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  1. Article ; Online: Long-term trends in the epidemiology of cardiovascular diseases in the UK: insights from the British Heart Foundation statistical compendium.

    Cheema, Katherine Margaret / Dicks, Ed / Pearson, Jeremy / Samani, Nilesh J

    Cardiovascular research

    2022  Volume 118, Issue 10, Page(s) 2267–2280

    Abstract: The British Heart Foundation's (BHF) annual statistical compendium is a comprehensive source of accessible epidemiological data in relation to cardiovascular disease (CVD) in the UK. Using datasets with multiple years of data from the compendium we have ... ...

    Abstract The British Heart Foundation's (BHF) annual statistical compendium is a comprehensive source of accessible epidemiological data in relation to cardiovascular disease (CVD) in the UK. Using datasets with multiple years of data from the compendium we have analysed trends in mortality, morbidity, and treatment for CVD within the UK. CVD mortality in the UK has consistently declined over recent decades, from 1045 deaths per 100 000 in 1969, shortly after the BHF was founded, to 255 per 100 000 in 2019. Despite this remarkable improvement, inequalities in CVD mortality persist in the UK nations, for example in 2019 the death rate in Scotland was 326 deaths per 100 000 compared with 246 per 100 000 in England. Improvements in CVD mortality have been paralleled by increased use of primary prevention medications (anti-hypertensives and statins) and interventional procedures. In recent years, progress in mortality outcomes has stalled, probably due to a combination of factors including a rise in risk factors such as obesity and diabetes. In terms of morbidity, CVD remains a significant burden in the UK, accounting for at least 1.18 million hospital admissions and reflects the enormous economic burden of CVD, estimated at £19bn in the UK. Our results highlight the importance of accessible and comprehensive statistics in relation to the burden of CVD and the value of the BHF's annual compendium in drawing out conclusions and opportunities for future research. One key area is to improve the data on which estimation of prevalence is based. There is also a need for ongoing work to better understand the root causes of disparity between socio-economic groups in relation to CVD. One important way to address this will be to improve the consistency of reporting of CVD health data across all nations of the UK. Understanding the causes will inform UK healthcare planning in addition to providing analytical insights that will be applicable in other countries.
    MeSH term(s) Cardiovascular Diseases/diagnosis ; Cardiovascular Diseases/epidemiology ; Cardiovascular Diseases/therapy ; Cause of Death ; Humans ; Prevalence ; Risk Factors ; United Kingdom/epidemiology
    Language English
    Publishing date 2022-04-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80340-6
    ISSN 1755-3245 ; 0008-6363
    ISSN (online) 1755-3245
    ISSN 0008-6363
    DOI 10.1093/cvr/cvac053
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Exome sequencing identifies

    Dicks, Ed M / Tyrer, Jonthan P / Ezquina, Suzana / Jones, Michelle / Baierl, John / Peng, Pei-Chen / Diaz, Michael / Goode, Ellen / Winham, Stacey J / Dörk, Thilo / Van Gorp, Toon / De Fazio, Ana / Bowtell, David / Odunsi, Kunle / Moysich, Kirsten / Pavanello, Marina / Campbell, Ian / Brenton, James D / Ramus, Susan J /
    Gayther, Simon A / Pharoah, Paul D P

    medRxiv : the preprint server for health sciences

    2024  

    Abstract: Rare, germline loss-of-function variants in a handful of genes that encode DNA repair proteins have been shown to be associated with epithelial ovarian cancer with a stronger association for the high-grade serous hiostotype. The aim of this study was to ... ...

    Abstract Rare, germline loss-of-function variants in a handful of genes that encode DNA repair proteins have been shown to be associated with epithelial ovarian cancer with a stronger association for the high-grade serous hiostotype. The aim of this study was to collate exome sequencing data from multiple epithelial ovarian cancer case cohorts and controls in order to systematically evaluate the role of coding, loss-of-function variants across the genome in epithelial ovarian cancer risk. We assembled exome data for a total of 2,573 non-mucinous cases (1,876 high-grade serous and 697 non-high grade serous) and 13,925 controls. Harmonised variant calling and quality control filtering was applied across the different data sets. We carried out a gene-by-gene simple burden test for association of rare loss-of-function variants (minor allele frequency < 0.1%) with all non-mucinous ovarian cancer, high grade serous ovarian cancer and non-high grade serous ovarian cancer using logistic regression adjusted for the top four principal components to account for cryptic population structure and genetic ancestry. Seven of the top 10 associated genes were associations of the known ovarian cancer susceptibility genes
    Language English
    Publishing date 2024-04-03
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.04.02.24304968
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: An updated PREDICT breast cancer prognostication and treatment benefit prediction model with independent validation.

    Candido Dos Reis, Francisco J / Wishart, Gordon C / Dicks, Ed M / Greenberg, David / Rashbass, Jem / Schmidt, Marjanka K / van den Broek, Alexandra J / Ellis, Ian O / Green, Andrew / Rakha, Emad / Maishman, Tom / Eccles, Diana M / Pharoah, Paul D P

    Breast cancer research : BCR

    2017  Volume 19, Issue 1, Page(s) 58

    Abstract: Background: PREDICT is a breast cancer prognostic and treatment benefit model implemented online. The overall fit of the model has been good in multiple independent case series, but PREDICT has been shown to underestimate breast cancer specific ... ...

    Abstract Background: PREDICT is a breast cancer prognostic and treatment benefit model implemented online. The overall fit of the model has been good in multiple independent case series, but PREDICT has been shown to underestimate breast cancer specific mortality in women diagnosed under the age of 40. Another limitation is the use of discrete categories for tumour size and node status resulting in 'step' changes in risk estimates on moving between categories. We have refitted the PREDICT prognostic model using the original cohort of cases from East Anglia with updated survival time in order to take into account age at diagnosis and to smooth out the survival function for tumour size and node status.
    Methods: Multivariable Cox regression models were used to fit separate models for ER negative and ER positive disease. Continuous variables were fitted using fractional polynomials and a smoothed baseline hazard was obtained by regressing the baseline cumulative hazard for each patients against time using fractional polynomials. The fit of the prognostic models were then tested in three independent data sets that had also been used to validate the original version of PREDICT.
    Results: In the model fitting data, after adjusting for other prognostic variables, there is an increase in risk of breast cancer specific mortality in younger and older patients with ER positive disease, with a substantial increase in risk for women diagnosed before the age of 35. In ER negative disease the risk increases slightly with age. The association between breast cancer specific mortality and both tumour size and number of positive nodes was non-linear with a more marked increase in risk with increasing size and increasing number of nodes in ER positive disease. The overall calibration and discrimination of the new version of PREDICT (v2) was good and comparable to that of the previous version in both model development and validation data sets. However, the calibration of v2 improved over v1 in patients diagnosed under the age of 40.
    Conclusions: The PREDICT v2 is an improved prognostication and treatment benefit model compared with v1. The online version should continue to aid clinical decision making in women with early breast cancer.
    MeSH term(s) Adult ; Breast/pathology ; Breast Neoplasms/epidemiology ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Estrogen Receptor alpha/genetics ; Female ; Humans ; Prognosis ; Proportional Hazards Models
    Chemical Substances Estrogen Receptor alpha
    Language English
    Publishing date 2017-05-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2015059-3
    ISSN 1465-542X ; 1465-5411
    ISSN (online) 1465-542X
    ISSN 1465-5411
    DOI 10.1186/s13058-017-0852-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A risk prediction algorithm for ovarian cancer incorporating BRCA1, BRCA2, common alleles and other familial effects.

    Jervis, Sarah / Song, Honglin / Lee, Andrew / Dicks, Ed / Harrington, Patricia / Baynes, Caroline / Manchanda, Ranjit / Easton, Douglas F / Jacobs, Ian / Pharoah, Paul P D / Antoniou, Antonis C

    Journal of medical genetics

    2015  Volume 52, Issue 7, Page(s) 465–475

    Abstract: Background: Although BRCA1 and BRCA2 mutations account for only ∼27% of the familial aggregation of ovarian cancer (OvC), no OvC risk prediction model currently exists that considers the effects of BRCA1, BRCA2 and other familial factors. Therefore, a ... ...

    Abstract Background: Although BRCA1 and BRCA2 mutations account for only ∼27% of the familial aggregation of ovarian cancer (OvC), no OvC risk prediction model currently exists that considers the effects of BRCA1, BRCA2 and other familial factors. Therefore, a currently unresolved problem in clinical genetics is how to counsel women with family history of OvC but no identifiable BRCA1/2 mutations.
    Methods: We used data from 1548 patients with OvC and their relatives from a population-based study, with known BRCA1/2 mutation status, to investigate OvC genetic susceptibility models, using segregation analysis methods.
    Results: The most parsimonious model included the effects of BRCA1/2 mutations, and the residual familial aggregation was accounted for by a polygenic component (SD 1.43, 95% CI 1.10 to 1.86), reflecting the multiplicative effects of a large number of genes with small contributions to the familial risk. We estimated that 1 in 630 individuals carries a BRCA1 mutation and 1 in 195 carries a BRCA2 mutation. We extended this model to incorporate the explicit effects of 17 common alleles that are associated with OvC risk. Based on our models, assuming all of the susceptibility genes could be identified we estimate that the half of the female population at highest genetic risk will account for 92% of all OvCs.
    Conclusions: The resulting model can be used to obtain the risk of developing OvC on the basis of BRCA1/2, explicit family history and common alleles. This is the first model that accounts for all OvC familial aggregation and would be useful in the OvC genetic counselling process.
    MeSH term(s) Alleles ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Counseling/methods ; Genetic Predisposition to Disease ; Humans ; Models, Genetic ; Multifactorial Inheritance/genetics ; Ovarian Neoplasms/diagnosis ; Risk Assessment/methods
    Language English
    Publishing date 2015-05-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 220881-7
    ISSN 1468-6244 ; 0022-2593
    ISSN (online) 1468-6244
    ISSN 0022-2593
    DOI 10.1136/jmedgenet-2015-103077
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population.

    Song, Honglin / Cicek, Mine S / Dicks, Ed / Harrington, Patricia / Ramus, Susan J / Cunningham, Julie M / Fridley, Brooke L / Tyrer, Jonathan P / Alsop, Jennifer / Jimenez-Linan, Mercedes / Gayther, Simon A / Goode, Ellen L / Pharoah, Paul D P

    Human molecular genetics

    2014  Volume 23, Issue 17, Page(s) 4703–4709

    Abstract: The aim of this study was to estimate the contribution of deleterious mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6 and PMS2 to invasive epithelial ovarian cancer (EOC) in the population. The coding sequence and splice site boundaries of all six genes were ...

    Abstract The aim of this study was to estimate the contribution of deleterious mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6 and PMS2 to invasive epithelial ovarian cancer (EOC) in the population. The coding sequence and splice site boundaries of all six genes were amplified in germline DNA from 2240 invasive EOC cases and 1535 controls. Barcoded fragment libraries were sequenced using the Illumina GAII or HiSeq and sequence data for each subject de-multiplexed prior to interpretation. GATK and Annovar were used for variant detection and annotation. After quality control 2222 cases (99.2%) and 1528 controls (99.5%) were included in the final analysis. We identified 193 EOC cases (8.7%) carrying a deleterious mutation in at least one gene compared with 10 controls (0.65%). Mutations were most frequent in BRCA1 and BRCA2, with 84 EOC cases (3.8%) carrying a BRCA1 mutation and 94 EOC cases (4.2%) carrying a BRCA2 mutation. The combined BRCA1 and BRCA2 mutation prevalence was 11% in high-grade serous disease. Seventeen EOC cases carried a mutation in a mismatch repair gene, including 10 MSH6 mutation carriers (0.45%) and 4 MSH2 mutation carriers (0.18%). At least 1 in 10 women with high-grade serous EOC has a BRCA1 or BRCA2 mutation. The development of next generation sequencing technologies enables rapid mutation screening for multiple susceptibility genes at once, suggesting that routine clinical testing of all incidence cases should be considered.
    MeSH term(s) Adult ; Age of Onset ; Aged ; BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; DNA Mismatch Repair/genetics ; Female ; Genetic Predisposition to Disease ; Germ-Line Mutation/genetics ; Humans ; Middle Aged ; Mutation, Missense/genetics ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Risk Factors ; Young Adult
    Chemical Substances BRCA1 Protein ; BRCA2 Protein
    Language English
    Publishing date 2014-04-12
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddu172
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Ovarian cancer familial relative risks by tumour subtypes and by known ovarian cancer genetic susceptibility variants.

    Jervis, Sarah / Song, Honglin / Lee, Andrew / Dicks, Ed / Tyrer, Jonathan / Harrington, Patricia / Easton, Douglas F / Jacobs, Ian J / Pharoah, Paul P D / Antoniou, Antonis C

    Journal of medical genetics

    2013  Volume 51, Issue 2, Page(s) 108–113

    Abstract: Background: Family history is one of the most important risk factors for epithelial ovarian cancer (EOC). Little is known, however, on how EOC familial relative risks (FRRs) vary by factors such as tumour subtype or the combined effects of common EOC ... ...

    Abstract Background: Family history is one of the most important risk factors for epithelial ovarian cancer (EOC). Little is known, however, on how EOC familial relative risks (FRRs) vary by factors such as tumour subtype or the combined effects of common EOC susceptibility alleles. In addition, no data currently exist on the FRRs associated with EOC after exclusion of BRCA1 or BRCA2 mutation carriers.
    Methods: EOC FRRs were computed from observed EOCs in relatives of 1548 patients with EOC recruited between 1999 and 2010 from a population-based cohort study with known BRCA1 and BRCA2 mutation status and tumour subtype, compared with the number expected in the general population.
    Results: The EOC FRR to all first-degree relatives was estimated to be 2.96 (95% CI 2.35 to 3.72) but there was no evidence of difference in the FRRs for mothers, sisters and daughters. There was significant evidence that the FRR for relatives of patients with EOC diagnosed under age 50 years is higher than that for older patients (4.72 (95% CI 3.21 to 6.95) and 2.53 (95% CI 1.91 to 3.35), p-diff=0.0052) and a suggestion that the FRR in relatives of patients with serous disease is higher than that for non-serous tumours (3.64 (95% CI 2.72 to 4.87) and 2.25 (95% CI 1.56 to 3.26), p-diff=0.0023). The FRR to relatives of cases without a deleterious mutation in BRCA1 or BRCA2 was estimated to be over twice that of the general population (2.24 (95% CI 1.71 to 2.94)). BRCA1 and BRCA2 mutations were estimated to account for about 24% of the EOC FRR to first-degree relatives. FRRs were found to increase with increasing polygenic risk score of the index patient, although the trend was not significant.
    Conclusions: These estimates could be useful in the counselling of relatives of patients with ovarian cancer.
    MeSH term(s) Adult ; Aged ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Predisposition to Disease ; Humans ; Middle Aged ; Mutation ; Neoplasms, Cystic, Mucinous, and Serous/genetics ; Neoplasms, Cystic, Mucinous, and Serous/pathology ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Polymorphism, Single Nucleotide ; Risk ; Young Adult
    Language English
    Publishing date 2013-11-25
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 220881-7
    ISSN 1468-6244 ; 0022-2593
    ISSN (online) 1468-6244
    ISSN 0022-2593
    DOI 10.1136/jmedgenet-2013-102015
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: RNA editing of human microRNAs.

    Blow, Matthew J / Grocock, Russell J / van Dongen, Stijn / Enright, Anton J / Dicks, Ed / Futreal, P Andrew / Wooster, Richard / Stratton, Michael R

    Genome biology

    2006  Volume 7, Issue 4, Page(s) R27

    Abstract: Background: MicroRNAs (miRNAs) are short RNAs of around 22 nucleotides that regulate gene expression. The primary transcripts of miRNAs contain double-stranded RNA and are therefore potential substrates for adenosine to inosine (A-to-I) RNA editing.: ... ...

    Abstract Background: MicroRNAs (miRNAs) are short RNAs of around 22 nucleotides that regulate gene expression. The primary transcripts of miRNAs contain double-stranded RNA and are therefore potential substrates for adenosine to inosine (A-to-I) RNA editing.
    Results: We have conducted a survey of RNA editing of miRNAs from ten human tissues by sequence comparison of PCR products derived from matched genomic DNA and total cDNA from the same individual. Six out of 99 (6%) miRNA transcripts from which data were obtained were subject to A-to-I editing in at least one tissue. Four out of seven edited adenosines were in the mature miRNA and were predicted to change the target sites in 3' untranslated regions. For a further six miRNAs, we identified A-to-I editing of transcripts derived from the opposite strand of the genome to the annotated miRNA. These miRNAs may have been annotated to the wrong genomic strand.
    Conclusion: Our results indicate that RNA editing increases the diversity of miRNAs and their targets, and hence may modulate miRNA function.
    MeSH term(s) Adenosine/metabolism ; Humans ; Inosine/metabolism ; MicroRNAs/chemistry ; MicroRNAs/metabolism ; RNA Editing ; RNA Precursors/chemistry ; RNA Precursors/metabolism ; RNA, Double-Stranded/chemistry ; RNA, Double-Stranded/metabolism
    Chemical Substances MicroRNAs ; RNA Precursors ; RNA, Double-Stranded ; Inosine (5A614L51CT) ; Adenosine (K72T3FS567)
    Language English
    Publishing date 2006
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2040529-7
    ISSN 1474-760X ; 1465-6914 ; 1465-6906
    ISSN (online) 1474-760X ; 1465-6914
    ISSN 1465-6906
    DOI 10.1186/gb-2006-7-4-r27
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Population-based targeted sequencing of 54 candidate genes identifies

