Melbourne School of Population and Global Health - Research Publications

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    Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci
    Tanskanen, T ; van den Berg, L ; Valimaki, N ; Aavikko, M ; Ness-Jensen, E ; Hveem, K ; Wettergren, Y ; Lindskog, EB ; Tonisson, N ; Metspalu, A ; Silander, K ; Orlando, G ; Law, PJ ; Tuupanen, S ; Gylfe, AE ; Hanninen, UA ; Cajuso, T ; Kondelin, J ; Sarin, A-P ; Pukkala, E ; Jousilahti, P ; Salomaa, V ; Ripatti, S ; Palotie, A ; Jarvinen, H ; Renkonen-Sinisalo, L ; Lepisto, A ; Bohm, J ; Mecklin, J-P ; Al-Tassan, NA ; Palles, C ; Martin, L ; Barclay, E ; Tenesa, A ; Farrington, SM ; Timofeeva, MN ; Meyer, BF ; Wakil, SM ; Campbell, H ; Smith, CG ; Idziaszczyk, S ; Maughan, TS ; Kaplan, R ; Kerr, R ; Kerr, D ; Buchanan, DD ; Win, AK ; Hopper, J ; Jenkins, MA ; Newcomb, PA ; Gallinger, S ; Conti, D ; Schumacher, FR ; Casey, G ; Cheadle, JP ; Dunlop, MG ; Tomlinson, IP ; Houlston, RS ; Palin, K ; Aaltonen, LA (WILEY, 2018-02-01)
    Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10-4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10-9 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.
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    Associations of alcohol intake, smoking, physical activity and obesity with survival following colorectal cancer diagnosis by stage, anatomic site and tumor molecular subtype
    Jayasekara, H ; English, DR ; Haydon, A ; Hodge, AM ; Lynch, BM ; Rosty, C ; Williamson, EJ ; Clendenning, M ; Southey, MC ; Jenkins, MA ; Room, R ; Hopper, JL ; Milne, RL ; Buchanan, DD ; Giles, GG ; MacInnis, RJ (WILEY, 2018-01-15)
    The influence of lifestyle factors on survival following a diagnosis of colorectal cancer (CRC) is not well established. We examined associations between lifestyle factors measured before diagnosis and CRC survival. The Melbourne Collaborative Cohort Study collected data on alcohol intake, cigarette smoking and physical activity, and body measurements at baseline (1990-1994) and wave 2 (2003-2007). We included participants diagnosed to 31 August 2015 with incident stages I-III CRC within 10-years post exposure assessment. Information on tumor characteristics and vital status was obtained. Tumor DNA was tested for microsatellite instability (MSI) and somatic mutations in oncogenes BRAF (V600E) and KRAS. We estimated hazard ratios (HRs) for associations between lifestyle factors and overall and CRC-specific mortality using Cox regression. Of 724 eligible CRC cases, 339 died (170 from CRC) during follow-up (average 9.0 years). Exercise (non-occupational/leisure-time) was associated with higher CRC-specific survival for stage II (HR = 0.25, 95% CI: 0.10-0.60) but not stages I/III disease (p for interaction = 0.01), and possibly for colon and KRAS wild-type tumors. Waist circumference was inversely associated with CRC-specific survival (HR = 1.25 per 10 cm increment, 95% CI: 1.08-1.44), independent of stage, anatomic site and tumor molecular status. Cigarette smoking was associated with lower overall survival, with suggestive evidence of worse survival for BRAF mutated CRC, but not with CRC-specific survival. Alcohol intake was not associated with survival. Survival did not differ by MSI status. We have identified pre-diagnostic predictors of survival following CRC that may have clinical and public health relevance.
