21 results on '"Dowty J.G."'
Search Results
2. Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing.
- Author
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Southey M.C., Dowty J.G., Riaz M., Steen J.A., Renault A.-L., Tucker K., Kirk J., James P., Winship I., Pachter N., Poplawski N., Grist S., Park D.J., Pope B.J., Mahmood K., Hammet F., Mahmoodi M., Tsimiklis H., Theys D., Rewse A., Willis A., Morrow A., Speechly C., Harris R., Sebra R., Schadt E., Lacaze P., McNeil J.J., Giles G.G., Milne R.L., Hopper J.L., Nguyen-Dumont T., Southey M.C., Dowty J.G., Riaz M., Steen J.A., Renault A.-L., Tucker K., Kirk J., James P., Winship I., Pachter N., Poplawski N., Grist S., Park D.J., Pope B.J., Mahmood K., Hammet F., Mahmoodi M., Tsimiklis H., Theys D., Rewse A., Willis A., Morrow A., Speechly C., Harris R., Sebra R., Schadt E., Lacaze P., McNeil J.J., Giles G.G., Milne R.L., Hopper J.L., and Nguyen-Dumont T.
- Abstract
Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing are urgently required. Most prior research has been based on women selected for high-risk features and more data is needed to make inference about breast cancer risk for women unselected for family history, an important consideration of population screening. We tested 1464 women diagnosed with breast cancer and 862 age-matched controls participating in the Australian Breast Cancer Family Study (ABCFS), and 6549 healthy, older Australian women enroled in the ASPirin in Reducing Events in the Elderly (ASPREE) study for rare germline variants using a 24-gene-panel. Odds ratios (ORs) were estimated using unconditional logistic regression adjusted for age and other potential confounders. We identified pathogenic variants in 11.1% of the ABCFS cases, 3.7% of the ABCFS controls and 2.2% of the ASPREE (control) participants. The estimated breast cancer OR [95% confidence interval] was 5.3 [2.1-16.2] for BRCA1, 4.0 [1.9-9.1] for BRCA2, 3.4 [1.4-8.4] for ATM and 4.3 [1.0-17.0] for PALB2. Our findings provide a population-based perspective to gene-panel testing for breast cancer predisposition and opportunities to improve predictors for identifying women who carry pathogenic variants in breast cancer predisposition genes.Copyright © 2021, The Author(s).
- Published
- 2022
3. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium
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Møller, P., Seppälä, T., Dowty, J.G., Haupt, S., Dominguez-Valentin, M., Sunde, L., Bernstein, I., Engel, C., Aretz, S., Nielsen, M., Capella, G., Evans, D.G., Burn, J., Holinski-Feder, E., Bertario, L., Bonanni, B., Lindblom, A., Levi, Z., Macrae, F., Winship, I., Plazzer, J.P., Sijmons, R., Laghi, L., Valle, A.D., Heinimann, K., Half, E., Lopez-Koestner, F., Alvarez-Valenzuela, K., Scott, R.J., Katz, L., Laish, I., Vainer, E., Vaccaro, C.A., Carraro, D.M., Gluck, N., Abu-Freha, N., Stakelum, A., Kennelly, R., Winter, D., Rossi, B.M., Greenblatt, M., Bohorquez, M., Sheth, H., Tibiletti, M.G., Lino-Silva, L.S., Horisberger, K., Portenkirchner, C., Nascimento, I., Rossi, N.T., Silva, L.A. da, Thomas, H, Zaránd, A., Mecklin, J.P., Pylvänäinen, K., Renkonen-Sinisalo, L., Lepisto, A., Peltomäki, P., Therkildsen, C., Lindberg, L.J., Thorlacius-Ussing, O., Doeberitz, M. von Knebel, Loeffler, M., Rahner, N., Steinke-Lange, V., Schmiegel, W., Vangala, D., Perne, C., Hüneburg, R., Vargas, A.F. de, Latchford, A., Gerdes, A.M., Backman, A.S., Guillén-Ponce, C., Snyder, C., Lautrup, C.K., Amor, D., Palmero, E., Stoffel, E., Duijkers, F., Hall, M.J., Hampel, H., Williams, H., Okkels, H., Lubiński, J., Reece, J., Ngeow, J., Guillem, J.G., Arnold, J., Wadt, K., Monahan, K., Senter, L., Rasmussen, L.J., Hest, L.P. van, Ricciardiello, L., Kohonen-Corish, M.R.J., Ligtenberg, M.J.L., Southey, M., Aronson, M., Zahary, M.N., Samadder, N.J., Hoogerbrugge, N., Sampson, J.R., Jenkins, M.A., Møller, P., Seppälä, T., Dowty, J.G., Haupt, S., Dominguez-Valentin, M., Sunde, L., Bernstein, I., Engel, C., Aretz, S., Nielsen, M., Capella, G., Evans, D.G., Burn, J., Holinski-Feder, E., Bertario, L., Bonanni, B., Lindblom, A., Levi, Z., Macrae, F., Winship, I., Plazzer, J.P., Sijmons, R., Laghi, L., Valle, A.D., Heinimann, K., Half, E., Lopez-Koestner, F., Alvarez-Valenzuela, K., Scott, R.J., Katz, L., Laish, I., Vainer, E., Vaccaro, C.A., Carraro, D.M., Gluck, N., Abu-Freha, N., Stakelum, A., Kennelly, R., Winter, D., Rossi, B.M., Greenblatt, M., Bohorquez, M., Sheth, H., Tibiletti, M.G., Lino-Silva, L.S., Horisberger, K., Portenkirchner, C., Nascimento, I., Rossi, N.T., Silva, L.A. da, Thomas, H, Zaránd, A., Mecklin, J.P., Pylvänäinen, K., Renkonen-Sinisalo, L., Lepisto, A., Peltomäki, P., Therkildsen, C., Lindberg, L.J., Thorlacius-Ussing, O., Doeberitz, M. von Knebel, Loeffler, M., Rahner, N., Steinke-Lange, V., Schmiegel, W., Vangala, D., Perne, C., Hüneburg, R., Vargas, A.F. de, Latchford, A., Gerdes, A.M., Backman, A.S., Guillén-Ponce, C., Snyder, C., Lautrup, C.K., Amor, D., Palmero, E., Stoffel, E., Duijkers, F., Hall, M.J., Hampel, H., Williams, H., Okkels, H., Lubiński, J., Reece, J., Ngeow, J., Guillem, J.G., Arnold, J., Wadt, K., Monahan, K., Senter, L., Rasmussen, L.J., Hest, L.P. van, Ricciardiello, L., Kohonen-Corish, M.R.J., Ligtenberg, M.J.L., Southey, M., Aronson, M., Zahary, M.N., Samadder, N.J., Hoogerbrugge, N., Sampson, J.R., and Jenkins, M.A.
