Clinical Pathology - Research Publications

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    Identification of new breast cancer predisposition genes via whole exome sequencing
    Southey, MC ; Park, DJ ; Lesueur, F ; Odefrey, F ; Nguyen-Dumont, T ; Hammet, F ; Neuhausen, SL ; John, EM ; Andrulis, IL ; Chenevix-Trench, G ; Baglietto, L ; Le Calvez-Kelm, F ; Pertesi, M ; Lonie, A ; Pope, B ; Sinilnikova, O ; Tsimiklis, H ; Giles, GG ; Hopper, JL ; Tavtigian, SV ; Goldgar, DE (Springer Science and Business Media LLC, 2012-01)
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    DNA methylation-based biological aging and cancer risk and survival: Pooled analysis of seven prospective studies
    Dugue, P-A ; Bassett, JK ; Joo, JE ; Jung, C-H ; Wong, EM ; Moreno-Betancur, M ; Schmidt, D ; Makalic, E ; Li, S ; Severi, G ; Hodge, AM ; Buchanan, DD ; English, DR ; Hopper, JL ; Southey, MC ; Giles, GG ; Milne, RL (WILEY, 2018-04-15)
    The association between aging and cancer is complex. Recent studies have developed measures of biological aging based on DNA methylation and called them "age acceleration." We aimed to assess the associations of age acceleration with risk of and survival from seven common cancers. Seven case-control studies of DNA methylation and colorectal, gastric, kidney, lung, prostate and urothelial cancer and B-cell lymphoma nested in the Melbourne Collaborative Cohort Study were conducted. Cancer cases, vital status and cause of death were ascertained through linkage with cancer and death registries. Conditional logistic regression and Cox models were used to estimate odds ratios (OR) and hazard ratios (HR) and 95% confidence intervals (CI) for associations of five age acceleration measures derived from the Human Methylation 450 K Beadchip assay with cancer risk (N = 3,216 cases) and survival (N = 1,726 deaths), respectively. Epigenetic aging was associated with increased cancer risk, ranging from 4% to 9% per five-year age acceleration for the 5 measures considered. Heterogeneity by study was observed, with stronger associations for risk of kidney cancer and B-cell lymphoma. An associated increased risk of death following cancer diagnosis ranged from 2% to 6% per five-year age acceleration, with no evidence of heterogeneity by cancer site. Cancer risk and mortality were increased by 15-30% for the fourth versus first quartile of age acceleration. DNA methylation-based measures of biological aging are associated with increased cancer risk and shorter cancer survival, independently of major health risk factors.
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    Lifetime alcohol intake and risk of non-Hodgkin lymphoma: Findings from the Melbourne Collaborative Cohort Study
    Jayasekara, H ; Juneja, S ; Hodge, AM ; Room, R ; Milne, RL ; Hopper, JL ; English, DR ; Giles, GG ; MacInnis, RJ (WILEY, 2018-03-01)
    Cohort studies have reported inconsistent evidence regarding alcohol intake and risk of non-Hodgkin lymphoma (NHL), mostly based on alcohol intake assessed close to study enrolment. We examined this association using alcohol intake measured from age 20 onwards. We calculated usual alcohol intake for 10-year periods from age 20 using recalled frequency and quantity of beverage-specific consumption for 37,990 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 alcohol intake (g/day) and NHL risk. After a mean follow-up of 19.3 years, 538 NHL cases were diagnosed. Approximately 80% of participants were either lifetime abstainers or consumed below 20 g of ethanol/day. All categories of lifetime alcohol intake were associated with about 20% lower incidence of NHL compared with lifetime abstention, but there was no evidence of a trend by amount consumed (HR = 0.97 per 10 g/day increment in intake, 95% CI: 0.92-1.03; p value = 0.3). HRs for beer, wine and spirits were 0.91 (95% CI: 0.83-1.00; p value = 0.05), 1.03 (95% CI: 0.94-1.12; p value = 0.6), and 1.06 (95% CI: 0.83-1.37; p value = 0.6), respectively, per 10 g/day increment in lifetime intake. There were no significant differences in associations between NHL subtypes. In this low-drinking cohort, we did not detect a dose-dependent association between lifetime alcohol intake and NHL risk.
