Clinical Pathology - Research Publications

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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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    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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    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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    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.
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    Benign breast disease increases breast cancer risk independent of underlying familial risk profile: Findings from a Prospective Family Study Cohort
    Zeinomar, N ; Phillips, K-A ; Daly, MB ; Milne, RL ; Dite, GS ; MacInnis, RJ ; Liao, Y ; Kehm, RD ; Knight, JA ; Southey, MC ; Chung, WK ; Giles, GG ; McLachlan, S-A ; Friedlander, ML ; Weideman, PC ; Glendon, G ; Nesci, S ; Andrulis, IL ; Buys, SS ; John, EM ; Hopper, JL ; Terry, MB (WILEY, 2019-07-15)
    Benign breast disease (BBD) is an established breast cancer (BC) risk factor, but it is unclear whether the magnitude of the association applies to women at familial or genetic risk. This information is needed to improve BC risk assessment in clinical settings. Using the Prospective Family Study Cohort, we used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of BBD with BC risk. We also examined whether the association with BBD differed by underlying familial risk profile (FRP), calculated using absolute risk estimates from the Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model. During 176,756 person-years of follow-up (median: 10.9 years, maximum: 23.7) of 17,154 women unaffected with BC at baseline, we observed 968 incident cases of BC. A total of 4,704 (27%) women reported a history of BBD diagnosis at baseline. A history of BBD was associated with a greater risk of BC: HR = 1.31 (95% CI: 1.14-1.50), and did not differ by underlying FRP, with HRs of 1.35 (95% CI: 1.11-1.65), 1.26 (95% CI: 1.00-1.60), and 1.40 (95% CI: 1.01-1.93), for categories of full-lifetime BOADICEA score <20%, 20 to <35%, ≥35%, respectively. There was no difference in the association for women with BRCA1 mutations (HR: 1.64; 95% CI: 1.04-2.58), women with BRCA2 mutations (HR: 1.34; 95% CI: 0.78-2.3) or for women without a known BRCA1 or BRCA2 mutation (HR: 1.31; 95% CI: 1.13-1.53) (pinteraction  = 0.95). Women with a history of BBD have an increased risk of BC that is independent of, and multiplies, their underlying familial and genetic risk.
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    Genome-wide association study of peripheral blood DNA methylation and conventional mammographic density measures
    Li, S ; Dugue, P-A ; Baglietto, L ; Severi, G ; Wong, EM ; Nguyen, TL ; Stone, J ; English, DR ; Southey, MC ; Giles, GG ; Hopper, JL ; Milne, RL (WILEY, 2019-10-01)
    Age- and body mass index (BMI)-adjusted mammographic density is one of the strongest breast cancer risk factors. DNA methylation is a molecular mechanism that could underlie inter-individual variation in mammographic density. We aimed to investigate the association between breast cancer risk-predicting mammographic density measures and blood DNA methylation. For 436 women from the Australian Mammographic Density Twins and Sisters Study and 591 women from the Melbourne Collaborative Cohort Study, mammographic density (dense area, nondense area and percentage dense area) defined by the conventional brightness threshold was measured using the CUMULUS software, and peripheral blood DNA methylation was measured using the HumanMethylation450 (HM450) BeadChip assay. Associations between DNA methylation at >400,000 sites and mammographic density measures adjusted for age and BMI were assessed within each cohort and pooled using fixed-effect meta-analysis. Associations with methylation at genetic loci known to be associated with mammographic density were also examined. We found no genome-wide significant (p < 10-7 ) association for any mammographic density measure from the meta-analysis, or from the cohort-specific analyses. None of the 299 methylation sites located at genetic loci associated with mammographic density was associated with any mammographic density measure after adjusting for multiple testing (all p > 0.05/299 = 1.7 × 10-4 ). In summary, our study did not find evidence for associations between blood DNA methylation, as measured by the HM450 assay, and conventional mammographic density measures that predict breast cancer risk.
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    Heritable methylation marks associated with breast and prostate cancer risk
    Dugue, P-A ; Dowty, JG ; Joo, JE ; Wong, EM ; Makalic, E ; Schmidt, DF ; English, DR ; Hopper, JL ; Pedersen, J ; Severi, G ; MacInnis, RJ ; Milne, RL ; Giles, GG ; Southey, MC (WILEY, 2018-09-15)
    BACKGROUND: DNA methylation can mimic the effects of germline mutations in cancer predisposition genes. Recently, we identified twenty-four heritable methylation marks associated with breast cancer risk. As breast and prostate cancer share genetic risk factors, including rare, high-risk mutations (eg, in BRCA2), we hypothesized that some of these heritable methylation marks might also be associated with the risk of prostate cancer. METHODS: We studied 869 incident prostate cancers (430 aggressive and 439 non-aggressive) and 869 matched controls nested within a prospective cohort study. DNA methylation was measured in pre-diagnostic blood samples using the Illumina Infinium HM450K BeadChip. Conditional logistic regression models, adjusted for prostate cancer risk factors and blood cell composition, were used to estimate odds ratios and 95% confidence intervals for the association between the 24 methylation marks and the risk of prostate cancer. RESULTS: Five methylation marks within the VTRNA2-1 promoter region (cg06536614, cg00124993, cg26328633, cg25340688, and cg26896946), and one in the body of CLGN (cg22901919) were associated with the risk of prostate cancer. In stratified analyses, the five VTRNA2-1 marks were associated with the risk of aggressive prostate cancer. CONCLUSIONS: This work highlights a potentially important new area of investigation for prostate cancer susceptibility and adds to our knowledge about shared risk factors for breast and prostate cancer.
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    Circulating concentrations of B group vitamins and urothelial cell carcinoma
    Bassett, JK ; Brinkman, MT ; Dugue, P-A ; Ueland, PM ; Midttun, O ; Ulvik, A ; Bolton, D ; Southey, MC ; English, DR ; Milne, RL ; Hodge, AM ; Giles, GG (WILEY, 2019-04-15)
    B-group vitamins, as components of the one carbon metabolism pathway, are involved in DNA synthesis, repair and methylation. Our aim was to investigate associations between circulating plasma levels of B vitamins and urothelial cell carcinoma (UCC). We conducted a nested case-control study of UCC within the Melbourne Collaborative Cohort Study. B vitamins were measured in pre-diagnostic plasma samples. Conditional logistic regression was used to estimate odds ratios (OR) for UCC risk associated with circulating B vitamins in 363 matched cases and controls. In a case-only analysis (N = 390), hazard ratios (HR) for overall survival associated with plasma B vitamins were estimated using Cox regression. There were no strong associations between UCC risk and pre-diagnostic levels of plasma B vitamins. No heterogeneity in UCC risk was observed by subtype (invasive or superficial), sex, smoking status or alcohol intake. There was no heterogeneity by country of birth for most B vitamins, except for folate (p-homogeneity = 0.03). In UCC cases, there were no strong associations between plasma B vitamins and overall survival. We found no associations between pre-diagnostic plasma concentrations of B-group vitamins and UCC risk or survival.