- Abstract
Item does not contain fulltext
- Published
- 2022
4. Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study
- Author
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Win, Aung Ko, Dowty, J.G., Reece, J.C., Lee, G., Templeton, A.S., Plazzer, J.P., Buchanan, Daniel D., Ligtenberg, M.J.L., Hoogerbrugge, N., Kohonen-Corish, M., Aronson, M., Win, Aung Ko, Dowty, J.G., Reece, J.C., Lee, G., Templeton, A.S., Plazzer, J.P., Buchanan, Daniel D., Ligtenberg, M.J.L., Hoogerbrugge, N., Kohonen-Corish, M., and Aronson, M.
- Abstract
Item does not contain fulltext
- Published
- 2021
5. Repeatability of methylation measures using a QIAseq targeted methyl panel and comparison with the Illumina HumanMethylation450 assay.
- Author
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Yu C., Dugue P.-A., Dowty J.G., Hammet F., Joo J.E., Wong E.M., Hosseinpour M., Giles G.G., Hopper J.L., Nguyen-Dumont T., MacInnis R.J., Southey M.C., Yu C., Dugue P.-A., Dowty J.G., Hammet F., Joo J.E., Wong E.M., Hosseinpour M., Giles G.G., Hopper J.L., Nguyen-Dumont T., MacInnis R.J., and Southey M.C.
- Abstract
OBJECTIVE: In previous studies using Illumina Infinium methylation arrays, we have identified DNA methylation marks associated with cancer predisposition and progression. In the present study, we have sought to find appropriate technology to both technically validate our data and expand our understanding of DNA methylation in these genomic regions. Here, we aimed to assess the repeatability of methylation measures made using QIAseq targeted methyl panel and to compare them with those obtained from the Illumina HumanMethylation450 (HM450K) assay. We included in the analysis high molecular weight DNA extracted from whole blood (WB) and DNA extracted from formalin-fixed paraffin-embedded tissues (FFPE). RESULT(S): The repeatability of QIAseq-methylation measures was assessed at 40 CpGs, using the Intraclass Correlation Coefficient (ICC). The mean ICCs and 95% confidence intervals (CI) were 0.72 (0.62-0.81), 0.59 (0.47-0.71) and 0.80 (0.73-0.88) for WB, FFPE and both sample types combined, respectively. For technical replicates measured using QIAseq and HM450K, the mean ICCs (95% CI) were 0.53 (0.39-0.68), 0.43 (0.31-0.56) and 0.70 (0.59-0.80), respectively. Bland-Altman plots indicated good agreement between QIAseq and HM450K measurements. These results demonstrate that the QIAseq targeted methyl panel produces reliable and reproducible methylation measurements across the 40 CpGs that were examined.Copyright © 2021. The Author(s).
- Published
- 2021
6. Population-based estimates of the age-specific cumulative risk of breast cancer for pathogenic variants in CHEK2: Findings from the australian breast cancer family registry.
- Author
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Southey M.C., Tsimiklis H., Winship I.M., Giles G.G., Milne R.L., Hopper J.L., Nguyen-dumont T.U., Dowty J.G., Steen J.A., Renault A.-L., Hammet F., Mahmoodi M., Theys D., Rewse A., Southey M.C., Tsimiklis H., Winship I.M., Giles G.G., Milne R.L., Hopper J.L., Nguyen-dumont T.U., Dowty J.G., Steen J.A., Renault A.-L., Hammet F., Mahmoodi M., Theys D., and Rewse A.
- Abstract
Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant CHEK2 c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (in-cluding likely pathogenic) variants combined. We conducted a population-based case-control-fam-ily study of pathogenic CHEK2 variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5-9.5) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02-11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5-12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11-30%) and 33% (95% CI 21-48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
- Published
- 2021
7. Rare germline pathogenic variants identified by multigene panel testing and the risk of aggressive prostate cancer.
- Author
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Milne R.L., Giles G.G., Nguyen-Dumont T., Dowty J.G., Macinnis R.J., Steen J.A., Riaz M., Dugue P.-A., Renault A.-L., Hammet F., Mahmoodi M., Theys D., Tsimiklis H., Severi G., Bolton D., Lacaze P., Sebra R., Schadt E., McNeil J., Southey M.C., Milne R.L., Giles G.G., Nguyen-Dumont T., Dowty J.G., Macinnis R.J., Steen J.A., Riaz M., Dugue P.-A., Renault A.-L., Hammet F., Mahmoodi M., Theys D., Tsimiklis H., Severi G., Bolton D., Lacaze P., Sebra R., Schadt E., McNeil J., and Southey M.C.
- Abstract
While gene panel sequencing is becoming widely used for cancer risk prediction, its clinical utility with respect to predicting aggressive prostate cancer (PrCa) is limited by our current understanding of the genetic risk factors associated with predisposition to this potentially lethal disease phenotype. This study included 837 men diagnosed with aggressive PrCa and 7261 controls (unaffected men and men who did not meet criteria for aggressive PrCa). Rare germline pathogenic variants (including likely pathogenic variants) were identified by targeted sequencing of 26 known or putative cancer predisposition genes. We found that 85 (10%) men with aggressive PrCa and 265 (4%) controls carried a pathogenic variant (p < 0.0001). Aggressive PrCa odds ratios (ORs) were estimated using unconditional logistic regression. Increased risk of aggressive PrCa (OR (95% confidence interval)) was identified for pathogenic variants in BRCA2 (5.8 (2.7-12.4)), BRCA1 (5.5 (1.8-16.6)), and ATM (3.8 (1.6-9.1)). Our study provides further evidence that rare germline pathogenic variants in these genes are associated with increased risk of this aggressive, clinically relevant subset of PrCa. These rare genetic variants could be incorporated into risk prediction models to improve their precision to identify men at highest risk of aggressive prostate cancer and be used to identify men with newly diagnosed prostate cancer who require urgent treatment.Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
- Published
- 2021
8. Vtrna2-1: Genetic variation, heritable methylation and disease association.
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Dugue P.-A., Yu C., McKay T., Wong E.M., Joo J.E., Tsimiklis H., Hammet F., Mahmoodi M., Theys D., Kconfab, Hopper J.L., Giles G.G., Milne R.L., Steen J.A., Dowty J.G., Nguyen-dumont T., Southey M.C., Dugue P.-A., Yu C., McKay T., Wong E.M., Joo J.E., Tsimiklis H., Hammet F., Mahmoodi M., Theys D., Kconfab, Hopper J.L., Giles G.G., Milne R.L., Steen J.A., Dowty J.G., Nguyen-dumont T., and Southey M.C.
