Melbourne School of Population and Global Health - Research Publications

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    The 'Pokemon' (ZBTB7) Gene: No Evidence of Association with Sporadic Breast Cancer.
    Salas, A ; Vega, A ; Milne, RL ; García-Magariños, M ; Ruibal, A ; Benítez, J ; Carracedo, A (SAGE Publications, 2008)
    It has been proposed that the excess of familiar risk associated with breast cancer could be explained by the cumulative effect of multiple weakly predisposing alleles. The transcriptional repressor FBI1, also known as Pokemon, has recently been identified as a critical factor in oncogenesis. This protein is encoded by the ZBTB7 gene. Here we aimed to determine whether polymorphisms in ZBTB7 are associated with breast cancer risk in a sample of cases and controls collected in hospitals from North and Central Spanish patients. We genotyped 15 SNPs in ZBTB7, including the flanking regions, with an average coverage of 1 SNP/2.4 Kb, in 360 sporadic breast cancer cases and 402 controls. Comparison of allele, genotype and haplotype frequencies between cases and controls did not reveal associations using Pearson's chi-square test and a permutation procedure to correct for multiple test. In this, the first study of the ZBTB7 gene in relation to, sporadic breast cancer, we found no evidence of an association.
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    Variants in the ATM gene and breast cancer susceptibility
    Milne, RL (BIOMED CENTRAL LTD, 2009-01-01)
    It has been established that heterozygous carriers of ataxia-telangiectasia-causing mutations in the ATM gene are at approximately two-fold higher risk of breast cancer. Several studies have attempted to assess the potential implication of the gene's more common variants in breast cancer susceptibility. Three large case-control studies have consistently found no evidence of association for variants with minor allele frequency greater than 5%. Other studies have evaluated associations for coding variants with intermediate frequency (1-5%), but the results are inconsistent. Larger and/or combined association studies are needed to clarify this issue.
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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, 2008-04-01)
    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, 2007-01-01)
    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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    More breast cancer genes?
    Hopper, JL (BIOMED CENTRAL LTD, 2001-01-01)
    A new gene associated with a high risk of breast cancer, termed BRCAX, may exist on chromosome 13q. Tumours from multicase Nordic breast cancer families, in which mutations in BRCA1 and BRCA2 had been excluded, were analyzed using comparative genomic hybridization in order to identify a region of interest, which was apparently confirmed and refined using linkage analysis on an independent sample. The present commentary discusses this work. It also asks why there should exist genetic variants associated with susceptibility to breast cancer other than mutations in BRCA1 and BRCA2, and what might be their modes of inheritance, allele frequencies and risks. Replication studies will be needed to clarify whether there really is a tumour suppressor gene other than BRCA2 on chromosome 13q.
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    Genetic analysis of the vitamin D receptor gene in two epithelial cancers: melanoma and breast cancer case-control studies
    Barroso, E ; Fernandez, LP ; Milne, RL ; Pita, G ; Sendagorta, E ; Floristan, U ; Feito, M ; Aviles, JA ; Martin-Gonzalez, M ; Arias, JI ; Zamora, P ; Blanco, M ; Lazaro, P ; Benitez, J ; Ribas, G (BMC, 2008-12-23)
    BACKGROUND: Vitamin D serum levels have been found to be related to sun exposure and diet, together with cell differentiation, growth control and consequently, cancer risk. Vitamin D receptor (VDR) genotypes may influence cancer risk; however, no epidemiological studies in sporadic breast cancer (BC) or malignant melanoma (MM) have been performed in a southern European population. In this study, the VDR gene has been evaluated in two epithelial cancers BC and MM. METHODS: We have conducted an analysis in 549 consecutive and non-related sporadic BC cases and 556 controls, all from the Spanish population, and 283 MM cases and 245 controls. Genotyping analyses were carried out on four putatively functional SNPs within the VDR gene. RESULTS: An association with the minor allele A of the non-synonymous SNP rs2228570 (rs10735810, FokI, Met1Thr) was observed for BC, with an estimated odds ratio (OR) of 1.26 (95% CI = 1.02-1.57; p = 0.036). The synonymous variant rs731236 (TaqI) appeared to be associated with protection from BC (OR = 0.80, 95%CI = 0.64-0.99; p = 0.047). No statistically significant associations with MM were observed for any SNP. Nevertheless, sub-group analyses revealed an association between rs2228570 (FokI) and absence of childhood sunburns (OR = 0.65, p = 0.003), between the 3'utr SNP rs739837 (BglI) and fair skin (OR = 1.31, p = 0.048), and between the promoter SNP rs4516035 and the more aggressive tumour location in head-neck and trunk (OR = 1.54, p = 0.020). CONCLUSION: In summary, we observed associations between SNPs in the VDR gene and BC risk, and a comprehensive analysis using clinical and tumour characteristics as outcome variables has revealed potential associations with MM. These associations required confirmation in independent studies.
