24 years and two individually matched controls for each case, follows a common protocol and builds upon the methodological experience of the INTERPHONE study. The design and conduct of a study on EMF exposure and brain tumor risk in young people in a large number of countries is complex and poses methodological challenges. This manuscript discusses the design of MOBI-Kids and describes the challenges and approaches chosen to address them, including: (1) the choice of controls operated for suspected appendicitis, to reduce potential selection bias related to low response rates among population controls; (2) investigating a young study population spanning a relatively wide age range; (3) conducting a large, multinational epidemiological study, while adhering to increasingly stricter ethics requirements; (4) investigating a rare and potentially fatal disease; and (5) assessing exposure to EMF from communication technologies. Our experience in thus far developing and implementing the study protocol indicates that MOBI-Kids is feasible and will generate results that will contribute to the understanding of potential brain tumor risks associated with use of mobile phones and other wireless communications technologies among young people.
doi:10.3389/fpubh.2014.00124
PMCID: PMC4172002  PMID: 25295243
children; adolescents; brain tumors; ELF–EMF; mobile phones; RF-EMF
9.  Feasibility of a GP delivered skin cancer prevention intervention in Australia 
BMC Family Practice  2014;15:137.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2296-15-137
PMCID: PMC4128422  PMID: 25070692
Feasibility studies; Skin neoplasms; Preventive medicine; General practice; Health behaviour
10.  Colon and rectal cancer incidence and water trihalomethane concentrations in New South Wales, Australia 
BMC Cancer  2014;14:445.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2407-14-445
PMCID: PMC4088985  PMID: 24938491
Cancer; Colon; Rectal; Disinfection by-products; Chlorination; Ecological studies
11.  The Childhood Leukemia International Consortium 
Cancer epidemiology  2013;37(3):336-347.
Background
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.
Objectives
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.
Methods
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.
Conclusions
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.
doi:10.1016/j.canep.2012.12.011
PMCID: PMC3652629  PMID: 23403126
Leukemia; Children; Consortium; Epidemiology; Genetics
12.  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.
doi:10.1038/ng.2652
PMCID: PMC3729927  PMID: 23770605
13.  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.
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s10552-012-0098-4
PMCID: PMC3529854  PMID: 23160945
Non-Hodgkin lymphoma; Gene environment interaction; Cigarette smoking; N-acetyltransferase; Follicular lymphoma
14.  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.
Background
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).
Methods
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.
Results
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).
Conclusion
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.
doi:10.1186/1471-2458-13-1196
PMCID: PMC3890550  PMID: 24344646
Cervical screening; Cervical cytology; Pap smear; Liquid based cytology; Australia
15.  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.
Objective
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.
Design
Survival analysis with median follow-up of 7.6 years (range 0.4-10.6).
Setting
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.
Participants
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.
Results
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).
Conclusion
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.
doi:10.1001/jamadermatol.2013.4581
PMCID: PMC3815536  PMID: 23784017
GEM; MPM; SPM; pathology characteristics; fatality; survival
16.  Cancer burden in China: a Bayesian approach 
BMC Cancer  2013;13:458.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2407-13-458
PMCID: PMC3850959  PMID: 24093796
Bayes Theorem; China; Incidence; Mortality; Neoplasm
17.  Sex- and Subtype-Specific Analysis of H2AFX Polymorphisms in Non-Hodgkin Lymphoma 
PLoS ONE  2013;8(9):e74619.
H2AFX encodes a histone variant involved in signaling sites of DNA damage and recruiting repair factors. Genetic variants in H2AFX may influence risk of non-Hodgkin lymphoma (NHL), a heterogeneous group of lymphoid tumors that are characterized by chromosomal translocations. We previously reported that rs2509049, a common variant in the promoter of H2AFX, was associated with risk for NHL in the British Columbia population. Here we report results for 13 single nucleotide polymorphisms (SNPs) in 100 Kb surrounding H2AFX in an expanded collection of 568 NHL cases and 547 controls. After correction for multiple testing, significant associations were present for mantle cell lymphoma (p=0.007 for rs604714) and all B-cell lymphomas (p=0.046 for rs2509049). Strong linkage disequilibrium in the 5 Kb upstream of H2AFX limited the ability to determine which specific SNP (rs2509049, rs7759, rs8551, rs643788, rs604714, or rs603826), if any, was responsible. There was a significant interaction between sex and rs2509049 in the all B-cell lymphomas group (p=0.002); a sex-stratified analysis revealed that the association was confined to females (p=0.001). Neither the overall nor the female-specific association with rs2509049 was replicated in any of four independent NHL sample sets. Meta-analysis of all five study populations (3,882 B-cell NHL cases and 3,718 controls) supported a weak association with B-cell lymphoma (OR=0.92, 95% CI=0.86-0.99, p=0.034), although this association was not significant after exclusion of the British Columbia data. Further research into the potential sex-specificity of the H2AFX-NHL association may identify a subset of NHL cases that are influenced by genotype at this locus.