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    Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia
    Gu, F ; Zhang, H ; Hyland, PL ; Berndt, S ; Gapstur, SM ; Wheeler, W ; Amos, CI ; Bezieau, S ; Bickeboller, H ; Brenner, H ; Brennan, P ; Chang-Claude, J ; Conti, DV ; Doherty, JA ; Gruber, SB ; Harrison, TA ; Hayes, RB ; Hoffmeister, M ; Houlston, RS ; Hung, RJ ; Jenkins, MA ; Kraft, P ; Lawrenson, K ; Mckay, J ; Markt, S ; Mucci, L ; Phelan, CM ; Qu, C ; Risch, A ; Rossing, MA ; Wichmann, H-E ; Shi, J ; Schernhammer, E ; Yu, K ; Landi, MT ; Caporaso, NE (WILEY, 2017-11-01)
    Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (ppathway  < 0.00625). The two most significant genes were NPAS2 (pgene  = 0.0062) and AANAT (pgene  = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (ppathway  = 0.021); this association was not confirmed in GECCO (ppathway  = 0.76) or the combined data (ppathway  = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.
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    Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer
    Rodriguez-Broadbent, H ; Law, PJ ; Sud, A ; Palin, K ; Tuupanen, S ; Gylfe, A ; Hanninen, UA ; Cajuso, T ; Tanskanen, T ; Kondelin, J ; Kaasinen, E ; Sarin, A-P ; Ripatti, S ; Eriksson, JG ; Rissanen, H ; Knekt, P ; Pukkala, E ; Jousilahti, P ; Salomaa, V ; Palotie, A ; Renkonen-Sinisalo, L ; Lepisto, A ; Bohm, J ; Mecklin, J-P ; Al-Tassan, NA ; Palles, C ; Martin, L ; Barclay, E ; Farrington, SM ; Timofeeva, MN ; Meyer, BF ; Wakil, SM ; Campbell, H ; Smith, CG ; Idziaszczyk, S ; Maughan, TS ; Kaplan, R ; Kerr, R ; Kerr, D ; Passarelli, MN ; Figueiredo, JC ; Buchanan, DD ; Win, AK ; Hopper, JL ; Jenkins, MA ; Lindor, NM ; Newcomb, PA ; Gallinger, S ; Conti, D ; Schumacher, F ; Casey, G ; Aaltonen, LA ; Cheadle, JP ; Tomlinson, IP ; Dunlop, MG ; Houlston, RS (WILEY, 2017-06-15)
    While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, p = 1.68 × 10-4 ). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, p = 0.49), 0.94 (95% CI: 0.84-1.05, p = 0.27), and 0.98 (95% CI: 0.85-1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49-0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.
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    Lifetime alcohol intake is associated with an increased risk of KRAS plus and BRAF-/KRAS- but not BRAF plus colorectal cancer
    Jayasekara, H ; MacInnis, RJ ; Williamson, EJ ; Hodge, AM ; Clendenning, M ; Rosty, C ; Walters, R ; Room, R ; Southey, MC ; Jenkins, MA ; Milne, RL ; Hopper, JL ; Giles, GG ; Buchanan, DD ; English, DR (WILEY, 2017-04)
    Ethanol in alcoholic beverages is a causative agent for colorectal cancer. Colorectal cancer is a biologically heterogeneous disease, and molecular subtypes defined by the presence of somatic mutations in BRAF and KRAS are known to exist. We examined associations between lifetime alcohol intake and molecular and anatomic subtypes of colorectal cancer. We calculated usual alcohol intake for 10-year periods from age 20 using recalled frequency and quantity of beverage-specific consumption for 38,149 participants aged 40-69 years from the Melbourne Collaborative Cohort Study. Cox regression was performed to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between lifetime alcohol intake and colorectal cancer risk. Heterogeneity in the HRs across subtypes of colorectal cancer was assessed. A positive dose-dependent association between lifetime alcohol intake and overall colorectal cancer risk (mean follow-up = 14.6 years; n = 596 colon and n = 326 rectal cancer) was observed (HR = 1.08, 95% CI: 1.04-1.12 per 10 g/day increment). The risk was greater for rectal than colon cancer (phomogeneity  = 0.02). Alcohol intake was associated with increased risks of KRAS+ (HR = 1.07, 95% CI: 1.00-1.15) and BRAF-/KRAS- (HR = 1.05, 95% CI: 1.00-1.11) but not BRAF+ tumors (HR = 0.89, 95% CI: 0.78-1.01; phomogeneity  = 0.01). Alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS- tumors originating via specific molecular pathways including the traditional adenoma-carcinoma pathway but not with BRAF+ tumors originating via the serrated pathway. Therefore, limiting alcohol intake from a young age might reduce colorectal cancer originating via the traditional adenoma-carcinoma pathway.