- Abstract
VTRNA2-1 is a metastable epiallele with accumulating evidence that methylation at this region is heritable, modifiable and associated with disease including risk and progression of cancer. This study investigated the influence of genetic variation and other factors such as age and adult lifestyle on blood DNA methylation in this region. We first sequenced the VTRNA2-1 gene region in multiple-case breast cancer families in which VTRNA2-1 methylation was identified as heritable and associated with breast cancer risk. Methylation quantitative trait loci (mQTL) were investigated using a prospective cohort study (4500 participants with genotyping and methylation data). The cis-mQTL analysis (334 variants +/- 50 kb of the most heritable CpG site) identified 43 variants associated with VTRNA2-1 methylation (p < 1.5 x 10-4 ); however, these explained little of the methylation variation (R2 < 0.5% for each of these variants). No genetic variants elsewhere in the genome were found to strongly influence VTRNA2-1 methylation. SNP-based heritability estimates were consistent with the mQTL findings (h2 = 0, 95%CI: -0.14 to 0.14). We found no evidence that age, sex, country of birth, smoking, body mass index, alcohol consumption or diet influenced blood DNA methylation at VTRNA2-1. Genetic factors and adult lifestyle play a minimal role in explaining methylation var-iability at the heritable VTRNA2-1 cluster.Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
- Published
- 2021
9. Novel mammogram-based measures improve breast cancer risk prediction beyond an established mammographic density measure.
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Southey M.C., Maskarinec G., Jenkins M.A., Milne R.L., Giles G.G., Hopper J.L., Nguyen T.L., Schmidt D.F., Makalic E., Li S., Dite G.S., Aung Y.K., Evans C.F., Trinh H.N., Baglietto L., Stone J., Song Y.-M., Sung J., MacInnis R.J., Dugue P.-A., Dowty J.G., Southey M.C., Maskarinec G., Jenkins M.A., Milne R.L., Giles G.G., Hopper J.L., Nguyen T.L., Schmidt D.F., Makalic E., Li S., Dite G.S., Aung Y.K., Evans C.F., Trinh H.N., Baglietto L., Stone J., Song Y.-M., Sung J., MacInnis R.J., Dugue P.-A., and Dowty J.G.
- Abstract
Mammograms contain information that predicts breast cancer risk. We developed two novel mammogram-based breast cancer risk measures based on image brightness (Cirrocumulus) and texture (Cirrus). Their risk prediction when fitted together, and with an established measure of conventional mammographic density (Cumulus), is not known. We used three studies consisting of: 168 interval cases and 498 matched controls; 422 screen-detected cases and 1197 matched controls; and 354 younger-diagnosis cases and 944 controls frequency-matched for age at mammogram. We conducted conditional and unconditional logistic regression analyses of individually- and frequency-matched studies, respectively. We estimated measure-specific risk gradients as the change in odds per standard deviation of controls after adjusting for age and body mass index (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). For interval, screen-detected and younger-diagnosis cancer risks, the best fitting models (OPERAs [95% confidence intervals]) involved: Cumulus (1.81 [1.41-2.31]) and Cirrus (1.72 [1.38-2.14]); Cirrus (1.49 [1.32-1.67]) and Cirrocumulus (1.16 [1.03 to 1.31]); and Cirrus (1.70 [1.48 to 1.94]) and Cirrocumulus (1.46 [1.27-1.68]), respectively. The AUCs were: 0.73 [0.68-0.77], 0.63 [0.60-0.66], and 0.72 [0.69-0.75], respectively. Combined, our new mammogram-based measures have twice the risk gradient for screen-detected and younger-diagnosis breast cancer (P <= 10-12), have at least the same discriminatory power as the current polygenic risk score, and are more correlated with causal factors than conventional mammographic density. Discovering more information about breast cancer risk from mammograms could help enable risk-based personalised breast screening.Copyright © 2020 UICC
- Published
- 2021
10. Mortality after breast cancer as a function of time since diagnosis by estrogen receptor status and age at diagnosis.
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Eccles D.M., Win A.K., Milne R.L., Giles G.G., Terry M.B., Southey M.C., Hopper J.L., Jayasekara H., MacInnis R.J., Chamberlain J.A., Dite G.S., Leoce N.M., Dowty J.G., Bickerstaffe A., Eccles D.M., Win A.K., Milne R.L., Giles G.G., Terry M.B., Southey M.C., Hopper J.L., Jayasekara H., MacInnis R.J., Chamberlain J.A., Dite G.S., Leoce N.M., Dowty J.G., and Bickerstaffe A.
- Abstract
Our aim was to estimate how long-term mortality following breast cancer diagnosis depends on age at diagnosis, tumor estrogen receptor (ER) status, and the time already survived. We used the population-based Australian Breast Cancer Family Study which followed-up 1,196 women enrolled during 1992-1999 when aged <60 years at diagnosis with a first primary invasive breast cancer, over-sampled for younger ages at diagnosis, for whom tumor pathology features and ER status were measured. There were 375 deaths (median follow-up = 15.7; range = 0.8-21.4, years). We estimated the mortality hazard as a function of time since diagnosis using a flexible parametric survival analysis with ER status a time-dependent covariate. For women with ER-negative tumors compared with those with ER-positive tumors, 5-year mortality was initially higher (p < 0.001), similar if they survived to 5 years (p = 0.4), and lower if they survived to 10 years (p = 0.02). The estimated mortality hazard for ER-negative disease peaked at ~3 years post-diagnosis, thereafter declined with time, and at 7 years post-diagnosis became lower than that for ER-positive disease. This pattern was more pronounced for women diagnosed at younger ages. Mortality was also associated with lymph node count (hazard ratio (HR) per 10 nodes = 2.52 [95% CI:2.11-3.01]) and tumor grade (HR per grade = 1.62 [95% CI:1.34-1.96]). The risk of death following a breast cancer diagnosis differs substantially and qualitatively with diagnosis age, ER status and time survived. For women who survive >7 years, those with ER-negative disease will on average live longer, and more so if younger at diagnosis.Copyright © 2019 UICC
- Published
- 2019
11. Cohort profile: The Tasmanian Longitudinal Health STUDY (TAHS).
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Walters E.H., Matheson M.C., Abramson M.J., Allen K., Benke G., Burgess J.A., Dowty J.G., Erbas B., Thomas P.S., Thompson B.R., Wood-Baker R., Dharmage S.C., Feather I.H., Frith P.A., Giles G.G., Gurrin L.C., Hamilton G.S., Hopper J.L., James A.L., Jenkins M.A., Johns D.P., Lodge C.J., Lowe A.J., Markos J., Morrison S.C., Perret J.L., Southey M.C., Walters E.H., Matheson M.C., Abramson M.J., Allen K., Benke G., Burgess J.A., Dowty J.G., Erbas B., Thomas P.S., Thompson B.R., Wood-Baker R., Dharmage S.C., Feather I.H., Frith P.A., Giles G.G., Gurrin L.C., Hamilton G.S., Hopper J.L., James A.L., Jenkins M.A., Johns D.P., Lodge C.J., Lowe A.J., Markos J., Morrison S.C., Perret J.L., and Southey M.C.
