M C Southey

Publications (61)301.9 Total impact

• Chapter: Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

  F J Couch, X Wang, L McGuffog, A Lee, C Olswold, K B Kuchenbaecker, P Soucy, Z Fredericksen, D Barrowdale, J Dennis, [......], D G Evans, L Izatt, R A Eeles, J Adlard, D M Eccles, J Cook, C Brewer, F Douglas, S Hodgson, others
  [show abstract] [hide abstract]
  ABSTRACT: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7x10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4x10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4x10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2x10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
  01/2013: pages e1003212;
• Chapter: Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

  M M Gaudet, K B Kuchenbaecker, J Vijai, R J Klein, T Kirchhoff, L McGuffog, D Barrowdale, A M Dunning, A Lee, J Dennis, [......], B Burwinkel, P Guenel, S E Bojesen, R L Milne, H Brenner, M Lochmann, K Aittomaki, T Dork, S Margolin, others
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  ABSTRACT: Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9x10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
  01/2013: pages e1003173;
• Article: Rare mutations in XRCC2 increase the risk of breast cancer.

  D J Park, F Lesueur, T Nguyen-Dumont, M Pertesi, F Odefrey, F Hammet, S L Neuhausen, E M John, I L Andrulis, M B Terry, [......], N Hoogerbrugge, A Barroso, A Osorio, G G Giles, P Devilee, J Benitez, J L Hopper, S V Tavtigian, D E Goldgar, M C Southey
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  ABSTRACT: An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p < 0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.
  The American Journal of Human Genetics 04/2012; 90(4):734-9. · 10.60 Impact Factor
• Article: Using tumour pathology to identify people at high genetic risk of breast and colorectal cancers.

  J L Hopper, M A Jenkins, J G Dowty, G S Dite, C Apicella, L Keogh, A K Win, J P Young, D Buchanan, M D Walsh, [......], L Baglietto, G Severi, K A Phillips, E M Wong, A Dobrovic, P Waring, I Winship, S J Ramus, G G Giles, M C Southey
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  ABSTRACT: Genes have been identified for which germline mutations are associated with high lifetime risks of breast, colorectal and other cancers. Identification of mutation carriers through genetic testing is important as it could help lower cancer incidence and mortality. The translation of genetic information into better health outcomes is expensive because of the costs of genetic counselling as well as laboratory testing. Approaches to triage for mutation screening of known genes which rely on cancer family history are not necessarily sensitive and specific or the most cost-effective. Recent population-based research has shown that the cancers and precancerous lesions arising in mutation carriers have specific molecular and morphological characteristics. People with colorectal cancer, especially those diagnosed at a young age, whose tumours exhibit microsatellite instability and some specific pathology and immunohistochemically-defined features are more likely to carry a germline mutation in one of four mismatch repair genes. Some morphological and immunohistochemically-defined features are associated with breast cancers arising in women who carry BRCA1 or BRCA2 germline mutations, especially if at a young age. Screening paradigms based on molecular and morphological features that predict mutation status, especially if focused on early-onset disease, have the potential to identify mutation carriers with greater sensitivity and specificity, and in a more cost-effective way, than those based on family history alone. Genetic testing results could help inform treatment if those affected are tested soon after diagnosis using pathology-led selection strategies to identify cases most likely to carry germline mutations. We propose how this new approach could be undertaken by having genetic testing and counselling prioritised to those with the greatest probability of carrying a germline mutation in these known cancer predisposition genes.
  Pathology 12/2011; 44(2):89-98. · 2.38 Impact Factor
• Article: Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk.

  K N Stevens, M Garcia-Closas, Z Fredericksen, M Kosel, V S Pankratz, J L Hopper, G S Dite, C Apicella, M C Southey, M K Schmidt, [......], K-Y Yoo, D-Y Noh, S Sangrajrang, V Gabrieau, P Brennan, J McKay, H Anton-Culver, A Ziogas, F J Couch, D F Easton
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  ABSTRACT: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.
  British Journal of Cancer 12/2011; 105(12):1934-9. · 5.04 Impact Factor
• Source

  Available from: PubMed Central

  Article: Morphological predictors of BRCA1 germline mutations in young women with breast cancer.

