Melbourne School of Population and Global Health - Research Publications

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    Detectable clonal mosaicism and its relationship to aging and cancer
    Jacobs, KB ; Yeager, M ; Zhou, W ; Wacholder, S ; Wang, Z ; Rodriguez-Santiago, B ; Hutchinson, A ; Deng, X ; Liu, C ; Horner, M-J ; Cullen, M ; Epstein, CG ; Burdett, L ; Dean, MC ; Chatterjee, N ; Sampson, J ; Chung, CC ; Kovaks, J ; Gapstur, SM ; Stevens, VL ; Teras, LT ; Gaudet, MM ; Albanes, D ; Weinstein, SJ ; Virtamo, J ; Taylor, PR ; Freedman, ND ; Abnet, CC ; Goldstein, AM ; Hu, N ; Yu, K ; Yuan, J-M ; Liao, L ; Ding, T ; Qiao, Y-L ; Gao, Y-T ; Koh, W-P ; Xiang, Y-B ; Tang, Z-Z ; Fan, J-H ; Aldrich, MC ; Amos, C ; Blot, WJ ; Bock, CH ; Gillanders, EM ; Harris, CC ; Haiman, CA ; Henderson, BE ; Kolonel, LN ; Le Marchand, L ; McNeill, LH ; Rybicki, BA ; Schwartz, AG ; Signorello, LB ; Spitz, MR ; Wiencke, JK ; Wrensch, M ; Wu, X ; Zanetti, KA ; Ziegler, RG ; Figueroa, JD ; Garcia-Closas, M ; Malats, N ; Marenne, G ; Prokunina-Olsson, L ; Baris, D ; Schwenn, M ; Johnson, A ; Landi, MT ; Goldin, L ; Consonni, D ; Bertazzi, PA ; Rotunno, M ; Rajaraman, P ; Andersson, U ; Freeman, LEB ; Berg, CD ; Buring, JE ; Butler, MA ; Carreon, T ; Feychting, M ; Ahlbom, A ; Gaziano, JM ; Giles, GG ; Hallmans, G ; Hankinson, SE ; Hartge, P ; Henriksson, R ; Inskip, PD ; Johansen, C ; Landgren, A ; McKean-Cowdin, R ; Michaud, DS ; Melin, BS ; Peters, U ; Ruder, AM ; Sesso, HD ; Severi, G ; Shu, X-O ; Visvanathan, K ; White, E ; Wolk, A ; Zeleniuch-Jacquotte, A ; Zheng, W ; Silverman, DT ; Kogevinas, M ; Gonzalez, JR ; Villa, O ; Li, D ; Duell, EJ ; Risch, HA ; Olson, SH ; Kooperberg, C ; Wolpin, BM ; Jiao, L ; Hassan, M ; Wheeler, W ; Arslan, AA ; Bueno-de-Mesquita, HB ; Fuchs, CS ; Gallinger, S ; Gross, MD ; Holly, EA ; Klein, AP ; LaCroix, A ; Mandelson, MT ; Petersen, G ; Boutron-Ruault, M-C ; Bracci, PM ; Canzian, F ; Chang, K ; Cotterchio, M ; Giovannucci, EL ; Goggins, M ; Bolton, JAH ; Jenab, M ; Khaw, K-T ; Krogh, V ; Kurtz, RC ; McWilliams, RR ; Mendelsohn, JB ; Rabe, KG ; Riboli, E ; Tjonneland, A ; Tobias, GS ; Trichopoulos, D ; Elena, JW ; Yu, H ; Amundadottir, L ; Stolzenberg-Solomon, RZ ; Kraft, P ; Schumacher, F ; Stram, D ; Savage, SA ; Mirabello, L ; Andrulis, IL ; Wunder, JS ; Patino Garcia, A ; Sierrasesumaga, L ; Barkauskas, DA ; Gorlick, RG ; Purdue, M ; Chow, W-H ; Moore, LE ; Schwartz, KL ; Davis, FG ; Hsing, AW ; Berndt, SI ; Black, A ; Wentzensen, N ; Brinton, LA ; Lissowska, J ; Peplonska, B ; McGlynn, KA ; Cook, MB ; Graubard, BI ; Kratz, CP ; Greene, MH ; Erickson, RL ; Hunter, DJ ; Thomas, G ; Hoover, RN ; Real, FX ; Fraumeni, JF ; Caporaso, NE ; Tucker, M ; Rothman, N ; Perez-Jurado, LA ; Chanock, SJ (NATURE PUBLISHING GROUP, 2012-06)
    In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
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    Genome-wide association analysis identifies three new breast cancer susceptibility loci
