Author
Deborah J. Thompson
Other affiliations: International Agency for Research on Cancer
Bio: Deborah J. Thompson is an academic researcher from University of Cambridge. The author has contributed to research in topics: Breast cancer & Genome-wide association study. The author has an hindex of 57, co-authored 143 publications receiving 20602 citations. Previous affiliations of Deborah J. Thompson include International Agency for Research on Cancer.
Papers published on a yearly basis
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University of Cambridge1, University of Toronto2, Yale University3, University of Iceland4, University of Melbourne5, Lund University6, National Institutes of Health7, Princess Anne Hospital8, The Chinese University of Hong Kong9, University of California, Irvine10, Pomeranian Medical University11, Helsinki University Central Hospital12, University of London13, Institute of Cancer Research14, St Mary's Hospital15
TL;DR: Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age and for variation in risk by mutation position for both genes, and some evidence for a reduction in risk in women from earlier birth cohorts is found.
Abstract: Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.
3,384 citations
University of Cambridge1, National Institutes of Health2, University of Southern California3, International Agency for Research on Cancer4, Academia Sinica5, Princess Anne Hospital6, St Mary's Hospital7, University of London8, The Breast Cancer Research Foundation9, Wellcome Trust Sanger Institute10, Peter MacCallum Cancer Centre11, QIMR Berghofer Medical Research Institute12, University of Copenhagen13, Curie Institute14, Nofer Institute of Occupational Medicine15, University of Helsinki16, Seoul National University17, University of Ulsan18, Harvard University19, Karolinska Institutet20, Agency for Science, Technology and Research21, Hannover Medical School22, Leiden University23, Erasmus University Rotterdam24, University of Minnesota25, University of Sheffield26, Mayo Clinic27, VU University Amsterdam28, Carlos III Health Institute29, University of Melbourne30, Cancer Council New South Wales31, University of Otago32, Cancer Council Victoria33, University of Tübingen34, Bosch35, German Cancer Research Center36, University of Eastern Finland37
TL;DR: To identify further susceptibility alleles, a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls was conducted, followed by a third stage in which 30 single nucleotide polymorphisms were tested for confirmation.
Abstract: Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2.0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P,1027). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P,0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.
2,288 citations
TL;DR: In carriers of BRCA1 mutations, the overall increased risk of cancer at sites other than breast and ovary is small and is observed in women but generally not in men.
Abstract: Background: Germline BRCA1 mutations confer a substantial lifetime risk of breast and ovarian cancer, but whether cancer at other sites is increased is less clear To evaluate the risks of other cancers in BRCA1 mutation carriers, we conducted a cohort study of 11 847 individuals from 699 families segregating a BRCA1 mutation that were ascertained in 30 centers across Europe and North America Methods: The observed cancer incidence was compared with the expected cancer incidence based on population cancer rates Relative risks (RRs) of each cancer type in BRCA1 carriers relative to risks for the general population were estimated by weighting individuals according to their estimated probability of being a mutation carrier All statistical tests were two-sided Results: BRCA1 mutation carriers were at a statistically significantly increased risk for several cancers, including pancreatic cancer (RR = 226, 95% confidence interval [CI] = 126 to 406, P = 004) and cancer of the uterine body and cervix (uterine body RR = 265, 95% CI = 169 to 416, P<001; cervix RR = 372, 95% CI = 226 to 610, P<001) There was some evidence of an elevated risk of prostate cancer in mutation carriers younger than 65 years old (RR = 182, 95% CI = 101 to 329, P = 05) but not in those 65 years old or older (RR = 084, 95% CI = 053 to 133, P = 45) Overall, increases in the risk for cancer at sites other than the breast or ovary were small and evident in women (RR = 230, 95% CI = 193 to 275, P = 001) but not in men (RR = 095, 95% CI = 081 to 112, P = 58) Conclusions: In carriers of BRCA1 mutations, the overall increased risk of cancer at sites other than breast and ovary is small and is observed in women but generally not in men BRCA1 mutations may confer increased risks of other abdominal cancers in women and increased risks of pancreatic cancer in men and women
1,095 citations
TL;DR: In this paper, the authors compared contrast enhanced magnetic resonance imaging (CE MRI) with mammography for screening of women genetically predisposed to breast cancer and found that CE MRI is more sensitive than mammography.
1,023 citations
Erasmus University Rotterdam1, University of Cambridge2, German Cancer Research Center3, Princess Anne Hospital4, University of Manchester5, St George's, University of London6, University of Toronto7, Institute of Cancer Research8, University of London9, University of Pennsylvania10, International Agency for Research on Cancer11, Leiden University12, Wellcome Trust13
TL;DR: The biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCa2 mutations, which is consistent with participation of the encoded proteins in the same pathway.
Abstract: Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer, but account for only a small fraction of breast cancer susceptibility. To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3,4,5). We show that CHEK2(*)1100delC, a truncating variant that abrogates the kinase activity, has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003), including 13.5% of individuals from families with male breast cancer (P = 0.00015). We estimate that the CHEK2(*)1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway.
1,018 citations
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TL;DR: This year's edition of the Statistical Update includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association’s 2020 Impact Goals.
Abstract: Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovas...
5,078 citations
01 Feb 2015
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
4,409 citations
01 Jan 2000
3,536 citations
University of Cambridge1, University of Toronto2, Yale University3, University of Iceland4, University of Melbourne5, Lund University6, National Institutes of Health7, Princess Anne Hospital8, The Chinese University of Hong Kong9, University of California, Irvine10, Pomeranian Medical University11, Helsinki University Central Hospital12, University of London13, Institute of Cancer Research14, St Mary's Hospital15
TL;DR: Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age and for variation in risk by mutation position for both genes, and some evidence for a reduction in risk in women from earlier birth cohorts is found.
Abstract: Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.
3,384 citations
TL;DR: A 'census' of cancer genes is conducted that indicates that mutations in more than 1% of genes contribute to human cancer.
Abstract: A central aim of cancer research has been to identify the mutated genes that are causally implicated in oncogenesis ('cancer genes'). After two decades of searching, how many have been identified and how do they compare to the complete gene set that has been revealed by the human genome sequence? We have conducted a 'census' of cancer genes that indicates that mutations in more than 1% of genes contribute to human cancer. The census illustrates striking features in the types of sequence alteration, cancer classes in which oncogenic mutations have been identified and protein domains that are encoded by cancer genes.
3,136 citations