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- 2019
12. Heritable methylation marks associated with breast and prostate cancer risk.
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Dugue P.-A., Dowty J.G., Joo J.E., Wong E.M., Makalic E., Schmidt D.F., English D.R., Hopper J.L., Pedersen J., Severi G., MacInnis R.J., Milne R.L., Giles G.G., Southey M.C., Dugue P.-A., Dowty J.G., Joo J.E., Wong E.M., Makalic E., Schmidt D.F., English D.R., Hopper J.L., Pedersen J., Severi G., MacInnis R.J., Milne R.L., Giles G.G., and Southey M.C.
- Abstract
Background: DNA methylation can mimic the effects of germline mutations in cancer predisposition genes. Recently, we identified twenty-four heritable methylation marks associated with breast cancer risk. As breast and prostate cancer share genetic risk factors, including rare, high-risk mutations (eg, in BRCA2), we hypothesized that some of these heritable methylation marks might also be associated with the risk of prostate cancer. Method(s): We studied 869 incident prostate cancers (430 aggressive and 439 non-aggressive) and 869 matched controls nested within a prospective cohort study. DNA methylation was measured in pre-diagnostic blood samples using the Illumina Infinium HM450K BeadChip. Conditional logistic regression models, adjusted for prostate cancer risk factors and blood cell composition, were used to estimate odds ratios and 95% confidence intervals for the association between the 24 methylation marks and the risk of prostate cancer. Result(s): Five methylation marks within the VTRNA2-1 promoter region (cg06536614, cg00124993, cg26328633, cg25340688, and cg26896946), and one in the body of CLGN (cg22901919) were associated with the risk of prostate cancer. In stratified analyses, the five VTRNA2-1 marks were associated with the risk of aggressive prostate cancer. Conclusion(s): This work highlights a potentially important new area of investigation for prostate cancer susceptibility and adds to our knowledge about shared risk factors for breast and prostate cancer.Copyright © 2018 Wiley Periodicals, Inc.
- Published
- 2018
13. Heritable DNA methylation marks associated with susceptibility to breast cancer /631/67/69 /631/337/176/1988 /692/699/67/1347 /692/308/2056 /45 /45/61 article.
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Hickie I., Saunders C., Hunt C., Scott C., Amor D., Marsh D., Edkins E., Salisbury E., Haan E., Neidermayr E., Macrae F., Farshid G., Lindeman G., Chenevix-Trench G., Mann G., Gill G., Thorne H., Campbell I., Winship I., Goldblatt J., Flanagan J., Kollias J., Visvader J., Stone J., Taylor J., Burke J., Saunus J., Forbes J., Beesley J., Kirk J., French J., Tucker K., Wu K., Phillips K., Lipton L., Andrews L., Lobb E., Walker L., Kentwell M., Spurdle A., Cummings M., Gleeson M., Harris M., Jenkins M., Young M.A., Delatycki M., Wallis M., Burgess M., Price M., Brown M., Bogwitz M., Field M., Friedlander M., Gattas M., Saleh M., Hayward N., Pachter N., Cohen P., Duijf P., James P., Simpson P., Fong P., Butow P., Williams R., Kefford R., Scott R., Balleine R., Dawson S.-J., Lok S., O'Connell S., Greening S., Nightingale S., Edwards S., Fox S., McLachlan S.-A., Lakhani S., Thomas S., Antill Y., Joo J.E., Dowty J.G., Milne R.L., Wong E.M., Dugue P.-A., English D., Hopper J.L., Goldgar D.E., Giles G.G., Southey M.C., Sexton A., Christian A., Trainer A., Spigelman A., Fellows A., Shelling A., De Fazio A., Blackburn A., Crook A., Meiser B., Patterson B., Clarke C., Hickie I., Saunders C., Hunt C., Scott C., Amor D., Marsh D., Edkins E., Salisbury E., Haan E., Neidermayr E., Macrae F., Farshid G., Lindeman G., Chenevix-Trench G., Mann G., Gill G., Thorne H., Campbell I., Winship I., Goldblatt J., Flanagan J., Kollias J., Visvader J., Stone J., Taylor J., Burke J., Saunus J., Forbes J., Beesley J., Kirk J., French J., Tucker K., Wu K., Phillips K., Lipton L., Andrews L., Lobb E., Walker L., Kentwell M., Spurdle A., Cummings M., Gleeson M., Harris M., Jenkins M., Young M.A., Delatycki M., Wallis M., Burgess M., Price M., Brown M., Bogwitz M., Field M., Friedlander M., Gattas M., Saleh M., Hayward N., Pachter N., Cohen P., Duijf P., James P., Simpson P., Fong P., Butow P., Williams R., Kefford R., Scott R., Balleine R., Dawson S.-J., Lok S., O'Connell S., Greening S., Nightingale S., Edwards S., Fox S., McLachlan S.-A., Lakhani S., Thomas S., Antill Y., Joo J.E., Dowty J.G., Milne R.L., Wong E.M., Dugue P.-A., English D., Hopper J.L., Goldgar D.E., Giles G.G., Southey M.C., Sexton A., Christian A., Trainer A., Spigelman A., Fellows A., Shelling A., De Fazio A., Blackburn A., Crook A., Meiser B., Patterson B., and Clarke C.
- Abstract
Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA samples provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case-control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk.Copyright © 2018 The Author(s).
- Published
- 2018
14. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS
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Southey, M.C., Goldgar, D.E., Winqvist, R., Pylkas, K., Couch, F., Tischkowitz, M., Foulkes, W.D., Dennis, J., Michailidou, K., Rensburg, E.J. van, Heikkinen, T., Nevanlinna, H., Hopper, J.L., Dork, T., Claes, K.B., Reis-Filho, J., Teo, Z.L., Radice, P., Catucci, I., Peterlongo, P., Tsimiklis, H., Odefrey, F.A., Dowty, J.G., Schmidt, M.K., Broeks, A., Hogervorst, F.B., Verhoef, S., Carpenter, J., Clarke, C., Scott, R.J., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Peto, J., Dos-Santos-Silva, I., Fletcher, O., Johnson, N., Bolla, M.K., Sawyer, E.J., Tomlinson, I., Kerin, M.J., Miller, N., Marme, F., Burwinkel, B., Yang, R., Guenel, P., Truong, T., Menegaux, F., Sanchez, M., Bojesen, S., Nielsen, S.F., Flyger, H., Benitez, J., Zamora, M.P., Perez, J.I., Menendez, P., Anton-Culver, H., Neuhausen, S., Ziogas, A., Clarke, C.A., Brenner, H., Arndt, V., Stegmaier, C., Brauch, H., Bruning, T., Ko, Y.D., Muranen, T.A., Aittomaki, K., Blomqvist, C., Bogdanova, N.V., Antonenkova, N.N., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Spurdle, A.B., Wauters, E., Smeets, D., Beuselinck, B., Floris, G., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Olson, J.E., Vachon, C., Pankratz, V.S., McLean, C., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. Le, Kristensen, V., Alnaes, G.G., Zheng, W., Hunter, D.J., Altena, A.M. van, Aben, K.K.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., et al., Southey, M.C., Goldgar, D.E., Winqvist, R., Pylkas, K., Couch, F., Tischkowitz, M., Foulkes, W.D., Dennis, J., Michailidou, K., Rensburg, E.J. van, Heikkinen, T., Nevanlinna, H., Hopper, J.L., Dork, T., Claes, K.B., Reis-Filho, J., Teo, Z.L., Radice, P., Catucci, I., Peterlongo, P., Tsimiklis, H., Odefrey, F.A., Dowty, J.G., Schmidt, M.K., Broeks, A., Hogervorst, F.B., Verhoef, S., Carpenter, J., Clarke, C., Scott, R.J., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Peto, J., Dos-Santos-Silva, I., Fletcher, O., Johnson, N., Bolla, M.K., Sawyer, E.J., Tomlinson, I., Kerin, M.J., Miller, N., Marme, F., Burwinkel, B., Yang, R., Guenel, P., Truong, T., Menegaux, F., Sanchez, M., Bojesen, S., Nielsen, S.F., Flyger, H., Benitez, J., Zamora, M.P., Perez, J.I., Menendez, P., Anton-Culver, H., Neuhausen, S., Ziogas, A., Clarke, C.A., Brenner, H., Arndt, V., Stegmaier, C., Brauch, H., Bruning, T., Ko, Y.D., Muranen, T.A., Aittomaki, K., Blomqvist, C., Bogdanova, N.V., Antonenkova, N.N., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Spurdle, A.B., Wauters, E., Smeets, D., Beuselinck, B., Floris, G., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Olson, J.E., Vachon, C., Pankratz, V.S., McLean, C., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. Le, Kristensen, V., Alnaes, G.G., Zheng, W., Hunter, D.J., Altena, A.M. van, Aben, K.K.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., and et al.
- Abstract
Contains fulltext : 171115.pdf (publisher's version ) (Open Access), BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. METHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. RESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1x10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9x10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p=0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. CONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
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- 2016
15. Lynch syndrome and cervical cancer.
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Lindor N.M., Le Marchand L., Hopper J.L., Newcomb P.A., Haile R.W., Church J., Tucker K.M., Buchanan D.D., Young J.P., Winship I.M., Jenkins M.A., Antill Y.C., Dowty J.G., Win A.K., Thompson T., Walsh M.D., Cummings M.C., Gallinger S., Lindor N.M., Le Marchand L., Hopper J.L., Newcomb P.A., Haile R.W., Church J., Tucker K.M., Buchanan D.D., Young J.P., Winship I.M., Jenkins M.A., Antill Y.C., Dowty J.G., Win A.K., Thompson T., Walsh M.D., Cummings M.C., and Gallinger S.
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Carriers of germline mutations in DNA mismatch repair (MMR) genes are at increased risk of several cancers including colorectal and gynecologic cancers (Lynch syndrome). There is no substantial evidence that these mutations are associated with an increased risk of cervical cancer. A total of 369 families with at least one carrier of a mutation in a MMR gene (133 MLH1, 174 MSH2, 35 MSH6 and 27 PMS2) were ascertained via population cancer registries or via family cancer clinics in Australia, New Zealand, Canada, and USA. Personal and family histories of cancer were obtained from participant interviews. Modified segregation analysis was used to estimate the hazard ratio (incidence rates for carriers relative to those for the general population), and age-specific cumulative risks of cervical cancer for carriers. A total of 65 cases of cervical cancer were reported (including 10 verified by pathology reports). The estimated incidence was 5.6 fold (95% CI: 2.3-13.8; p = 0.001) higher for carriers than for the general population with a corresponding cumulative risk to 80 years of 4.5% (95% CI: 1.9-10.7%) compared with 0.8% for the general population. The mean age at diagnosis was 43.1 years (95% CI: 40.0-46.2), 3.9 years younger than the reported USA population mean of 47.0 years (p = 0.02). Women with MMR gene mutations were found to have an increased risk of cervical cancer. Due to limited pathology verification we cannot be certain that a proportion of these cases were not lower uterine segment endometrial cancers involving the endocervix, a recognized cancer of Lynch syndrome. What's new? Women with DNA mismatch repair gene mutations (Lynch syndrome) are at increased risk for several cancers but it is unclear whether cervical cancer is one of them. Using data from international cancer registries the authors show that women with Lynch syndrome have an increased risk of cervical cancer that is six times higher than the general population. Carriers of cervical cancers wer
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- 2015
16. Cancer Risks for MLH1 and MSH2 Mutation Carriers.
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Jenkins M.A., Ahnen D.J., Baron J.A., Parry S., Goldblatt J., Young J.P., Hopper J.L., Dowty J.G., Win A.K., Buchanan D.D., Lindor N.M., Macrae F.A., Clendenning M., Antill Y.C., Thibodeau S.N., Casey G., Gallinger S., Marchand L.L., Newcomb P.A., Haile R.W., Young G.P., James P.A., Giles G.G., Gunawardena S.R., Leggett B.A., Gattas M., Boussioutas A., Jenkins M.A., Ahnen D.J., Baron J.A., Parry S., Goldblatt J., Young J.P., Hopper J.L., Dowty J.G., Win A.K., Buchanan D.D., Lindor N.M., Macrae F.A., Clendenning M., Antill Y.C., Thibodeau S.N., Casey G., Gallinger S., Marchand L.L., Newcomb P.A., Haile R.W., Young G.P., James P.A., Giles G.G., Gunawardena S.R., Leggett B.A., Gattas M., and Boussioutas A.
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We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available. © 2012 Wiley Periodicals, Inc.
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- 2013
17. Cancer risk in 680 000 people exposed to computed tomography scans in childhood or adolescence: Data linkage study of 11 million Australians.
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Forsythe A.V., Wallace A.B., Anderson P.R., McGale P., Cain T.M., Dowty J.G., Guiver T.A., Bickerstaffe A.C., Darby S.C., Giles G.G., Byrnes G.B., Goergen S.K., Butler M.W., Mathews J.D., Brady Z., Forsythe A.V., Wallace A.B., Anderson P.R., McGale P., Cain T.M., Dowty J.G., Guiver T.A., Bickerstaffe A.C., Darby S.C., Giles G.G., Byrnes G.B., Goergen S.K., Butler M.W., Mathews J.D., and Brady Z.
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Objective: To assess the cancer risk in children and adolescents following exposure to low dose ionising radiation from diagnostic computed tomography (CT) scans. Design(s): Population based, cohort, data linkage study in Australia. Cohort members: 10.9 million people identified from Australian Medicare records, aged 0-19 years on 1 January 1985 or born between 1 January 1985 and 31 December 2005; all exposures to CT scans funded by Medicare during 1985-2005 were identified for this cohort. Cancers diagnosed in cohort members up to 31 December 2007 were obtained through linkage to national cancer records. Main outcome: Cancer incidence rates in individuals exposed to a CT scan more than one year before any cancer diagnosis, compared with cancer incidence rates in unexposed individuals. Result(s): 60 674 cancers were recorded, including 3150 in 680 211 people exposed to a CT scan at least one year before any cancer diagnosis. The mean duration of follow-up after exposure was 9.5 years. Overall cancer incidence was 24% greater for exposed than for unexposed people, after accounting for age, sex, and year of birth (incidence rate ratio (IRR) 1.24 (95% confidence interval 1.20 to 1.29); P<0.001). We saw a dose-response relation, and the IRR increased by 0.16 (0.13 to 0.19) for each additional CT scan. The IRR was greater after exposure at younger ages (P<0.001 for trend). At 1-4, 5-9, 10-14, and 15 or more years since first exposure, IRRs were 1.35 (1.25 to 1.45), 1.25 (1.17 to 1.34), 1.14 (1.06 to 1.22), and 1.24 (1.14 to 1.34), respectively. The IRR increased significantly for many types of solid cancer (digestive organs, melanoma, soft tissue, female genital, urinary tract, brain, and thyroid); leukaemia, myelodysplasia, and some other lymphoid cancers. There was an excess of 608 cancers in people exposed to CT scans (147 brain, 356 other solid, 48 leukaemia or myelodysplasia, and 57 other lymphoid). The absolute excess incidence rate for all cancers combined was 9.3
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- 2013
18. Body mass index in early adulthood and endometrial cancer risk for mismatch repair gene mutation carriers.
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Hopper J.L., Le Marchand L., Lindor N.M., Newcomb P.A., Jenkins M.A., Win A.K., Dowty J.G., Antill Y.C., English D.R., Baron J.A., Young J.P., Giles G.G., Southey M.C., Winship I., Lipton L., Parry S., Thibodeau S.N., Haile R.W., Gallinger S., Hopper J.L., Le Marchand L., Lindor N.M., Newcomb P.A., Jenkins M.A., Win A.K., Dowty J.G., Antill Y.C., English D.R., Baron J.A., Young J.P., Giles G.G., Southey M.C., Winship I., Lipton L., Parry S., Thibodeau S.N., Haile R.W., and Gallinger S.
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Objective: To investigate the association of body mass index (BMI) in early adulthood and endometrial cancer risk for carriers of a germline mutation in a DNA mismatch repair gene. Method(s): We estimated the association between BMI at age 18-20 years and endometrial cancer risk for mismatch repair gene mutation carriers and, as a comparison group, noncarriers using 601 female carriers of a germline mutation in a mismatch repair gene (245 MLH1, 299 MSH2, 38 MSH6, and 19 PMS2) and 533 female noncarriers from the Colon Cancer Family Registry using a weighted Cox proportional hazards regression. Result(s): During 51,693 person-years of observation, we observed diagnoses of endometrial cancer for 126 carriers and eight noncarriers. For carriers, there was no evidence of an association between BMI at age 20 years and endometrial cancer (adjusted hazard ratio 0.73 per 5 kg/m; 95% confidence interval [CI], 0.40-1.34; P=.31). For noncarriers, endometrial cancer risk increased by 74% for each 5-kg/m increment in BMI (adjusted hazard ratio 1.74; 95% CI 1.27-2.37; P<.001). The hazard ratio for BMI and endometrial cancer for noncarriers was greater than for carriers (P=.04). Conclusion(s): The effect of body mass on endometrial cancer risk depends on the woman's mismatch repair gene mutation carrier status, suggesting obesity-independent endometrial carcinogenesis for carriers. © 2011 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins.
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- 2012
19. Risks of lynch syndrome cancers for msh6 mutation carriers
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Baglietto, L. (Laura), Lindor, N.M. (Noralane), Dowty, J.G. (James), White, D.M. (Darren), Wagner, A. (Anja), Gómez García, E.B. (Encarna), Vriends, A.H.J.T. (Anette), Cartwright, N.R. (Nicola), Barnetson, R.A. (Rebecca), Farrington, S.M. (Susan), Tenesa, A. (Albert), Hampel, H. (Heather), Buchanan, D. (Daniel), Arnold, S. (Sven), Young, J. (Joanne), Walsh, M.D. (Michael), Jass, J. (Jeremy), Macrae, F.A. (Finlay), Antill, Y. (Yoland), Winship, I.M. (Ingrid), Giles, G.G. (Graham), Goldblatt, J. (Jack), Parry, S. (Susan), Suthers, G. (Graeme), Leggett, B. (Barbara), Butz, M. (Malinda), Aronson, M. (Melyssa), Poynter, J.N. (Jenny), Baron, J.A. (John), Le Marchand, L. (Loic), Haile, R. (Robert), Gallinger, S. (Steve), Hopper, J.L. (John), Potter, J. (John), La Chapelle, A. (Albert) de, Vasen, H. (Hans), Dunlop, M.G. (Malcolm), Thibodeau, S.N. (Stephen), Jenkins, M.A. (Mark), Baglietto, L. (Laura), Lindor, N.M. (Noralane), Dowty, J.G. (James), White, D.M. (Darren), Wagner, A. (Anja), Gómez García, E.B. (Encarna), Vriends, A.H.J.T. (Anette), Cartwright, N.R. (Nicola), Barnetson, R.A. (Rebecca), Farrington, S.M. (Susan), Tenesa, A. (Albert), Hampel, H. (Heather), Buchanan, D. (Daniel), Arnold, S. (Sven), Young, J. (Joanne), Walsh, M.D. (Michael), Jass, J. (Jeremy), Macrae, F.A. (Finlay), Antill, Y. (Yoland), Winship, I.M. (Ingrid), Giles, G.G. (Graham), Goldblatt, J. (Jack), Parry, S. (Susan), Suthers, G. (Graeme), Leggett, B. (Barbara), Butz, M. (Malinda), Aronson, M. (Melyssa), Poynter, J.N. (Jenny), Baron, J.A. (John), Le Marchand, L. (Loic), Haile, R. (Robert), Gallinger, S. (Steve), Hopper, J.L. (John), Potter, J. (John), La Chapelle, A. (Albert) de, Vasen, H. (Hans), Dunlop, M.G. (Malcolm), Thibodeau, S.N. (Stephen), and Jenkins, M.A. (Mark)
- Abstract
Background: Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene
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- 2010
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20. Using tumour pathology to identify people at high genetic risk of breast and colorectal cancers
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Hopper, J.L., primary, Jenkins, M.A., additional, Dowty, J.G., additional, Dite, G.S., additional, Apicella, C., additional, Keogh, L., additional, Win, A.K., additional, Young, J.P., additional, Buchanan, D., additional, Walsh, M.D., additional, Rosty, C., additional, Baglietto, L., additional, Severi, G., additional, Phillips, K.A., additional, Wong, E.M., additional, Dobrovic, A., additional, Waring, P., additional, Winship, I., additional, Ramus, S.J., additional, Giles, G.G., additional, and Southey, M.C., additional
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- 2012
- Full Text
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21. Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study
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Seçil Aksoy, Michael O. Woods, Heinric Williams, Bruno Buecher, Finlay A. Macrae, Lotte N. Krogh, Jay Qiu, Wan K.W. Juhari, Jan T. Lowery, Anne-Marie Gerdes, Magnus von Knebel Doeberitz, Luigi Ricciardiello, Karsten Schulmann, Jose Luis Soto, Kristina Lagerstedt-Robinson, Kiwamu Akagi, Raj Ramesar, Uffe Birk Jensen, Angel Alonso, Robert Hüneburg, Olivier Caron, Michel Longy, Jan Lubinski, Kate Green, Annabel Goodwin, D. Gareth Evans, Julie Wods, Leigha Senter, Matthew F. Kalady, Mark Clendenning, Barbara A. Leggett, Ravindran Ankathil, Swati G. Patel, Julian Barwell, Katherine M. Tucker, Grant Lee, Pascaline Berthet, Dawn M. Nixon, Sonia S. Kupfer, Naohiro Tomita, Susan Parry, Trinidad Caldés, Robert W. Haile, Edenir Inêz Palmero, Karin Alvarez, Cassandra B. Nichols, Mark A. Jenkins, N. Jewel Samadder, Loic LeMarchand, John Burn, Francisco Lopez, Rodney J. Scott, Pierre Laurent-Puig, Julie Arnold, Christina Therkildsen, Hans K. Schackert, Pilar Garre, Reinhard Buettner, Adriana Della Valle, Patricia Esperon, Wolff Schmiegel, Karl Heinimann, Inge Bernstein, Matthias Kloor, Nicoline Hoogerbrugge, Rui Manuel Reis, Fränzel J.B. Van Duijnhoven, Christoph Engel, Mohd Nizam Zahary, Sylviane Olschwang, Sapna Syngal, Valérie Bonadona, Nicholas Pachter, Matilde Navarro, Albert de la Chapelle, Beate Betz, Jukka-Pekka Mecklin, Catherine Noguès, Elena M. Stoffel, Toni T. Seppälä, Chrystelle Colas, Anneke Lucassen, Allan D. Spigelman, Youenn Drouet, Elisa J. Cops, Uri Ladabaum, Steve Thibodeau, Jeffrey N. Weitzel, Fiona Lalloo, Patrick J. Morrison, Maurizio Genuardi, Kohji Tanakaya, Patrick M. Lynch, Frederik J. Hes, William D. Foulkes, Carmen Guillén-Ponce, Jenny von Salomé, Emilia Rogoża-Janiszewska, Andrew Latchford, John L. Hopper, Carrie Snyder, Verónica Barca-Tierno, Gabriela Möslein, Lauren M. Gima, Melissa C. Southey, Paul A. James, Marion Dhooge, Claudia Perne, Steven Gallinger, Heather Hampel, Amanda B. Spurdle, Ingrid Winship, Emmanuelle Fourme, Rish K. Pai, Daniela Turchetti, Marta Pineda, Jürgen Weitz, James Hill, Daniel D. Buchanan, Carlos A. Vaccaro, Noralane M. Lindor, Rachel Pearlman, Pål Møller, Christian P. Strassburg, Jane C. Figueiredo, Aída Falcón de Vargas, Silke Zachariae, Karolin Bucksch, Joanne Ngeow, Silke Redler, Henrik Okkels, Maija R.J. Kohonen-Corish, Hans F. A. Vasen, Verena Steinke-Lange, Roselyne Guimbaud, Deepak Vangala, Isabelle