doi:10.1371/journal.pone.0074619
PMCID: PMC3775730  PMID: 24069324
18.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1186/1471-2407-13-406
PMCID: PMC3766240  PMID: 24134749
MC1R; Risk prediction; Accuracy; Melanoma; Sun exposure; Early-onset; Pigmentation; Nevi
19.  Risk of Non-Melanoma Cancers in First-Degree Relatives of CDKN2A Mutation Carriers 
The purpose of this study was to quantify the risk of cancers other than melanoma among family members of CDKN2A mutation carriers using data from the Genes, Environment and Melanoma study. Relative risks (RRs) of all non-melanoma cancers among first-degree relatives (FDRs) of melanoma patients with CDKN2A mutations (n = 65) and FDRs of melanoma patients without mutations (n = 3537) were calculated as the ratio of estimated event rates (number of cancers/total person-years) in FDRs of carriers vs noncarriers with exact Clopper–Pearson-type tests and 95% confidence intervals (CIs). All statistical tests were two-sided. There were 56 (13.1%) non-melanoma cancers reported among 429 FDRs of mutation carriers and 2199 (9.4%) non-melanoma cancers in 23 452 FDRs of noncarriers. The FDRs of carriers had an increased risk of any cancer other than melanoma (56 cancers among 429 FDRs of carrier probands vs 2199 cancers among 23 452 FDRs of noncarrier probands; RR = 1.5, 95% CI = 1.2 to 2.0, P = .005), gastrointestinal cancer (20 cancers among 429 FDRs of carrier probands vs 506 cancers among 23 452 FDRs of noncarrier probands; RR = 2.4, 95% CI = 1.4 to 3.7, P = .001), and pancreatic cancer (five cancers among 429 FDRs of carrier probands vs 41 cancers among 23 452 FDRs of noncarrier probands; RR = 7.4, 95% CI = 2.3 to 18.7, P = .002). Wilms tumor was reported in two FDRs of carrier probands and three FDRs of noncarrier probands (RR = 40.4, 95% CI = 3.4 to 352.7, P = .005). The lifetime risk of any cancer other than melanoma among CDKN2A mutation carriers was estimated as 59.0% by age 85 years (95% CI = 39.0% to 75.4%) by the kin-cohort method, under the standard assumptions of Mendelian genetics on the genotype distribution of FDRs conditional on proband genotype.
doi:10.1093/jnci/djs221
PMCID: PMC3379723  PMID: 22534780
20.  Participation in paediatric cancer studies: timing and approach to recruitment 
BMC Research Notes  2013;6:191.
Background
Participation in epidemiological studies has fallen significantly over the past 30 years; this has been attributed to a busier lifestyle and longer working hours. In case–control studies, participation among cases is usually higher than among controls due to the personal relevance. In Australia, between 2003 and 2011, we conducted three national population-based case–control studies of risk factors for childhood cancers; brain tumors, acute leukemia and neuroblastoma and Wilms’ tumor. In this sub-study, we aimed to investigate factors that may have influenced study participation and completeness of survey completion.
Findings
The proportion of incident cases that were eligible to participate was lowest in the brain tumor study (Aus-CBT) (83.1%), as was the proportion of eligible families that consented (57%). The percentage of eligible cases that consented was highest in the leukemia study (Aus-ALL) (80.2%). The mode of invitation used was associated with families’ consent in each of the studies. Families invited in person, at clinic appointments, were more likely to consent than families invited by letter or phone. Timing of invitation following the child’s diagnosis differed among studies but, the likelihood of consent did not appear to be directly related to this. The return of questionnaires, completion of interview, and provision of DNA (blood sample) was highest in Aus-ALL (93%) and lowest in Aus-CBT (81%).
Conclusions
Studies of childhood cancer, and possibly other childhood diseases, should arrange for the family to be invited in person and, where possible, by a doctor with whom they are familiar. Whilst telephone interviews are time consuming and costly, particularly for large studies, they should be preferred over questionnaires for obtaining complete data.
doi:10.1186/1756-0500-6-191
PMCID: PMC3658929  PMID: 23656733
Recruitment; Pediatric cancer; Study invitation; Participation; Questionnaire
21.  Clinicopathologic features of incident and subsequent tumors in patients with multiple primary cutaneous melanomas 
Annals of Surgical Oncology  2011;19(3):1024-1033.