    Song, Honglin / Dicks, Ed M / Tyrer, Jonathan / Intermaggio, Maria / Chenevix-Trench, Georgia / Bowtell, David D / Traficante, Nadia / Group, Aocs / Brenton, James / Goranova, Teodora / Hosking, Karen / Piskorz, Anna / van Oudenhove, Elke / Doherty, Jen / Harris, Holly R / Rossing, Mary Anne / Duerst, Matthias / Dork, Thilo / Bogdanova, Natalia V /
    Modugno, Francesmary / Moysich, Kirsten / Odunsi, Kunle / Ness, Roberta / Karlan, Beth Y / Lester, Jenny / Jensen, Allan / Krüger Kjaer, Susanne / Høgdall, Estrid / Campbell, Ian G / Lázaro, Conxi / Pujara, Miguel Angel / Cunningham, Julie / Vierkant, Robert / Winham, Stacey J / Hildebrandt, Michelle / Huff, Chad / Li, Donghui / Wu, Xifeng / Yu, Yao / Permuth, Jennifer B / Levine, Douglas A / Schildkraut, Joellen M / Riggan, Marjorie J / Berchuck, Andrew / Webb, Penelope M / Group, Opal Study / Cybulski, Cezary / Gronwald, Jacek / Jakubowska, Anna / Lubinski, Jan / Alsop, Jennifer / Harrington, Patricia / Chan, Isaac / Menon, Usha / Pearce, Celeste L / Wu, Anna H / de Fazio, Anna / Kennedy, Catherine J / Goode, Ellen / Ramus, Susan / Gayther, Simon / Pharoah, Paul

    Journal of medical genetics

    2020  Volume 58, Issue 5, Page(s) 305–313

    Abstract: Purpose: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian ...

    Abstract Purpose: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.
    Methods: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.
    Results: The ORs associated for high-grade serous ovarian cancer were 3.01 for
    Conclusions: We have found strong evidence that carriers of
    MeSH term(s) Case-Control Studies ; Fanconi Anemia Complementation Group N Protein/genetics ; Female ; Genetic Predisposition to Disease ; Genetic Variation ; Humans ; Ovarian Neoplasms/genetics ; Risk Assessment
    Chemical Substances Fanconi Anemia Complementation Group N Protein ; PALB2 protein, human
    Language English
    Publishing date 2020-06-16
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 220881-7
    ISSN 1468-6244 ; 0022-2593
    ISSN (online) 1468-6244
    ISSN 0022-2593
    DOI 10.1136/jmedgenet-2019-106739
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D.

    Yang, Xin / Song, Honglin / Leslie, Goska / Engel, Christoph / Hahnen, Eric / Auber, Bernd / Horváth, Judit / Kast, Karin / Niederacher, Dieter / Turnbull, Clare / Houlston, Richard / Hanson, Helen / Loveday, Chey / Dolinsky, Jill S / LaDuca, Holly / Ramus, Susan J / Menon, Usha / Rosenthal, Adam N / Jacobs, Ian /
    Gayther, Simon A / Dicks, Ed / Nevanlinna, Heli / Aittomäki, Kristiina / Pelttari, Liisa M / Ehrencrona, Hans / Borg, Åke / Kvist, Anders / Rivera, Barbara / Hansen, Thomas V O / Djursby, Malene / Lee, Andrew / Dennis, Joe / Bowtell, David D / Traficante, Nadia / Diez, Orland / Balmaña, Judith / Gruber, Stephen B / Chenevix-Trench, Georgia / Investigators, kConFab / Jensen, Allan / Kjær, Susanne K / Høgdall, Estrid / Castéra, Laurent / Garber, Judy / Janavicius, Ramunas / Osorio, Ana / Golmard, Lisa / Vega, Ana / Couch, Fergus J / Robson, Mark / Gronwald, Jacek / Domchek, Susan M / Culver, Julie O / de la Hoya, Miguel / Easton, Douglas F / Foulkes, William D / Tischkowitz, Marc / Meindl, Alfons / Schmutzler, Rita K / Pharoah, Paul D P / Antoniou, Antonis C

    Journal of the National Cancer Institute

    2020  Volume 112, Issue 12, Page(s) 1242–1250

    Abstract: Background: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D.: Methods: We analyzed data from 6178 families, 125 with ... ...

    Abstract Background: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D.
    Methods: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided.
    Results: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC.
    Conclusions: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.
    MeSH term(s) Adolescent ; Adult ; Aged ; Aged, 80 and over ; Breast Neoplasms/genetics ; DNA-Binding Proteins/genetics ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genetic Testing ; Germ-Line Mutation ; Heterozygote ; Humans ; Middle Aged ; Ovarian Neoplasms/genetics ; Risk Factors ; Young Adult
    Chemical Substances DNA-Binding Proteins ; RAD51C protein, human ; RAD51D protein, human
    Language English
    Publishing date 2020-02-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2992-0
    ISSN 1460-2105 ; 0027-8874 ; 0198-0157
    ISSN (online) 1460-2105
    ISSN 0027-8874 ; 0198-0157
    DOI 10.1093/jnci/djaa030
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: PPM1D Mosaic Truncating Variants in Ovarian Cancer Cases May Be Treatment-Related Somatic Mutations.

    Pharoah, Paul D P / Song, Honglin / Dicks, Ed / Intermaggio, Maria P / Harrington, Patricia / Baynes, Caroline / Alsop, Kathryn / Bogdanova, Natalia / Cicek, Mine S / Cunningham, Julie M / Fridley, Brooke L / Gentry-Maharaj, Aleksandra / Hillemanns, Peter / Lele, Shashi / Lester, Jenny / McGuire, Valerie / Moysich, Kirsten B / Poblete, Samantha / Sieh, Weiva /
    Sucheston-Campbell, Lara / Widschwendter, Martin / Whittemore, Alice S / Dörk, Thilo / Menon, Usha / Odunsi, Kunle / Goode, Ellen L / Karlan, Beth Y / Bowtell, David D / Gayther, Simon A / Ramus, Susan J

    Journal of the National Cancer Institute

    2016  Volume 108, Issue 3

    Abstract: Mosaic truncating mutations in the protein phosphatase, Mg(2+)/Mn(2+)-dependent, 1D (PPM1D) gene have recently been reported with a statistically significantly greater frequency in lymphocyte DNA from ovarian cancer case patients compared with unaffected ...

    Abstract Mosaic truncating mutations in the protein phosphatase, Mg(2+)/Mn(2+)-dependent, 1D (PPM1D) gene have recently been reported with a statistically significantly greater frequency in lymphocyte DNA from ovarian cancer case patients compared with unaffected control patients. Using massively parallel sequencing (MPS) we identified truncating PPM1D mutations in 12 of 3236 epithelial ovarian cancer (EOC) case patients (0.37%) but in only one of 3431 unaffected control patients (0.03%) (P = .001). All statistical tests were two-sided. A combination of Sanger sequencing, pyrosequencing, and MPS data suggested that 12 of the 13 mutations were mosaic. All mutations were identified in post-chemotherapy treatment blood samples from case patients (n = 1827) (average 1234 days post-treatment in carriers) rather than from cases collected pretreatment (less than 14 days after diagnosis, n = 1384) (P = .002). These data suggest that PPM1D variants in EOC cases are primarily somatic mosaic mutations caused by treatment and are not associated with germline predisposition to EOC.
    MeSH term(s) Adult ; Aged ; Antineoplastic Agents/therapeutic use ; Case-Control Studies ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; High-Throughput Nucleotide Sequencing ; Humans ; Middle Aged ; Mosaicism ; Mutation ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Phosphoprotein Phosphatases/genetics ; Polymerase Chain Reaction ; Protein Phosphatase 2C
    Chemical Substances Antineoplastic Agents ; PPM1D protein, human (EC 3.1.3.16) ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; Protein Phosphatase 2C (EC 3.1.3.16)
    Language English
    Publishing date 2016-01-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2992-0
    ISSN 1460-2105 ; 0027-8874 ; 0198-0157
    ISSN (online) 1460-2105
    ISSN 0027-8874 ; 0198-0157
    DOI 10.1093/jnci/djv347
    Database MEDical Literature Analysis and Retrieval System OnLINE

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