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    Physical activity and the risk of colorectal cancer in Lynch syndrome
    Dashti, SG ; Win, AK ; Hardikar, SS ; Glombicki, SE ; Mallenahalli, S ; Thirumurthi, S ; Peterson, SK ; You, YN ; Buchanan, DD ; Figueiredo, JC ; Campbell, PT ; Gallinger, S ; Newcomb, PA ; Potter, JD ; Lindor, NM ; Le Marchand, L ; Haile, RW ; Hopper, JL ; Jenkins, MA ; Basen-Engquist, KM ; Lynch, PM ; Pande, M (WILEY, 2018-11-01)
    Greater physical activity is associated with a decrease in risk of colorectal cancer for the general population; however, little is known about its relationship with colorectal cancer risk in people with Lynch syndrome, carriers of inherited pathogenic mutations in genes affecting DNA mismatch repair (MMR). We studied a cohort of 2,042 MMR gene mutations carriers (n = 807, diagnosed with colorectal cancer), from the Colon Cancer Family Registry. Self-reported physical activity in three age-periods (20-29, 30-49 and ≥50 years) was summarized as average metabolic equivalent of task hours per week (MET-hr/week) during the age-period of cancer diagnosis or censoring (near-term exposure) and across all age-periods preceding cancer diagnosis or censoring (long-term exposure). Weighted Cox regression was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for the association between physical activity and colorectal cancer risk. Near-term physical activity was associated with a small reduction in the risk of colorectal cancer (HR ≥35 vs. <3.5 MET-hr/week, 0.71; 95% CI, 0.53-0.96). The strength and direction of associations were similar for long-term physical activity, although the associations were not nominally significant. Our results suggest that physical activity is inversely associated with the risk of colorectal cancer for people with Lynch syndrome; however, further confirmation is warranted. The potential modifying effect of physical activity on colorectal cancer risk in people with Lynch syndrome could be useful for risk prediction and support counseling advice for lifestyle modification to reduce cancer risk.
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    Evaluation of the benefits, harms and cost-effectiveness of potential alternatives to iFOBT testing for colorectal cancer screening in Australia
    Lew, J-B ; St John, DJB ; Macrae, FA ; Emery, JD ; Ee, HC ; Jenkins, MA ; He, E ; Grogan, P ; Caruana, M ; Sarfati, D ; Greuter, MJE ; Coupe, VMH ; Canfell, K (WILEY, 2018-07-15)
    The Australian National Bowel Cancer Screening Program (NBCSP) will fully roll-out 2-yearly screening using the immunochemical Faecal Occult Blood Testing (iFOBT) in people aged 50 to 74 years by 2020. In this study, we aimed to estimate the comparative health benefits, harms, and cost-effectiveness of screening with iFOBT, versus other potential alternative or adjunctive technologies. A comprehensive validated microsimulation model, Policy1-Bowel, was used to simulate a total of 13 screening approaches involving use of iFOBT, colonoscopy, sigmoidoscopy, computed tomographic colonography (CTC), faecal DNA (fDNA) and plasma DNA (pDNA), in people aged 50 to 74 years. All strategies were evaluated in three scenarios: (i) perfect adherence, (ii) high (but imperfect) adherence, and (iii) low adherence. When assuming perfect adherence, the most effective strategies involved using iFOBT (annually, or biennially with/without adjunct sigmoidoscopy either at 50, or at 54, 64 and 74 years for individuals with negative iFOBT), or colonoscopy (10-yearly, or once-off at 50 years combined with biennial iFOBT). Colorectal cancer incidence (mortality) reductions for these strategies were 51-67(74-80)% in comparison with no screening; 2-yearly iFOBT screening (i.e. the NBCSP) would be associated with reductions of 51(74)%. Only 2-yearly iFOBT screening was found to be cost-effective in all scenarios in context of an indicative willingness-to-pay threshold of A$50,000/life-year saved (LYS); this strategy was associated with an incremental cost-effectiveness ratio of A$2,984/LYS-A$5,981/LYS (depending on adherence). The fully rolled-out NBCSP is highly cost-effective, and is also one of the most effective approaches for bowel cancer screening in Australia.
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    Discussions about predictive genetic testing for Lynch syndrome: the role of health professionals and families in decisions to decline
    Kanga-Parabia, A ; Gaff, C ; Flander, L ; Jenkins, M ; Keogh, LA (SPRINGER, 2018-10)
    Unaffected relatives of individuals with Lynch syndrome can be offered predictive genetic testing to guide surveillance recommendations. The decision-making process of those who decline testing, particularly those who do not attend a clinical genetics service, is poorly understood. We have addressed this gap by interviewing 33 individuals from Lynch syndrome mutation-carrying families, unaffected by cancer, who declined predictive genetic testing. Here, we analyse the data provided by 20 participants who unequivocally declined testing. Those who indicated they did not have enough information to make a decision or intended to undergo testing in the future were excluded. Analysis revealed that few decliners discussed their decision with general practitioners or genetic counsellors. Family members were commonly involved to varying degrees, with participants either (1) making group decisions with family members, (2) feeling persuaded by family members to either accept or decline testing, (3) discussing the test but making their own decision. A minority did not discuss testing with family members while making their decision. This research reveals the health communication activities of an understudied group, those declining predictive testing, and indicates that for many, health professionals play a minor role in the decision compared to family.
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    Screening participation for people at increased risk of colorectal cancer due to family history: a systematic review and meta-analysis
    Ouakrim, DA ; Lockett, T ; Boussioutas, A ; Hopper, JL ; Jenkins, MA (SPRINGER, 2013-09)
    We conducted a systematic review and a meta-analysis of observational studies to identify and summarise the level of colorectal cancer (CRC) screening participation for people at increased risk due to family history of the disease. Medline, Cinhal, Embase and PsychInfo databases were comprehensively searched between January 1995 and May 2012 to identify relevant articles. To be included, studies had to report on screening for people who had at least one first-degree relative with CRC and no previous personal diagnosis of the disease. Pooled screening participation levels were calculated for each screening modality. Seventeen studies, accounting for a total of 13,269 subjects with a family history of CRC met the inclusion criteria. Seven studies, including a total of 6,901 subjects had a pooled faecal occult blood testing screening participation (at least once) of 25 % (95 % CI 12-38). Five studies including a total of 5,091 subjects had a pooled sigmoidoscopy-based screening participation (at least once) of 16 % (95 % CI 7-27). Seven studies including a total of 9,965 subjects had pooled participation colonoscopy-based screening (at least once) of 40 % (95 % CI 26-54). There was a significant level of screening heterogeneity between studies. This review identified a substantial underuse of CRC screening for people at increased risk of developing the disease. It highlights the potential opportunity that exists for increasing screening participation among this segment of the population and the need to adjust the current CRC screening policies towards that objective.
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    Meta-Analysis Combining New and Existing Data Sets Confirms that the TERT-CLPTM1L Locus Influences Melanoma Risk
    Law, MH ; Montgomery, GW ; Brown, KM ; Martin, NG ; Mann, GJ ; Hayward, NK ; MacGregor, S (NATURE PUBLISHING GROUP, 2012-02)