Background
0.6–12.7% of patients with primary cutaneous melanoma will develop additional melanomas. Pathologic features of tumors in patients with multiple primary cutaneous melanomas have not been well described. In this large international multi-center case-control study, we compared the clinicopathologic features of a subsequent melanoma with the preceding (usually the first) melanoma in patients with multiple primary cutaneous melanomas, and with those of melanomas in patients with single primary cutaneous melanomas.
Methods
Multiple primary melanoma (cases) and single primary invasive melanoma (controls) patients from the Genes, Environment and Melanoma (GEM) study were included if their tumors were available for pathologic review and confirmed as melanoma. Clinicopathologic characteristics of invasive subsequent and first melanomas in cases and invasive single melanomas in controls were compared.
Results
473 pairs comprising a subsequent and a first melanoma and 1989 single melanomas were reviewed. Forward stepwise regression modeling in 395 pairs with complete data showed that, compared to first melanomas, subsequent melanomas were: more commonly contiguous with a dysplastic nevus; more prevalent on the head/neck and legs than other sites; and thinner. Compared with single primary melanomas, subsequent melanomas were also more likely to be: associated with a contiguous dysplastic nevus; more prevalent on the head/neck and legs; and thinner. The same differences were observed when subsequent melanomas were compared with single melanomas. First melanomas were more likely than single melanomas to have associated solar elastosis and no observed mitoses.
Conclusions
Thinner subsequent than first melanomas suggest earlier diagnosis, perhaps due to closer clinical scrutiny. The association of subsequent melanomas with dysplastic nevi is consistent with the latter being risk factors or risk markers for melanoma.
doi:10.1245/s10434-011-2058-8
PMCID: PMC3288399  PMID: 21913010
Diagnosis; Melanoma; Multiple primary melanoma; Pathology; Risk factors
22.  Vitamin D receptor polymorphisms in patients with cutaneous melanoma 
The vitamin D receptor (VDR) gene has been associated with cancer risk, but only a few polymorphisms have been studied in relation to melanoma risk and the results have been inconsistent. We examined 38 VDR gene SNPs in a large international multi-center population-based case-control study of melanoma.
Buccal DNAs were obtained from 1207 people with incident multiple primary melanoma and 2469 with incident single primary melanoma. SNPs with known or suspected impact on VDR activity, htSNPs with ≥10% MAF in Caucasians, and SNPs reported as significant in other association studies were examined. Logistic regression was used to calculate the relative risks conferred by the individual SNP.
Eight of 38 SNPs in the promoter, coding, and 3’ gene regions were individually significantly associated with multiple primary melanoma after adjusting for covariates. The estimated increase in risk for individuals who were homozygous for the minor allele ranged from 25% to 33% for 6 polymorphisms: rs10875712 (OR 1.28; 95%CI, 1.01–1.62), rs4760674 (OR 1.33; 95% CI, 1.06–1.67), rs7139166 (OR 1.26; 95%CI, 1.02–1.56), rs4516035 (OR 1.25; 95%CI, 1.01–1.55), rs11168287 (OR 1.27; 95%CI, 1.03–1.57), rs1544410 (OR 1.30; 95%CI, 1.04–1.63); for 2 polymorphisms, homozygous carriers had a decreased risk: rs7305032 (OR 0.81; 95%CI 0.65–1.02), rs7965281 (OR, 0.78; 95%CI, 0.62–0.99). We recognize the potential false positive findings due to multiple comparisons; however the 8 significant SNPs in this study outnumbered the 2 significant tests expected to occur by chance. The vitamin D receptor may play a role in melanomagenesis.
doi:10.1002/ijc.26023
PMCID: PMC3135781  PMID: 21365644
VDR; SNP; melanoma; polymorphism; vitamin D
23.  Participation in Cervical Screening by Older Asian and Middle Eastern Migrants in New South Wales, Australia 
Health Promotion Perspectives  2012;2(2):274-286.
Background: There is little information on the detailed patterns of cervical screening uptake in older migrant women in Australia. This linkage study was performed to assess cervical screening participation in older migrants.
Methods: We linked year 2000-2001 records for 14,228 Middle Eastern/Asian-born women 40-64 years of age, and an age and area matched random sample of 13,939 Australian-born women in the New South Wales (NSW) Admitted Patients Data Collection (APDC), which records country of birth, to screening register records. Screening behaviour after 1st July 2001 was assessed in women without a recorded prior cervical abnormality
Results: Compared to Australian-born women, women born in South Central Asia had a lower screening participation rate (odds ratio for being screened at least once within a 3 year period 0.78, 95% CI 0.70-0.88). However, participation appeared relatively higher (17%-25%) in women born in the Middle East or other parts of Asia. Screening increased with increasing socioeconomic status (SES) in Australian-born women, but this trend was not observed in the migrant women. When we broadly corrected for hysterectomy, the apparent excess of screening in women from the Middle East and other parts of Asia was substantially eliminated and in contrast, the apparent deficiency in screening in women from South Central Asia increased.