Coupier, Nils Rahner, Berrin Tunca, Sanne W. Bajwa-ten Broeke, Niels de Wind, Sophie Lejeune, José Gaston Guillem, Karin Wadt, Polly A. Newcomb, Elke Holinski-Feder, Florencia Neffa, Rodrigo Santa Cruz Guindalini, Paul E. Wise, Julian R. Sampson, Graham Casey, Lene Juel Rasmussen, Rolf H. Sijmons, Tadeusz Dębniak, Ann-Sofie Backman, Joji Utsunomiya, Melyssa Aronson, Aung Ko Win, Yves-Jean Bignon, Judy W. C. Ho, Robyn L. Ward, Mev Dominguez-Valentin, Karolina Malińska, Elizabeth E. Half, John-Paul Plazzer, Marjolijn J. L. Ligtenberg, Rachel Austin, Nicola K. Poplawski, Marcia Cruz-Correa, Nagahide Matsubara, Charlotte Kvist Lautrup, Thomas Hansen, Tatsuro Yamaguchi, Thomas John, David J. Amor, Ilana Solomon, Yun-Hee Choi, Meghan J. van Wanzeele, Rakefet Shtoyerman, Vanessa Huntley, Maartje Nielsen, Deborah Neklason, Kevin J. Monahan, Gülçin Tezcan, Stefan Aretz, Talya Boisjoli, Sophie Giraud, Thierry Frebourg, Christophe Rosty, Heike Görgens, Lone Sunde, Allyson Templeton, Jacob Nattermann, Mala Pande, Joan Brunet, Nancy Uhrhammer, James M. Church, Florencia Spirandelli, Laurent Briollais, James G. Dowty, Jeanette C. Reece, Rachel Susman, Fay Kastrinos, Kirsi Pylvänäinen, Gabriel Capellá, Helène Schuster, Min H. Chew, Markus Loeffler, Christine Lasset, Michael J. Hall, Capuccine Delnatte, Floor A. Duijkers, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Digital Precision Cancer Medicine (iCAN), ATG - Applied Tumor Genomics, HUS Abdominal Center, Clinical sciences, Medical Genetics, Win A.K., Dowty J.G., Reece J.C., Lee G., Templeton A.S., Plazzer J.-P., Buchanan D.D., Akagi K., Aksoy S., Alonso A., Alvarez K., Amor D.J., Ankathil R., Aretz S., Arnold J.L., Aronson M., Austin R., Backman A.-S., Bajwa-ten Broeke S.W., Barca-Tierno V., Barwell J., Bernstein I., Berthet P., Betz B., Bignon Y.-J., Boisjoli T., Bonadona V., Briollais L., Brunet J., Bucksch K., Buecher B., Buettner R., Burn J., Caldes T., Capella G., Caron O., Casey G., Chew M.H., Choi Y.-H., Church J., Clendenning M., Colas C., Cops E.J., Coupier I., Cruz-Correa M., de la Chapelle A., de Wind N., Debniak T., Della Valle A., Delnatte C., Dhooge M., Dominguez-Valentin M., Drouet Y., Duijkers F.A., Engel C., Esperon P., Evans D.G., Falcon de Vargas A., Figueiredo J.C., Foulkes W., Fourme E., Frebourg T., Gallinger S., Garre P., Genuardi M., Gerdes A.-M., Gima L.M., Giraud S., Goodwin A., Gorgens H., Green K., Guillem J., Guillen-Ponce C., Guimbaud R., Guindalini R.S.C., Half E.E., Hall M.J., Hampel H., Hansen T.V.O., Heinimann K., Hes F.J., Hill J., Ho J.W.C., Holinski-Feder E., Hoogerbrugge N., Huneburg R., Huntley V., James P.A., Jensen U.B., John T., Juhari W.K.W., Kalady M., Kastrinos F., Kloor M., Kohonen-Corish M.R., Krogh L.N., Kupfer S.S., Ladabaum U., Lagerstedt-Robinson K., Lalloo F., Lasset C., Latchford A., Laurent-Puig P., Lautrup C.K., Leggett B.A., Lejeune S., LeMarchand L., Ligtenberg M., Lindor N., Loeffler M., Longy M., Lopez F., Lowery J., Lubinski J., Lucassen A.M., Lynch P.M., Malinska K., Matsubara N., Mecklin J.-P., Moller P., Monahan K., Morrison P.J., Nattermann J., Navarro M., Neffa F., Neklason D., Newcomb P.A., Ngeow J., Nichols C., Nielsen M., Nixon D.M., Nogues C., Okkels H., Olschwang S., Pachter N., Pai R.K., Palmero E.I., Pande M., Parry S., Patel S.G., Pearlman R., Perne C., Pineda M., Poplawski N.K., Pylvanainen K., Qiu J., Rahner N., Ramesar R., Rasmussen L.J., Redler S., Reis R.M., Ricciardiello L., Rogoza-Janiszewska E., Rosty C., Samadder N.J., Sampson J.R., Schackert H.K., Schmiegel W., Schulmann K., Schuster H., Scott R., Senter L., Seppala T.T., Shtoyerman R., Sijmons R.H., Snyder C., Solomon I.B., Soto J.L., Southey M.C., Spigelman A., Spirandelli F., Spurdle A.B., Steinke-Lange V., Stoffel E.M., Strassburg C.P., Sunde L., Susman R., Syngal S., Tanakaya K., Tezcan G., Therkildsen C., Thibodeau S., Tomita N., Tucker K.M., Tunca B., Turchetti D., Uhrhammer N., Utsunomiya J., Vaccaro C., van Duijnhoven F.J.B., van Wanzeele M.J., Vangala D.B., Vasen H.F.A., von Knebel Doeberitz M., von Salome J., Wadt K.A.W., Ward R.L., Weitz J., Weitzel J.N., Williams H., Winship I., Wise P.E., Wods J., Woods M.O., Yamaguchi T., Zachariae S., Zahary M.N., Hopper J.L., Haile R.W., Macrae F.A., Moslein G., and Jenkins M.A.
- Subjects
0301 basic medicine ,Proband ,Oncology ,Male ,Heredity ,DNA mismatch repair ,[SDV]Life Sciences [q-bio] ,SUSCEPTIBILITY ,Settore MED/03 - GENETICA MEDICA ,0302 clinical medicine ,Residence Characteristics ,Risk Factors ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,PMS2 ,ComputingMilieux_MISCELLANEOUS ,MLH1 ,Age Factors ,Middle Aged ,Penetrance ,Lynch syndrome ,3. Good health ,Pedigree ,Phenotype ,030220 oncology & carcinogenesis ,Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis ,Female ,Adult ,medicine.medical_specialty ,PENETRANCE ,congenital, hereditary, and neonatal diseases and abnormalities ,GENES ,3122 Cancers ,colorectal cancer ,BREAST ,Risk Assessment ,03 medical and health sciences ,Sex Factors ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Retrospective Studies ,business.industry ,MUTATIONS ,Cancer ,medicine.disease ,digestive system diseases ,MSH2 ,MSH6 ,MODEL ,INDIVIDUALS ,030104 developmental biology ,Lynch Syndrome ,Gene-Environment Interaction ,business - Abstract
Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.
- Published
- 2021
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