    Ghoussaini, M ; Fletcher, O ; Michailidou, K ; Turnbull, C ; Schmidt, MK ; Dicks, E ; Dennis, J ; Wang, Q ; Humphreys, MK ; Luccarini, C ; Baynes, C ; Conroy, D ; Maranian, M ; Ahmed, S ; Driver, K ; Johnson, N ; Orr, N ; Silva, IDS ; Waisfisz, Q ; Meijers-Heijboer, H ; Uitterlinden, AG ; Rivadeneira, F ; Hall, P ; Czene, K ; Irwanto, A ; Liu, J ; Nevanlinna, H ; Aittomaki, K ; Blomqvist, C ; Meindl, A ; Schmutzler, RK ; Mueller-Myhsok, B ; Lichtner, P ; Chang-Claude, J ; Hein, R ; Nickels, S ; Flesch-Janys, D ; Tsimiklis, H ; Makalic, E ; Schmidt, D ; Bui, M ; Hopper, JL ; Apicella, C ; Park, DJ ; Southey, M ; Hunter, DJ ; Chanock, SJ ; Broeks, A ; Verhoef, S ; Hogervorst, FBL ; Fasching, PA ; Lux, MP ; Beckmann, MW ; Ekici, AB ; Sawyer, E ; Tomlinson, I ; Kerin, M ; Marme, F ; Schneeweiss, A ; Sohn, C ; Burwinkel, B ; Guenel, P ; Truong, T ; Cordina-Duverger, E ; Menegaux, F ; Bojesen, SE ; Nordestgaard, BG ; Nielsen, SF ; Flyger, H ; Milne, RL ; Rosario Alonso, M ; Gonzalez-Neira, A ; Benitez, J ; Anton-Culver, H ; Ziogas, A ; Bernstein, L ; Dur, CC ; Brenner, H ; Mueller, H ; Arndt, V ; Stegmaier, C ; Justenhoven, C ; Brauch, H ; Bruening, T ; Wang-Gohrke, S ; Eilber, U ; Doerk, T ; Schuermann, P ; Bremer, M ; Hillemanns, P ; Bogdanova, NV ; Antonenkova, NN ; Rogov, YI ; Karstens, JH ; Bermisheva, M ; Prokofieva, D ; Khusnutdinova, E ; Lindblom, A ; Margolin, S ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, JM ; Lambrechts, D ; Yesilyurt, BT ; Floris, G ; Leunen, K ; Manoukian, S ; Bonanni, B ; Fortuzzi, S ; Peterlongo, P ; Couch, FJ ; Wang, X ; Stevens, K ; Lee, A ; Giles, GG ; Baglietto, L ; Severi, G ; McLean, C ; Alnaes, GG ; Kristensen, V ; Borrensen-Dale, A-L ; John, EM ; Miron, A ; Winqvist, R ; Pylkas, K ; Jukkola-Vuorinen, A ; Kauppila, S ; Andrulis, IL ; Glendon, G ; Mulligan, AM ; Devilee, P ; van Asperen, CJ ; Tollenaar, RAEM ; Seynaeve, C ; Figueroa, JD ; Garcia-Closas, M ; Brinton, L ; Lissowska, J ; Hooning, MJ ; Hollestelle, A ; Oldenburg, RA ; van den Ouweland, AMW ; Cox, A ; Reed, MWR ; Shah, M ; Jakubowska, A ; Lubinski, J ; Jaworska, K ; Durda, K ; Jones, M ; Schoemaker, M ; Ashworth, A ; Swerdlow, A ; Beesley, J ; Chen, X ; Muir, KR ; Lophatananon, A ; Rattanamongkongul, S ; Chaiwerawattana, A ; Kang, D ; Yoo, K-Y ; Noh, D-Y ; Shen, C-Y ; Yu, J-C ; Wu, P-E ; Hsiung, C-N ; Perkins, A ; Swann, R ; Velentzis, L ; Eccles, DM ; Tapper, WJ ; Gerty, SM ; Graham, NJ ; Ponder, BAJ ; Chenevix-Trench, G ; Pharoah, PDP ; Lathrop, M ; Dunning, AM ; Rahman, N ; Peto, J ; Easton, DF (NATURE PUBLISHING GROUP, 2012-03)
    Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
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    Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2
    Kirchhoff, T ; Gaudet, MM ; Antoniou, AC ; McGuffog, L ; Humphreys, MK ; Dunning, AM ; Bojesen, SE ; Nordestgaard, BG ; Flyger, H ; Kang, D ; Yoo, K-Y ; Noh, D-Y ; Ahn, S-H ; Dork, T ; Schuermann, P ; Karstens, JH ; Hillemanns, P ; Couch, FJ ; Olson, J ; Vachon, C ; Wang, X ; Cox, A ; Brock, I ; Elliott, G ; Reed, MWR ; Burwinkel, B ; Meindl, A ; Brauch, H ; Hamann, U ; Ko, Y-D ; Broeks, A ; Schmidt, MK ; Van 't Veer, LJ ; Braaf, LM ; Johnson, N ; Fletcher, O ; Gibson, L ; Peto, J ; Turnbull, C ; Seal, S ; Renwick, A ; Rahman, N ; Wu, P-E ; Yu, J-C ; Hsiung, C-N ; Shen, C-Y ; Southey, MC ; Hopper, JL ; Hammet, F ; Van Dorpe, T ; Dieudonne, A-S ; Hatse, S ; Lambrechts, D ; Andrulis, IL ; Bogdanova, N ; Antonenkova, N ; Rogov, JI ; Prokofieva, D ; Bermisheva, M ; Khusnutdinova, E ; van Asperen, CJ ; Tollenaar, RAEM ; Hooning, MJ ; Devilee, P ; Margolin, S ; Lindblom, A ; Milne, RL ; Ignacio Arias, J ; Pilar Zamora, M ; Benitez, J ; Severi, G ; Baglietto, L ; Giles, GG ; Spurdle, AB ; Beesley, J ; Chen, X ; Holland, H ; Healey, S ; Wang-Gohrke, S ; Chang-Claude, J ; Mannermaa, A ; Kosma, V-M ; Kauppinen, J ; Kataja, V ; Agnarsson, BA ; Caligo, MA ; Godwin, AK ; Nevanlinna, H ; Heikkinen, T ; Fredericksen, Z ; Lindor, N ; Nathanson, KL ; Domchek, SM ; Loman, N ; Karlsson, P ; Askmalm, MS ; Melin, B ; von Wachenfeldt, A ; Hogervorst, FBL ; Verheus, M ; Rookus, MA ; Seynaeve, C ; Oldenburg, RA ; Ligtenberg, MJ ; Ausems, MGEM ; Aalfs, CM ; Gille, HJP ; Wijnen, JT ; Garcia, EBG ; Peock, S ; Cook, M ; Oliver, CT ; Frost, D ; Luccarini, C ; Pichert, G ; Davidson, R ; Chu, C ; Eccles, D ; Ong, K-R ; Cook, J ; Douglas, F ; Hodgson, S ; Evans, DG ; Eeles, R ; Gold, B ; Pharoah, PDP ; Offit, K ; Chenevix-Trench, G ; Easton, DF ; Prokunina-Olsson, L (PUBLIC LIBRARY SCIENCE, 2012-06-29)
    Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
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    Second to fourth digit ratio (2D: 4D), breast cancer risk factors, and breast cancer risk: a prospective cohort study
    Muller, DC ; Baglietto, L ; Manning, JT ; McLean, C ; Hopper, JL ; English, DR ; Giles, GG ; Severi, G (NATURE PUBLISHING GROUP, 2012-10-23)
    BACKGROUND: We aimed to assess whether 2D:4D measures are associated with breast cancer risk. METHODS: We derived the ratio of the lengths of the index and ring fingers (2D:4D), and right minus left 2D:4D (Δ(r-l)) from digit lengths measured from photocopies of participants' hands collected during a recent follow-up of the Melbourne Collaborative Cohort Study, a prospective study including 24 469 women. Of the 9044 women with available data, we identified 573 incident breast cancer cases. Hazard ratios (HR) and 95% confidence intervals (CI) for a one standard deviation difference in 2D:4D measures were obtained from Weibull survival models, and linear regression models were used to examine potential associations between 2D:4D measures and age at menarche and menopause. RESULTS: We found a direct association between left 2D:4D and breast cancer risk, an inverse association between Δ(r-l) and risk of breast cancer, but no association between right 2D:4D and breast cancer risk. Among breast cancer cases, both right 2D:4D and Δ(r-l) were inversely associated with age at diagnosis. We also observed associations between both right 2D:4D and Δ(r-l) and age at menopause, with increasing digit ratio measures related to earlier mean age at menopause. CONCLUSION: Digit ratio measures might be associated with breast cancer risk and age at onset of breast cancer. If confirmed in other studies, this suggests that lower exposure or sensitivity to prenatal testosterone might be associated with lower risk of breast cancer.