Conclusions: Older women from the Middle East, and North East and South East Asian countries appeared to have similar overall screening participation to that of Australian-born women. Women from South Central Asia appeared less likely than Australian-born women to participate in cervical screening at the recommended interval.
doi:10.5681/hpp.2012.033
PMCID: PMC3963638  PMID: 24688944
Cervical cancer; Cervical screening; Record linkage; Screening in migrants
24.  Sun Exposure, Vitamin D Receptor Polymorphisms FokI and BsmI and Risk of Multiple Primary Melanoma 
Cancer epidemiology  2011;35(6):e105-e110.
Sunlight exposure increases risk of melanoma. Sunlight also potentiates cutaneous synthesis of vitamin D, which can inhibit melanoma cell growth and promote apoptosis. Vitamin D effects are mediated through the vitamin D receptor (VDR). We hypothesized that genetic variation in VDR affects the relationship of sun exposure to risk of a further melanoma in people who have already had one.
We investigated the interaction between VDR polymorphisms and sun exposure in a population-based multinational study comparing 1138 patients with a multiple (second or subsequent) primary melanoma (cases) to 2151 patients with a first primary melanoma (controls); essentially a case-control study of melanoma in a population of melanoma survivors. Sun exposure was assessed using a questionnaire and interview, and was shown to be associated with multiple primary melanoma. VDR was genotyped at the FokI and BsmI loci and the main effects of variants at these loci and their interactions with sun exposure were analyzed.
Only the BsmI variant was associated with multiple primary melanoma (OR = 1.27, 95% CI 0.99-1.62 for the homozygous variant genotype). Joint effects analyses showed highest ORs in the high exposure, homozygous variant BsmI genotype category for each sun exposure variable. Stratified analyses showed somewhat higher ORs for the homozygous BsmI variant genotype in people with high sun exposure than with low sun exposure. P values for interaction, however, were high.
These results suggest that risk of multiple primary melanoma is increased in people who have the BsmI variant of VDR.
doi:10.1016/j.canep.2011.03.003
PMCID: PMC3182291  PMID: 21612999
melanoma; FokI; BsmI; sun exposure
25.  Using administrative health data to describe colorectal and lung cancer care in New South Wales, Australia: a validation study 
Background
Monitoring treatment patterns is crucial to improving cancer patient care. Our aim was to determine the accuracy of linked routinely collected administrative health data for monitoring colorectal and lung cancer care in New South Wales (NSW), Australia.
Methods
Colorectal and lung cancer cases diagnosed in NSW between 2000 and 2002 were identified from the NSW Central Cancer Registry (CCR) and linked to their hospital discharge records in the NSW Admitted Patient Data Collection (APDC). These records were then linked to data from two relevant population-based patterns of care surveys. The main outcome measures were the sensitivity and specificity of data from the CCR and APDC for disease staging, investigative procedures, curative surgery, chemotherapy, radiotherapy, and selected comorbidities.
Results
Data for 2917 colorectal and 1580 lung cancer cases were analysed. Unknown disease stage was more common for lung cancer in the administrative data (18%) than in the survey (2%). Colonoscopies were captured reasonably accurately in the administrative data compared with the surveys (82% and 79% respectively; 91% sensitivity, 53% specificity) but all other colorectal or lung cancer diagnostic procedures were under-enumerated. Ninety-one percent of colorectal cancer cases had potentially curative surgery recorded in the administrative data compared to 95% in the survey (96% sensitivity, 92% specificity), with similar accuracy for lung cancer (16% and 17%; 92% sensitivity, 99% specificity). Chemotherapy (~40% sensitivity) and radiotherapy (sensitivity≤30%) were vastly under-enumerated in the administrative data. The only comorbidity that was recorded reasonably accurately in the administrative data was diabetes.
Conclusions
Linked routinely collected administrative health data provided reasonably accurate information on potentially curative surgical treatment, colonoscopies and comorbidities such as diabetes. Other diagnostic procedures, comorbidities, chemotherapy and radiotherapy were not well enumerated in the administrative data. Other sources of data will be required to comprehensively monitor the primary management of cancer patients.
doi:10.1186/1472-6963-12-387
PMCID: PMC3512511  PMID: 23140341
Linked data; Validation; Colorectal cancer; Lung cancer; Investigative procedures; Disease stage; Surgery; Chemotherapy; Radiotherapy; Comorbidities

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