  M C Southey, S J Ramus, J G Dowty, L D Smith, A A Tesoriero, E E M Wong, G S Dite, M A Jenkins, G B Byrnes, I Winship, K-A Phillips, G G Giles, J L Hopper
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  ABSTRACT: Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data. We studied a population-based sample of 452 Australian women with invasive breast cancer diagnosed before age 40 years for whom we conducted extensive germline mutation testing (29 carried a BRCA1 mutation) and a systematic pathology review, and collected three-generational family history and tumour ER and PR status. Predictors of mutation status were identified using multiple logistic regression. Areas under receiver operator characteristic (ROC) curves were estimated using five-fold stratified cross-validation. The probability of being a BRCA1 mutation carrier increased with number of selected histology features even after adjusting for family history and ER and PR status (P<0.0001). From the most parsimonious multivariate model, the odds ratio for being a carrier were: 9.7 (95% confidence interval: 2.6-47.0) for trabecular growth pattern (P=0.001); 7.8 (2.7-25.7) for mitotic index over 50 mitoses per 10 high-powered field (P=0.0003); and 2.7 (1.3-5.9) for each first-degree relative with breast cancer diagnosed before age 60 years (P=0.01).The area under the ROC curve was 0.87 (0.83-0.90). Pathology review, with attention to a few specific morphological features of invasive breast cancers, can identify almost all BRCA1 germline mutation carriers among women with early-onset breast cancer without taking into account family history.
  British Journal of Cancer 02/2011; 104(6):903-9. · 5.04 Impact Factor
• Article: Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

  K. M. Im, T. Kirchhoff, X. Wang, T. Green, C. Y. Chow, J. Vijai, J. Korn, M. M. Gaudet, Z. Fredericksen, V. Shane Pankratz, [......], R. J. Klein, M. J. Daly, E. Friedman, M. Dean, A. G. Clark, D. M. Altshuler, A. C. Antoniou, F. J. Couch, K. Offit, B. Gold
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  ABSTRACT: Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.
  Human genetics. 01/2011; 130(5):685-99.
• Article: Comprehensive analysis of the cytokine-rich chromosome 5q31.1 region suggests a role for IL-4 gene variants in prostate cancer risk.

  E A Tindall, G Severi, H N Hoang, C S Ma, P Fernandez, M C Southey, D R English, J L Hopper, C F Heyns, S G Tangye, G G Giles, V M Hayes
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  ABSTRACT: Although inflammation is emerging as a candidate prostate cancer risk factor, the T-helper cytokine-rich [interleukins (IL)-5, 13 and 4] chromosomal region at 5q31.1 has been implicated in prostate cancer pathogenesis. In particular, IL-4 has been associated with prostate cancer progression, whereas the IL-4 -589C>T (rs2243250) promoter variant has been associated with differential gene expression. We genotyped rs2243250 and 11 tag single-nucleotide polymorphisms (SNPs) spanning 200 kb across the 5q31.1 region on 825 cases and 732 controls from the Risk Factors for Prostate Cancer Study. The minor alleles of rs2243250 and an IL-4 tagSNP rs2227284 were associated with a small increase in prostate cancer risk. Per allele odds ratios (ORs) are 1.32 [95% confidence interval (CI) 1.08-1.61, P = 0.006] and 1.26 (95% CI 1.07-1.48, P = 0.005), respectively. Although these associations were not replicated in an analysis of the Melbourne Collaborative Cohort Study, including 810 cases and 1733 controls, no clinicopathological characteristic was implicated for this divergence. Correlating rs2243250 genotypes to IL-4 gene transcript levels and circulating IL-4 plasma levels, we observe in contrast to previous reports, a non-significant trend toward the minor T-allele decreasing the likelihood of IL-4 activity. From our observed association between a low IL-4 producing promoter T-allele and prostate cancer risk, our study suggests an antitumor role for IL-4 in prostate cancer. Although we saw no association for IL-5 or IL-13 gene variants and prostate cancer risk, our findings call for further evaluation of IL-4 as a contributor to prostate cancer susceptibility.
  Carcinogenesis 10/2010; 31(10):1748-54. · 5.70 Impact Factor
• Source

  Available from: Richard Moore

  Article: Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers.

  K A Schrader, S Masciari, N Boyd, C Salamanca, J Senz, D N Saunders, E Yorida, S Maines-Bandiera, P Kaurah, N Tung, [......], I L Andrulis, J A Knight, F P O'Malley, M Daly, P Bender, R Moore, M C Southey, J L Hopper, J E Garber, D G Huntsman
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  ABSTRACT: Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition. To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions. No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis. Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.
  Journal of Medical Genetics 10/2010; 48(1):64-8. · 6.36 Impact Factor
• Source

  Available from: PubMed Central

  Article: Increased cancer risks for relatives of very early-onset breast cancer cases with and without BRCA1 and BRCA2 mutations.

  G S Dite, A S Whittemore, J A Knight, E M John, R L Milne, I L Andrulis, M C Southey, M R E McCredie, G G Giles, A Miron, A I Phipps, D W West, J L Hopper
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  ABSTRACT: Little is known regarding cancer risks for relatives of women with very early-onset breast cancer. We studied 2208 parents and siblings of 504 unselected population-based Caucasian women with breast cancer diagnosed before age 35 years (103 from USA, 124 from Canada and 277 from Australia), 41 known to carry a mutation (24 in BRCA1, 16 in BRCA2 and one in both genes). Cancer-specific standardised incidence ratios (SIRs) were estimated by comparing the number of affected relatives (50% verified overall) with that expected based on incidences specific for country, sex, age and year of birth. For relatives of carriers, the female breast cancer SIRs were 13.13 (95% CI 6.57-26.26) and 12.52 (5.21-30.07) for BRCA1 and BRCA2, respectively. The ovarian cancer SIR was 12.38 (3.1-49.51) for BRCA1 and the prostate cancer SIR was 18.55 (4.64-74.17) for BRCA2. For relatives of non-carriers, the SIRs for female breast, prostate, lung, brain and urinary cancers were 4.03 (2.91-5.93), 5.25 (2.50-11.01), 7.73 (4.74-12.62), 5.19 (2.33-11.54) and 4.35 (1.81-10.46), respectively. For non-carriers, the SIRs remained elevated and were statistically significant for breast and prostate cancer when based on verified cancers. First-degree relatives of women with very early-onset breast cancer are at increased risk of cancers not explained by BRCA1 and BRCA2 mutations.
  British Journal of Cancer 09/2010; 103(7):1103-8. · 5.04 Impact Factor
• Source

  Available from: Rodney Sinclair

  Article: Plasma concentration of Propionibacterium acnes antibodies and prostate cancer risk: results from an Australian population-based case-control study.

  G Severi, B A Shannon, H N Hoang, L Baglietto, D R English, J L Hopper, J Pedersen, M C Southey, R Sinclair, R J Cohen, G G Giles
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  ABSTRACT: Recent studies in prostatic tissue suggest that Propionibacterium acnes (P. acnes), a bacterium associated with acne that normally lives on the skin, is the most prevalent bacterium in the prostate and in men with benign prostatic hyperplasia. Its prevalence is higher in samples from patients subsequently diagnosed with prostate cancer. The aim of our study was to test whether circulating levels of P. acnes antibodies are associated with prostate cancer risk and tumour characteristics using plasma samples from a population-based case-control study. We measured plasma concentration of P. acnes antibodies for 809 cases and 584 controls using a recently developed ELISA assay. We compared antibody titres between cases and controls using unconditional logistic regression adjusted for batch and variables associated with the study design (i.e., age, year of selection and centre). The primary analysis included P. acnes titres in the model as a dichotomous variable using the median value for controls as the cut-off value. P. acnes antibody titres for both cases and controls ranged from 1 : 16 (i.e., low concentration) to 1 : 65,536 (i.e., high concentration; median value=1 : 1024). The odds ratio for prostate cancer associated with titres at or above the median value was 0.73 (95% CI 0.58-0.91, P=0.005). The association appeared to be particularly strong for advanced prostate cancer (AJCC Stage grouping III-IV) for which the odds ratio was 0.59 (95% CI 0.43-0.81, P=0.001) but there was insufficient evidence that the association differed by tumour stage (p heterogeneity=0.07). These results need to be confirmed in prospective studies but they are consistent with the hypothesis that P. acnes has a role in prostate cancer.
  British Journal of Cancer 07/2010; 103(3):411-5. · 5.04 Impact Factor
• Article: Are PALB2 mutations associated with increased risk of male breast cancer?

  A Sauty de Chalon, Z Teo, D J Park, F A Odefrey, J L Hopper, M C Southey
  Breast Cancer Research and Treatment 05/2010; 121(1):253-5. · 4.43 Impact Factor
• Article: Sibship analysis of associations between SNP haplotypes and a continuous trait with application to mammographic density.

  J Stone, L C Gurrin, V M Hayes, M C Southey, J L Hopper, G B Byrnes
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  ABSTRACT: Haplotype-based association studies have been proposed as a powerful comprehensive approach to identify causal genetic variation underlying complex diseases. Data comparisons within families offer the additional advantage of dealing naturally with complex sources of noise, confounding and population stratification. Two problems encountered when investigating associations between haplotypes and a continuous trait using data from sibships are (i) the need to define within-sibship comparisons for sibships of size greater than two and (ii) the difficulty of resolving the joint distribution of haplotype pairs within sibships in the absence of parental genotypes. We therefore propose first a method of orthogonal transformation of both outcomes and exposures that allow the decomposition of between- and within-sibship regression effects when sibship size is greater than two. We conducted a simulation study, which confirmed analysis using all members of a sibship is statistically more powerful than methods based on cross-sectional analysis or using subsets of sib-pairs. Second, we propose a simple permutation approach to avoid errors of inference due to the within-sibship correlation of any errors in haplotype assignment. These methods were applied to investigate the association between mammographic density (MD), a continuously distributed and heritable risk factor for breast cancer, and single nucleotide polymorphisms (SNPs) and haplotypes from the VDR gene using data from a study of 430 twins and sisters. We found evidence of association between MD and a 4-SNP VDR haplotype. In conclusion, our proposed method retains the benefits of the between- and within-pair analysis for pairs of siblings and can be implemented in standard software.
  Genetic Epidemiology 11/2009; 34(4):309-18. · 3.44 Impact Factor
• Conference Proceeding: SNPs associated with iron indices in a candidate gene study of hereditary haemochromatosis

  C. C. Constantine, C. D. Vulpe, G. J. Anderson, C. E. McLaren, M Bahlo, HL Yeap, KJ Allen, NJ Osborne, N. Bertalli, D. M. Gertig, M. Delatycki, J. Olynyk, KB Beckman, V Chen, D. English, M. C. Southey, J. L. Hopper, G. Giles, L Gurrin
  BioIron, Porto, Portugal; 01/2009
• Article: The natural history of serum iron indices for HFE C282Y homozygosity associated with hereditary hemochromatosis.

  Lyle C Gurrin, Nicholas J Osborne, Clare C Constantine, Christine E McLaren, Dallas R English, Dorota M Gertig, Martin B Delatycki, Melissa C Southey, John L Hopper, Graham G Giles, Gregory J Anderson, John K Olynyk, Laurie W Powell, Katrina J Allen
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  ABSTRACT: There are few longitudinal studies of serum ferritin (SF) and transferrin saturation (TS) levels in individuals homozygous for the C282Y mutation. We characterized the development of elevated iron measures in C282Y homozygotes followed for 12 years. From 31,192 people aged 40-69 years at baseline, we identified 203 C282Y homozygotes (95 males), of whom 116 had SF and fasting TS levels measured at baseline (mean age, 55 years) and 86 were untreated and had iron measures at follow-up (mean, 12 years later). The probabilities of SF at follow-up exceeding clinical thresholds were predicted from baseline SF and TS under a multivariate normal model. For C282Y homozygotes, at baseline, 84% of males and 65% of females had elevated SF and 37% of males and 3% of females had SF >1000 microg/L. For males with SF 300-1000 microg/L at baseline, the predicted probability of progressing to SF >1000 microg/L at follow-up was between 13% and 35% and, for females, between 16% and 22%. For C282Y homozygotes with normal baseline SF, <15% were predicted to develop SF >1000 microg/L if left untreated. The majority of C282Y homozygotes who are likely to develop SF levels sufficient to place them at risk of iron overload-related disease will have done so by mean age 55 years. TS >95% at mean age 55 years in males increases the likelihood that SF levels will be elevated at mean age 65 years, but this effect is absent in females, most likely because of physiologic blood loss associated with menstruation.
  Gastroenterology 09/2008; 135(6):1945-52. · 11.68 Impact Factor
• Article: The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions.

  A C Antoniou, A P Cunningham, J Peto, D G Evans, F Lalloo, S A Narod, H A Risch, J E Eyfjord, J L Hopper, M C Southey, [......], J Lubinski, J Gronwald, B Gorski, L Tryggvadottir, K Syrjakoski, O P Kallioniemi, H Eerola, H Nevanlinna, P D P Pharoah, D F Easton
  British Journal of Cancer 07/2008; 98(12):2015. · 5.04 Impact Factor
• Source

  Available from: Hannaleena Eerola

  Article: The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions.