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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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    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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    Genome-Wide Measures of Peripheral Blood Dna Methylation and Prostate Cancer Risk in a Prospective Nested Case-Control Study
    FitzGerald, LM ; Naeem, H ; Makalic, E ; Schmidt, DF ; Dowty, JG ; Joo, JE ; Jung, C-H ; Bassett, JK ; Dugue, P-A ; Chung, J ; Lonie, A ; Milne, RL ; Wong, EM ; Hopper, JL ; English, DR ; Severi, G ; Baglietto, L ; Pedersen, J ; Giles, GG ; Southey, MC (WILEY, 2017-04-01)
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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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    Mould-sensitized adults have lower Th2 cytokines and a higher prevalence of asthma than those sensitized to other aeroallergens
    Matheson, MC ; Reece, JC ; Kandane-Rathnayake, RK ; Tang, MLK ; Simpson, JA ; Feather, IH ; Southey, MC ; Tsimiklis, H ; Hopper, JL ; Morrison, SC ; Giles, GG ; Walters, EH ; Dharmage, SC (WILEY, 2016-12)
    BACKGROUND: Evidence suggests that specific allergen sensitizations are associated with different allergic diseases which may reflect different underlying immune profiles. We aimed to examine the cytokine profiles of individuals sensitized to eight common aeroallergens. METHODS: We used data from the Tasmanian Longitudinal Health Study a population-based cohort study of 45-year-olds. Serum cytokines (IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α) were measured in 1157 subjects using the LINCOplex assays. Participants underwent skin prick testing for house dust mite, cat, grasses and moulds. Multivariable linear regression was used to compare serum cytokine levels between sensitized and nonatopic subjects. RESULTS: The prevalence of allergic sensitization to any aeroallergen was 51% (95% CI 47-54). Being sensitized to any aeroallergen was strongly associated with current asthma (OR = 3.7, 95% CI 2.6-5.3), and being sensitized to any moulds was associated with a very high risk of current asthma (OR = 6.40, 95% CI 4.06-10.1). The geometric mean (GM) levels of Th2 cytokines (IL-4, IL-5 and IL-6) for adults sensitized to Cladosporium were significantly lower than the levels for nonatopic individuals (IL-4 ratio of GMs = 0.25, 95% CI 0.10-0.62, P = 0.003; IL-5 GM = 0.55, 95% CI 0.30-0.99, P = 0.05; and IL-6 GM = 0.50, 95% CI 0.24-1.07, P = 0.07). Individuals sensitized to other aeroallergens all showed elevated Th2 cytokine levels. CONCLUSION: Our study is the first large population-based study to demonstrate reduced Th2 cytokines levels in people sensitized to mould. Underlying biological mechanisms driving allergic inflammatory responses in adults sensitized to moulds may differ from those sensitized to other aeroallergens. These findings suggest that it may be necessary to tailor treatments in individuals sensitized to moulds compared with other aeroallergens in order to optimize outcomes.
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    Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer
    Shi, J ; Zhang, Y ; Zheng, W ; Michailidou, K ; Ghoussaini, M ; Bolla, MK ; Wang, Q ; Dennis, J ; Lush, M ; Milne, RL ; Shu, X-O ; Beesley, J ; Kar, S ; Andrulis, IL ; Anton-Culver, H ; Arndt, V ; Beckmann, MW ; Zhao, Z ; Guo, X ; Benitez, J ; Beeghly-Fadiel, A ; Blot, W ; Bogdanova, NV ; Bojesen, SE ; Brauch, H ; Brenner, H ; Brinton, L ; Broeks, A ; Bruening, T ; Burwinkel, B ; Cai, H ; Canisius, S ; Chang-Claude, J ; Choi, J-Y ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Darabi, H ; Devilee, P ; Droit, A ; Dork, T ; Fasching, PA ; Fletcher, O ; Flyger, H ; Fostira, F ; Gaborieau, V ; Garcia-Closas, M ; Giles, GG ; Grip, M ; Guenel, P ; Haiman, CA ; Hamann, U ; Hartman, M ; Miao, H ; Hollestelle, A ; Hopper, JL ; Hsiung, C-N ; Investigators, K ; Ito, H ; Jakubowska, A ; Johnson, N ; Torres, D ; Kabisch, M ; Kang, D ; Khan, S ; Knight, JA ; Kosma, V-M ; Lambrechts, D ; Li, J ; Lindblom, A ; Lophatananon, A ; Lubinski, J ; Mannermaa, A ; Manoukian, S ; Le Marchand, L ; Margolin, S ; Marme, F ; Matsuo, K ; McLean, C ; Meindl, A ; Muir, K ; Neuhausen, SL ; Nevanlinna, H ; Nord, S ; Borresen-Dale, A-L ; Olson, JE ; Orr, N ; van den Ouweland, AMW ; Peterlongo, P ; Putti, TC ; Rudolph, A ; Sangrajrang, S ; Sawyer, EJ ; Schmidt, MK ; Schmutzler, RK ; Shen, C-Y ; Hou, M-F ; Shrubsole, MJ ; Southey, MC ; Swerdlow, A ; Teo, SH ; Thienpont, B ; Toland, AE ; Tollenaar, RAEM ; Tomlinson, I ; Truong, T ; Tseng, C-C ; Wen, W ; Winqvist, R ; Wu, AH ; Yip, CH ; Zamora, PM ; Zheng, Y ; Floris, G ; Cheng, C-Y ; Hooning, MJ ; Martens, JWM ; Seynaeve, C ; Kristensen, VN ; Hall, P ; Pharoah, PDP ; Simard, J ; Chenevix-Trench, G ; Dunning, AM ; Antoniou, AC ; Easton, DF ; Cai, Q ; Long, J (WILEY, 2016-09-15)
    Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2)  = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.