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    PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2
    Wishart, GC ; Bajdik, CD ; Dicks, E ; Provenzano, E ; Schmidt, MK ; Sherman, M ; Greenberg, DC ; Green, AR ; Gelmon, KA ; Kosma, V-M ; Olson, JE ; Beckmann, MW ; Winqvist, R ; Cross, SS ; Severi, G ; Huntsman, D ; Pylkas, K ; Ellis, I ; Nielsen, TO ; Giles, G ; Blomqvist, C ; Fasching, PA ; Couch, FJ ; Rakha, E ; Foulkes, WD ; Blows, FM ; Begin, LR ; van't Veer, LJ ; Southey, M ; Nevanlinna, H ; Mannermaa, A ; Cox, A ; Cheang, M ; Baglietto, L ; Caldas, C ; Garcia-Closas, M ; Pharoah, PDP (NATURE PUBLISHING GROUP, 2012-08-21)
    BACKGROUND: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. METHODS: The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. RESULTS: All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. CONCLUSION: Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.
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    Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)
    Hein, R ; Maranian, M ; Hopper, JL ; Kapuscinski, MK ; Southey, MC ; Park, DJ ; Schmidt, MK ; Broeks, A ; Hogervorst, FBL ; Bueno-de-Mesquit, HB ; Muir, KR ; Lophatananon, A ; Rattanamongkongul, S ; Puttawibul, P ; Fasching, PA ; Hein, A ; Ekici, AB ; Beckmann, MW ; Fletcher, O ; Johnson, N ; Silva, IDS ; Peto, J ; Sawyer, E ; Tomlinson, I ; Kerin, M ; Miller, N ; Marmee, F ; Schneeweiss, A ; Sohn, C ; Burwinkel, B ; Guenel, P ; Cordina-Duverger, E ; Menegaux, F ; Truong, T ; Bojesen, SE ; Nordestgaard, BG ; Flyger, H ; Milne, RL ; Arias Perez, JI ; Pilar Zamora, M ; Benitez, J ; Anton-Culver, H ; Ziogas, A ; Bernstein, L ; Clarke, CA ; Brenner, H ; Mueller, H ; Arndt, V ; Stegmaier, C ; Rahman, N ; Seal, S ; Turnbull, C ; Renwick, A ; Meindl, A ; Schott, S ; Bartram, CR ; Schmutzler, RK ; Brauch, H ; Hamann, U ; Ko, Y-D ; Wang-Gohrke, S ; Doerk, T ; Schuermann, P ; Karstens, JH ; Hillemanns, P ; Nevanlinna, H ; Heikkinen, T ; Aittomaki, K ; Blomqvist, C ; Bogdanova, NV ; Zalutsky, IV ; Antonenkova, NN ; Bermisheva, M ; Prokovieva, D ; Farahtdinova, A ; Khusnutdinova, E ; Lindblom, A ; Margolin, S ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, J ; Chen, X ; Beesley, J ; Lambrechts, D ; Zhao, H ; Neven, P ; Wildiers, H ; Nickels, S ; Flesch-Janys, D ; Radice, P ; Peterlongo, P ; Manoukian, S ; Barile, M ; Couch, FJ ; Olson, JE ; Wang, X ; Fredericksen, Z ; Giles, GG ; Baglietto, L ; McLean, CA ; Severi, G ; Offit, K ; Robson, M ; Gaudet, MM ; Vijai, J ; Alnaes, GG ; Kristensen, V ; Borresen-Dale, A-L ; John, EM ; Miron, A ; Winqvist, R ; Pylkas, K ; Jukkola-Vuorinen, A ; Grip, M ; Andrulis, IL ; Knight, JA ; Glendon, G ; Mulligan, AM ; Figueroa, JD ; Garcia-Closas, M ; Lissowska, J ; Sherman, ME ; Hooning, M ; Martens, JWM ; Seynaeve, C ; Collee, M ; Hall, P ; Humpreys, K ; Czene, K ; Liu, J ; Cox, A ; Brock, IW ; Cross, SS ; Reed, MWR ; Ahmed, S ; Ghoussaini, M ; Pharoah, PDP ; Kang, D ; Yoo, K-Y ; Noh, D-Y ; Jakubowska, A ; Jaworska, K ; Durda, K ; Zlowocka, E ; Sangrajrang, S ; Gaborieau, V ; Brennan, P ; McKay, J ; Shen, C-Y ; Yu, J-C ; Hsu, H-M ; Hou, M-F ; Orr, N ; Schoemaker, M ; Ashworth, A ; Swerdlow, A ; Trentham-Dietz, A ; Newcomb, PA ; Titus, L ; Egan, KM ; Chenevix-Trench, G ; Antoniou, AC ; Humphreys, MK ; Morrison, J ; Chang-Claude, J ; Easton, DF ; Dunning, AM ; Chan, KYK (PUBLIC LIBRARY SCIENCE, 2012-08-07)
