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Incorporating Truncating Variants in PALB2, CHEK2 and ATM into the BOADICEA Breast Cancer Risk Model

PURPOSE: The proliferation of gene-panel testing precipitates the need for a breast cancer (BC) risk model that incorporates the effects of mutations in several genes and family history (FH). We extended the BOADICEA model to incorporate the effects of truncating variants in PALB2, CHEK2 and ATM. ME...

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Autores principales: Lee, Andrew J., Cunningham, Alex P., Tischkowitz, Marc, Simard, Jacques, Pharoah, Paul D., Easton, Douglas F., Antoniou, Antonis C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086091/
https://www.ncbi.nlm.nih.gov/pubmed/27464310
http://dx.doi.org/10.1038/gim.2016.31
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author Lee, Andrew J.
Cunningham, Alex P.
Tischkowitz, Marc
Simard, Jacques
Pharoah, Paul D.
Easton, Douglas F.
Antoniou, Antonis C.
author_facet Lee, Andrew J.
Cunningham, Alex P.
Tischkowitz, Marc
Simard, Jacques
Pharoah, Paul D.
Easton, Douglas F.
Antoniou, Antonis C.
author_sort Lee, Andrew J.
collection PubMed
description PURPOSE: The proliferation of gene-panel testing precipitates the need for a breast cancer (BC) risk model that incorporates the effects of mutations in several genes and family history (FH). We extended the BOADICEA model to incorporate the effects of truncating variants in PALB2, CHEK2 and ATM. METHODS: The BC incidence was modelled via the explicit effects of truncating variants in BRCA1/2, PALB2, CHEK2 and ATM and other unobserved genetic effects using segregation analysis methods. RESULTS: The predicted average BC risk by age 80 for an ATM mutation carrier is 28%, 30% for CHEK2, 50% for PALB2, 74% for BRCA1 and BRCA2. However, the BC risks are predicted to increase with FH-burden. In families with mutations, predicted risks for mutation-negative members depend on both FH and the specific mutation. The reduction in BC risk after negative predictive-testing is greatest when a BRCA1 mutation is identified in the family, but for women whose relatives carry a CHEK2 or ATM mutation, the risks decrease slightly. CONCLUSIONS: The model may be a valuable tool for counselling women who have undergone gene-panel testing for providing consistent risks and harmonizing their clinical management. A web-application can be used to obtain BC- risks in clinical practice (http://ccge.medschl.cam.ac.uk/boadicea/).
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spelling pubmed-50860912016-12-06 Incorporating Truncating Variants in PALB2, CHEK2 and ATM into the BOADICEA Breast Cancer Risk Model Lee, Andrew J. Cunningham, Alex P. Tischkowitz, Marc Simard, Jacques Pharoah, Paul D. Easton, Douglas F. Antoniou, Antonis C. Genet Med Article PURPOSE: The proliferation of gene-panel testing precipitates the need for a breast cancer (BC) risk model that incorporates the effects of mutations in several genes and family history (FH). We extended the BOADICEA model to incorporate the effects of truncating variants in PALB2, CHEK2 and ATM. METHODS: The BC incidence was modelled via the explicit effects of truncating variants in BRCA1/2, PALB2, CHEK2 and ATM and other unobserved genetic effects using segregation analysis methods. RESULTS: The predicted average BC risk by age 80 for an ATM mutation carrier is 28%, 30% for CHEK2, 50% for PALB2, 74% for BRCA1 and BRCA2. However, the BC risks are predicted to increase with FH-burden. In families with mutations, predicted risks for mutation-negative members depend on both FH and the specific mutation. The reduction in BC risk after negative predictive-testing is greatest when a BRCA1 mutation is identified in the family, but for women whose relatives carry a CHEK2 or ATM mutation, the risks decrease slightly. CONCLUSIONS: The model may be a valuable tool for counselling women who have undergone gene-panel testing for providing consistent risks and harmonizing their clinical management. A web-application can be used to obtain BC- risks in clinical practice (http://ccge.medschl.cam.ac.uk/boadicea/). 2016-04-14 2016-12 /pmc/articles/PMC5086091/ /pubmed/27464310 http://dx.doi.org/10.1038/gim.2016.31 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Lee, Andrew J.
Cunningham, Alex P.
Tischkowitz, Marc
Simard, Jacques
Pharoah, Paul D.
Easton, Douglas F.
Antoniou, Antonis C.
Incorporating Truncating Variants in PALB2, CHEK2 and ATM into the BOADICEA Breast Cancer Risk Model
title Incorporating Truncating Variants in PALB2, CHEK2 and ATM into the BOADICEA Breast Cancer Risk Model
title_full Incorporating Truncating Variants in PALB2, CHEK2 and ATM into the BOADICEA Breast Cancer Risk Model
title_fullStr Incorporating Truncating Variants in PALB2, CHEK2 and ATM into the BOADICEA Breast Cancer Risk Model
title_full_unstemmed Incorporating Truncating Variants in PALB2, CHEK2 and ATM into the BOADICEA Breast Cancer Risk Model
title_short Incorporating Truncating Variants in PALB2, CHEK2 and ATM into the BOADICEA Breast Cancer Risk Model
title_sort incorporating truncating variants in palb2, chek2 and atm into the boadicea breast cancer risk model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086091/
https://www.ncbi.nlm.nih.gov/pubmed/27464310
http://dx.doi.org/10.1038/gim.2016.31
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