  A C Antoniou, A P Cunningham, J Peto, D G Evans, F Lalloo, S A Narod, H A Risch, J E Eyfjord, J L Hopper, M C Southey, [......], J Lubinski, J Gronwald, B Gorski, L Tryggvadottir, K Syrjakoski, O-P Kallioniemi, H Eerola, H Nevanlinna, P D P Pharoah, D F Easton
  [show abstract] [hide abstract]
  ABSTRACT: 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).
  British Journal of Cancer 05/2008; 98(8):1457-66. · 5.04 Impact Factor
• Article: Validation study of the LAMBDA model for predicting the BRCA1 or BRCA2 mutation carrier status of North American Ashkenazi Jewish women.

  C Apicella, J G Dowty, G S Dite, M A Jenkins, R T Senie, M B Daly, I L Andrulis, E M John, S S Buys, F P Li, G Glendon, W Chung, H Ozcelik, A Miron, K Kotar, M C Southey, W D Foulkes, J L Hopper
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  ABSTRACT: LAMBDA is a model that estimates the probability an Ashkenazi Jewish (AJ) woman carries an ancestral BRCA1 or BRCA2 mutation from her personal and family cancer history. LAMBDA is relevant to clinical practice, and its implementation does not require a computer. It was developed principally from Australian and UK data. We conducted a validation study using 1286 North American AJ women tested for the mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Most had a personal or family history of breast cancer. We observed 197 carriers. The area under the receiver operator characteristic (ROC) curve (a measure of ranking) was 0.79 [95% confidence interval (CI) = 0.77-0.81], similar to that for the model-generating data (0.78; 95% CI = 0.75-0.82). LAMBDA predicted 232 carriers (18% more than observed; p = 0.002) and was overdispersed (p = 0.009). The Bayesian computer program BRCAPRO gave a similar area under the ROC curve (0.78; 95% CI = 0.76-0.80), but predicted 367 carriers (86% more than observed; p < 0.0001), and was substantially overdispersed (p < 0.0001). Therefore, LAMBDA is comparable to BRCAPRO for ranking AJ women according to their probability of being a BRCA1 or BRCA2 mutation carrier and is more accurate than brcapro which substantially overpredicts carriers in this population.
  Clinical Genetics 08/2007; 72(2):87-97. · 3.13 Impact Factor
• Article: BRCA1 promoter deletions in young women with breast cancer and a strong family history: a population-based study.

  L D Smith, A A Tesoriero, S J Ramus, G Dite, S G Royce, G G Giles, M R E McCredie, J L Hopper, M C Southey
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  ABSTRACT: Women diagnosed with breast cancer before the age of 40 years who have a strong family history of breast and/or ovarian cancer were selected from an Australian population-based case-control-family study for large deletion screening within the BRCA1 promoter. Deletions within the BRCA1 promoter region are usually not detected by the methods applied in routine clinical mutation detection strategies. Fifty-one of the 66 women (77%) who met our inclusion criteria were tested for promoter deletions using linkage disequilibrium analysis of two BRCA1 polymorphic sites (C/G1802 and Pro871Leu) and multiplex ligation-dependent probe amplification. Two cases of BRCA1 promoter deletion involving exons 1A-2 and exons 1A-23 were detected. The morphology of the breast cancers arising in these women with BRCA1 promoter deletions was consistent with the morphology associated with other germline BRCA1 mutations. Large genomic deletions that involve the promoter regions of BRCA1 make up 20% (2/10) of all known BRCA1 mutations in this group of young women with a strong family history of breast and ovarian cancer. Our data support the inclusion of testing for large genomic alterations in the BRCA1 promoter region in routine clinical mutation detection within BRCA1.
  European Journal of Cancer 04/2007; 43(5):823-7. · 5.54 Impact Factor
• Article: Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry.

  J L Bernstein, S Teraoka, M C Southey, M A Jenkins, I L Andrulis, J A Knight, E M John, R Lapinski, A L Wolitzer, A S Whittemore, D West, D Seminara, E R Olson, A B Spurdle, G Chenevix-Trench, G G Giles, J L Hopper, P Concannon
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  ABSTRACT: The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.
  Human Mutation 12/2006; 27(11):1122-8. · 5.69 Impact Factor