    The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.
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    Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families
    Bailey-Wilson, JE ; Childs, EJ ; Cropp, CD ; Schaid, DJ ; Xu, J ; Camp, NJ ; Cannon-Albright, LA ; Farnham, JM ; George, A ; Powell, I ; Carpten, JD ; Giles, GG ; Hopper, JL ; Severi, G ; English, DR ; Foulkes, WD ; Maehle, L ; Moller, P ; Eeles, R ; Easton, D ; Guy, M ; Edwards, S ; Badzioch, MD ; Whittemore, AS ; Oakley-Girvan, I ; Hsieh, C-L ; Dimitrov, L ; Stanford, JL ; Karyadi, DM ; Deutsch, K ; McIntosh, L ; Ostrander, EA ; Wiley, KE ; Isaacs, SD ; Walsh, PC ; Thibodeau, SN ; McDonnell, SK ; Hebbring, S ; Lange, EM ; Cooney, KA ; Tammela, TLJ ; Schleutker, J ; Maier, C ; Bochum, S ; Hoegel, J ; Gronberg, H ; Wiklund, F ; Emanuelsson, M ; Cancel-Tassin, G ; Valeri, A ; Cussenot, O ; Isaacs, WB (BMC, 2012-06-19)
    BACKGROUND: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. METHODS: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. RESULTS: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. CONCLUSIONS: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.
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    Association between adult height, genetic susceptibility and risk of glioma
    Kitahara, CM ; Wang, SS ; Melin, BS ; Wang, Z ; Braganza, M ; Inskip, PD ; Albanes, D ; Andersson, U ; Freeman, LEB ; Buring, JE ; Carreon, T ; Feychting, M ; Gapstur, SM ; Gaziano, JM ; Giles, GG ; Hallmans, G ; Hankinson, SE ; Henriksson, R ; Hsing, AW ; Johansen, C ; Linet, MS ; McKean-Cowdin, R ; Michaud, DS ; Peters, U ; Purdue, MP ; Rothman, N ; Ruder, AM ; Sesso, HD ; Severi, G ; Shu, X-O ; Stevens, VL ; Visvanathan, K ; Waters, MA ; White, E ; Wolk, A ; Zeleniuch-Jacquotte, A ; Zheng, W ; Hoover, R ; Fraumeni, JF ; Chatterjee, N ; Yeager, M ; Chanock, SJ ; Hartge, P ; Rajaraman, P (OXFORD UNIV PRESS, 2012-08)
    BACKGROUND: Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub-types, and investigated effect modification by genetic susceptibility to the disease. METHODS: We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case-control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants. RESULTS: Among men, we found a positive association between height and glioma risk (≥ 190 vs 170-174 cm, pooled OR = 1.70, 95% CI: 1.11-2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17-3.38; P-trend = 0.02). Among women, these associations were less clear (≥ 175 vs 160-164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70-1.62; P-trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77-2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma-related genotypes on the association between height and glioma risk. CONCLUSION: An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease.