Melbourne School of Population and Global Health - Research Publications

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    Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)
    Osorio, A ; Milne, RL ; Pita, G ; Peterlongo, P ; Heikkinen, T ; Simard, J ; Chenevix-Trench, G ; Spurdle, AB ; Beesley, J ; Chen, X ; Healey, S ; Neuhausen, SL ; Ding, YC ; Couch, FJ ; Wang, X ; Lindor, N ; Manoukian, S ; Barile, M ; Viel, A ; Tizzoni, L ; Szabo, CI ; Foretova, L ; Zikan, M ; Claes, K ; Greene, MH ; Mai, P ; Rennert, G ; Lejbkowicz, F ; Barnett-Griness, O ; Andrulis, IL ; Ozcelik, H ; Weerasooriya, N ; Gerdes, A-M ; Thomassen, M ; Cruger, DG ; Caligo, MA ; Friedman, E ; Kaufman, B ; Laitman, Y ; Cohen, S ; Kontorovich, T ; Gershoni-Baruch, R ; Dagan, E ; Jernstrom, H ; Askmalm, MS ; Arver, B ; Malmer, B ; Domchek, SM ; Nathanson, KL ; Brunet, J ; Ramon y Cajal, T ; Yannoukakos, D ; Hamann, U ; Hogervorst, FBL ; Verhoef, S ; Gomez Garcia, EB ; Wijnen, JT ; van den Ouweland, A ; Easton, DF ; Peock, S ; Cook, M ; Oliver, CT ; Frost, D ; Luccarini, C ; Evans, DG ; Lalloo, F ; Eeles, R ; Pichert, G ; Cook, J ; Hodgson, S ; Morrison, PJ ; Douglas, F ; Godwin, AK ; Sinilnikova, OM ; Barjhoux, L ; Stoppa-Lyonnet, D ; Moncoutier, V ; Giraud, S ; Cassini, C ; Olivier-Faivre, L ; Revillion, F ; Peyrat, J-P ; Muller, D ; Fricker, J-P ; Lynch, HT ; John, EM ; Buys, S ; Daly, M ; Hopper, JL ; Terry, MB ; Miron, A ; Yassin, Y ; Goldgar, D ; Singer, CF ; Gschwantler-Kaulich, D ; Pfeiler, G ; Spiess, A-C ; Hansen, TVO ; Johannsson, OT ; Kirchhoff, T ; Offit, K ; Kosarin, K ; Piedmonte, M ; Rodriguez, GC ; Wakeley, K ; Boggess, JF ; Basil, J ; Schwartz, PE ; Blank, SV ; Toland, AE ; Montagna, M ; Casella, C ; Imyanitov, EN ; Allavena, A ; Schmutzler, RK ; Versmold, B ; Engel, C ; Meindl, A ; Ditsch, N ; Arnold, N ; Niederacher, D ; Deissler, H ; Fiebig, B ; Varon-Mateeva, R ; Schaefer, D ; Froster, UG ; Caldes, T ; de la Hoya, M ; McGuffog, L ; Antoniou, AC ; Nevanlinna, H ; Radice, P ; Benitez, J (SPRINGERNATURE, 2009-12-08)
    BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.
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    Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics
    Garcia-Closas, M ; Hall, P ; Nevanlinna, H ; Pooley, K ; Morrison, J ; Richesson, DA ; Bojesen, SE ; Nordestgaard, BG ; Axelsson, CK ; Arias, JI ; Milne, RL ; Ribas, G ; Gonzalez-Neira, A ; Benitez, J ; Zamora, P ; Brauch, H ; Justenhoven, C ; Hamann, U ; Ko, Y-D ; Bruening, T ; Haas, S ; Doerk, T ; Schuermann, P ; Hillemanns, P ; Bogdanova, N ; Bremer, M ; Karstens, JH ; Fagerholm, R ; Aaltonen, K ; Aittomaki, K ; Von Smitten, K ; Blomqvist, C ; Mannermaa, A ; Uusitupa, M ; Eskelinen, M ; Tengstrom, M ; Kosma, V-M ; Kataja, V ; Chenevix-Trench, G ; Spurdle, AB ; Beesley, J ; Chen, X ; Devilee, P ; Van Asperen, CJ ; Jacobi, CE ; Tollenaar, RAEM ; Huijts, PEA ; Klijn, JGM ; Chang-Claude, J ; Kropp, S ; Slanger, T ; Flesch-Janys, D ; Mutschelknauss, E ; Salazar, R ; Wang-Gohrke, S ; Couch, F ; Goode, EL ; Olson, JE ; Vachon, C ; Fredericksen, ZS ; Giles, GG ; Baglietto, L ; Severi, G ; Hopper, JL ; English, DR ; Southey, MC ; Haiman, CA ; Henderson, BE ; Kolonel, LN ; Le Marchand, L ; Stram, DO ; Hunter, DJ ; Hankinson, SE ; Cox, DG ; Tamimi, R ; Kraft, P ; Sherman, ME ; Chanock, SJ ; Lissowska, J ; Brinton, LA ; Peplonska, B ; Klijn, JGM ; Hooning, MJ ; Meijers-Heijboer, H ; Collee, JM ; Van den Ouweland, A ; Uitterlinden, AG ; Liu, J ; Lin, LY ; Yuqing, L ; Humphreys, K ; Czene, K ; Cox, A ; Balasubramanian, SP ; Cross, SS ; Reed, MWR ; Blows, F ; Driver, K ; Dunning, A ; Tyrer, J ; Ponder, BAJ ; Sangrajrang, S ; Brennan, P ; Mckay, J ; Odefrey, F ; Gabrieau, V ; Sigurdson, A ; Doody, M ; Struewing, JP ; Alexander, B ; Easton, DF ; Pharoah, PD ; Leal, SM (PUBLIC LIBRARY SCIENCE, 2008-04)
    A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.
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    An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers:: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2(CIMBA)
    Chenevix-Trench, G ; Milne, RL ; Antoniou, AC ; Couch, FJ ; Easton, DF ; Goldgar, DE (BIOMED CENTRAL LTD, 2007)
    BRCA1 and BRCA2 mutations exhibit variable penetrance that is likely to be accounted for, in part, by other genetic factors among carriers. However, studies aimed at identifying these factors have been limited in size and statistical power, and have yet to identify any convincingly validated modifiers of the BRCA1 and BRCA2 phenotype. To generate sufficient statistical power to identify modifier genes, the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) has been established. CIMBA contains about 30 affiliated groups who together have collected DNA and clinical data from approximately 10,000 BRCA1 and 5,000 BRCA2 mutation carriers. Initial efforts by CIMBA to identify modifiers of breast cancer risk for BRCA1 and BRCA2 mutation carriers have focused on validation of common genetic variants previously associated with risk in smaller studies of carriers or unselected breast cancers. Future studies will involve replication of findings from pathway-based and genome-wide association studies in both unselected and familial breast cancer. The identification of genetic modifiers of breast cancer risk for BRCA1 and BRCA2 mutation carriers will lead to an improved understanding of breast cancer and may prove useful for the determination of individualized risk of cancer amongst carriers.
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    Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories?
    Byrnes, GB ; Southey, MC ; Hopper, JL (BMC, 2008)
    A woman typically presents for genetic counselling because she has a strong family history and is interested in knowing the probability she will develop disease in the future; that is, her absolute risk. Relative risk for a given factor refers to risk compared with either population average risk (sense a), or risk when not having the factor, with all other factors held constant (sense b). Not understanding that these are three distinct concepts can result in failure to correctly appreciate the consequences of studies on clinical genetic testing. Several studies found that the frequencies of mutations in ATM, BRIP1, PALB2 and CHEK2 were many times greater for cases with a strong family history than for controls. To account for the selected case sampling (ascertainment), a statistical model that assumes that the effect of any measured variant multiplies the effect of unmeasured variants was applied. This multiplicative polygenic model in effect estimated the relative risk in the sense b, not sense a, and found it was in the range of 1.7 to 2.4. The authors concluded that the variants are "low penetrance". They failed to note that their model fits predicted that, for some women, absolute risk may be as high as for BRCA2 mutation carriers. This is because the relative risk multiplies polygenic risk, and the latter is predicted by family history. Therefore, mutation testing of these genes for women with a strong family history, especially if it is of early onset, may be as clinically relevant as it is for BRCA1 and BRCA2.
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    Does smoking among friends explain apparent genetic effects on current smoking in adolescence and young adulthood?
    White, VM ; Byrnes, GB ; Webster, B ; Hopper, JL (NATURE PUBLISHING GROUP, 2008-04-22)
    We used data from a prospective cohort study of twins to investigate the influence of unmeasured genetic and measured and unmeasured environmental factors on the smoking behaviour of adolescents and young adults. Twins were surveyed in 1988 (aged 11-18 years), 1991, 1996 and 2004 with data from 1409, 1121, 732 and 758 pairs analysed from each survey wave, respectively. Questionnaires assessed the smoking behaviour of twins and the perceived smoking behaviour of friends and parents. Using a novel logistic regression analysis, we simultaneously modelled individual risk and excess concordance for current smoking as a function of zygosity, survey wave, parental smoking and peer smoking. Being concordant for having peers who smoked was a predictor of concordance for current smoking (P<0.001). After adjusting for peer smoking, monozygotic (MZ) pairs were no more alike than dizygotic pairs for current smoking at waves 2, 3 and 4. Genetic explanations are not needed to explain the greater concordance for current smoking among adult MZ pairs. However, if they are invoked, the role of genes may be due to indirect effects acting through the social environment. Smoking prevention efforts may benefit more by targeting social factors than attempting to identify genetic factors associated with smoking.
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    The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions
    Antoniou, AC ; Cunningham, AP ; Peto, J ; Evans, DG ; Lalloo, F ; Narod, SA ; Risch, HA ; Eyfjord, JE ; Hopper, JL ; Southey, MC ; Olsson, H ; Johannsson, O ; Borg, A ; Passini, B ; Radice, P ; Manoukian, S ; Eccles, DM ; Tang, N ; Olah, E ; Anton-Culver, H ; Warner, E ; Lubinski, J ; Gronwald, J ; Gorski, B ; Tryggvadottir, L ; Syrjakoski, K ; Kallioniemi, O-P ; Eerola, H ; Nevanlinna, H ; Pharoah, PDP ; Easton, DF (NATURE PUBLISHING GROUP, 2008-04-22)
    Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html).
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    Evaluation of models to predict BRCA germline mutations
    Kang, HH ; Williams, R ; Leary, J ; Ringland, C ; Kirk, J ; Ward, R (NATURE PUBLISHING GROUP, 2006-10-09)
    The selection of candidates for BRCA germline mutation testing is an important clinical issue yet it remains a significant challenge. A number of risk prediction models have been developed to assist in pretest counselling. We have evaluated the performance and the inter-rater reliability of four of these models (BRCAPRO, Manchester, Penn and the Myriad-Frank). The four risk assessment models were applied to 380 pedigrees of families who had undergone BRCA1/2 mutation analysis. Sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the receiver operator characteristic (ROC) curve were calculated for each model. Using a greater than 10% probability threshold, the likelihood that a BRCA test result was positive in a mutation carrier compared to the likelihood that the same result would be expected in an individual without a BRCA mutation was 2.10 (95% confidence interval (CI) 1.66-2.67) for Penn, 1.74 (95% CI 1.48-2.04) for Myriad, 1.35 (95% CI 1.19-1.53) for Manchester and 1.68 (95% CI 1.39-2.03) for BRCAPRO. Application of these models, therefore, did not rule in BRCA mutation carrier status. Similar trends were observed for separate BRCA1/2 performance measures except BRCA2 assessment in the Penn model where the positive likelihood ratio was 5.93. The area under the ROC curve for each model was close to 0.75. In conclusion, the four models had very little impact on the pre-test probability of disease; there were significant clinical barriers to using some models and risk estimates varied between experts. Use of models for predicting BRCA mutation status is not currently justified for populations such as that evaluated in the current study.
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    A discrete choice experiment of preferences for genetic counselling among Jewish women seeking cancer genetics services
    Peacock, S ; Apicella, C ; Andrews, L ; Tucker, K ; Bankier, A ; Daly, MB ; Hopper, JL (NATURE PUBLISHING GROUP, 2006-11-20)
    To determine which aspects of breast cancer genetic counselling are important to Ashkenazi Jewish women, a discrete choice experiment was conducted. Participants consisted of 339 Australian Ashkenazi Jewish women who provided a blood sample for research used to test for Ashkenazi Jewish ancestral mutations in the genes BRCA1 and BRCA2, and were offered their genetic test result through a cancer genetics service. Main outcome measures were women's preferences for, and trade-offs between, the genetic counselling aspects of providing cancer, gene, and risk information (information); giving advice about cancer surveillance (surveillance); preparing for genetic testing (preparation); and, assistance with decision-making (direction). Respondents most valued information, about twice as much as advice about surveillance, four times as much as preparation for testing, and nine times as much as assistance with decision-making, which was least valued. Women's preferences were consistent with the major goals of genetic counselling, which include providing information and surveillance advice, and avoiding direction by facilitating autonomous decision-making. There were differences between the women in which aspects they most favoured, suggesting that counselling that elicits and responds to clients' preferences is more likely to meet clients' needs.
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    Is there a positive association between mammographic density and bone mineral density?
    Dite, GS ; Wark, JD ; Giles, GG ; English, DR ; McCredie, MRE ; Hopper, JL (BMC, 2006)
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    Cytomegalovirus, Epstein-Barr virus and risk of breast cancer before age 40 years: a case-control study
    Richardson, AK ; Cox, B ; McCredie, M ; Dite, GS ; Chang, JH ; Gertig, DM ; Southey, MC ; Giless, GG ; Hopper, JL (NATURE PUBLISHING GROUP, 2004-06-01)
    We investigated whether there is an association between cytomegalovirus (CMV) and Epstein-Barr virus (EBV) IgG levels and risk of breast cancer before age 40 years. CMV and EBV IgG levels were measured in stored plasma from 208 women with breast cancer and 169 controls who participated in the Australian Breast Cancer Family Study (ABCFS), a population-based case-control study. CMV and EBV IgG values were measured in units of optical density (OD). Cases and controls did not differ in seropositivity for CMV (59 and 57% respectively; P=0.8) or EBV (97 and 96% respectively; P=0.7). In seropositive women, mean IgG values were higher in cases than controls for CMV (1.20 vs 0.98 OD, P=0.005) but not for EBV (2.65 vs 2.57 OD, P=0.5). The adjusted odds ratios per OD unit were 1.46 (95% CI 1.06-2.03) for CMV IgG and 1.11 (0.93-1.33) for EBV IgG. The higher mean CMV IgG levels found in women with breast cancer could be the result of a more recent infection with CMV, and may mean that late exposure to CMV is a risk factor for breast cancer.