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    The Variant rs1867277 in FOXE1 Gene Confers Thyroid Cancer Susceptibility through the Recruitment of USF1/USF2 Transcription Factors
    Landa, I ; Ruiz-Llorente, S ; Montero-Conde, C ; Inglada-Perez, L ; Schiavi, F ; Leskelae, S ; Pita, G ; Milne, R ; Maravall, J ; Ramos, I ; Andia, V ; Rodriguez-Poyo, P ; Jara-Albarran, A ; Meoro, A ; del Peso, C ; Arribas, L ; Iglesias, P ; Caballero, J ; Serrano, J ; Pico, A ; Pomares, F ; Gimenez, G ; Lopez-Mondejar, P ; Castello, R ; Merante-Boschin, I ; Pelizzo, M-R ; Mauricio, D ; Opocher, G ; Rodriguez-Antona, C ; Gonzalez-Neira, A ; Matias-Guiu, X ; Santisteban, P ; Robledo, M ; Gibson, G (PUBLIC LIBRARY SCIENCE, 2009-09-01)
    In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30-1.70; P = 5.9x10(-9)). Functional assays of rs1867277 (NM_004473.3:c.-283G>A) within the FOXE1 5' UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/alphaCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.
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    CYP17 genetic polymorphism, breast cancer, and breast cancer risk factors: Australian Breast Cancer Family Study
    Chang, JH ; Gertig, DM ; Chen, XQ ; Dite, GS ; Jenkins, MA ; Milne, RL ; Southey, MC ; McCredie, MRE ; Giles, GG ; Chenevix-Trench, G ; Hopper, JL ; Spurdle, AB (BMC, 2005-01-01)
    INTRODUCTION: Because CYP17 can influence the degree of exposure of breast tissues to oestrogen, the interaction between polymorphisms in this gene and hormonal risk factors is of particular interest. We attempted to replicate the findings of studies assessing such interactions with the -34T-->C polymorphism. METHODS: Risk factor and CYP17 genotyping data were derived from a large Australian population-based case-control-family study of 1,284 breast cancer cases and 679 controls. Crude and adjusted odds ratio (OR) estimates and 95% confidence intervals (CIs) were calculated by unconditional logistic regression analyses. RESULTS: We found no associations between the CYP17 genotype and breast cancer overall. Premenopausal controls with A2/A2 genotype had a later age at menarche (P < 0.01). The only associations near statistical significance were that postmenopausal women with A1/A1 (wild-type) genotype had an increased risk of breast cancer if they had ever used hormone replacement therapy (OR 2.40, 95% CI 1.0 to 5.7; P = 0.05) and if they had menopause after age 47 years (OR 2.59, 95% CI 1.0 to 7.0; P = 0.06). We found no associations in common with any other studies, and no evidence for interactions. CONCLUSION: We observed no evidence of effect modification of reproductive risk factors by CYP17 genotype, although the experiment did not have sufficient statistical power to detect small main effects and modest effects in subgroups. Associations found only in subgroup analyses based on relatively small numbers require cautious interpretation without confirmation by other studies. This emphasizes the need for replication in multiple and large population-based studies to provide convincing evidence for gene-environment interactions.