High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer
High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer
Background: while the likelihood of identifyingconstitutional breast cancer-associated BRCA1, BRCA2and TP53 pathogenic variants (PVs) increases with earlierdiagnosis age, little is known about the correlation withage at diagnosis in other predisposition genes. Here,we assessed the contribution of known breast cancerassociated genes to very early onset disease.
Methods: sequencing of BRCA1, BRCA2, TP53 andCHEK2 c.1100delC was undertaken in women withbreast cancer diagnosed ≤30 years. Those testingnegative were screened for PVs in a minimum of eightadditional breast cancer-associated genes. Rates ofPVs were compared with cases ≤30 years from theProspective study of Outcomes in Sporadic vs Hereditarybreast cancer (POSH) study.
Results: testing 379 women with breast cancer aged≤30 years identified 75 PVs (19.7%) in BRCA1, 35(9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%)CHEK2 c.1100delC. Extended screening of 184 PVnegative women only identified eight additionalactionable PVs. BRCA1/2 PVs were more common inwomen aged 26–30 years than in younger women(p=0.0083) although the younger age group had ratesmore similar to those in the POSH cohort. Out of 26women with ductal carcinoma in situ (DCIS) alone,most were high-grade and 11/26 (42.3%) had a PV(TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yieldis similar to the 61 (48.8%) BRCA1/2 PVs identified in125 women with triple-negative breast cancer. The POSHcohort specifically excluded pure DCIS which may explainlower TP53 PV rates in this group (1.7%).
Conclusion: the rates of BRCA1, BRCA2 and TP53PVs are high in very early onset breast cancer, withlimited benefit from testing of additional breast cancerassociated genes.
genetic testing, genetics, human genetics
115-121
Evans, D. Gareth
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van Veen, Elke M.
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Byers, Helen J.
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Evans, Sarah J.
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Burghel, George J.
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Woodward, Emma R.
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Harkness, Elaine F.
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Eccles, Diana
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Greville-Haygate, Stephanie L.
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Ellingford, Jamie M.
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Bowers, Naomi L.
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Pereira, Marta
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Wallace, Andrew J.
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Howell, Sasha J.
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Howell, Anthony
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Lalloo, Fiona
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Newman, William G.
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Smith, Miriam Jane
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1 February 2022
Evans, D. Gareth
141c5f82-b4c6-4d79-a5b4-ed24e98c4979
van Veen, Elke M.
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Byers, Helen J.
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Evans, Sarah J.
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Burghel, George J.
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Woodward, Emma R.
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Harkness, Elaine F.
928d851e-2284-49ee-a738-01750c8cbbde
Eccles, Diana
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Greville-Haygate, Stephanie L.
fc1c2774-4195-4f7a-a1f1-95c204e1e2e3
Ellingford, Jamie M.
0965ec10-dc5e-4995-8b3e-4d3f0aae27a4
Bowers, Naomi L.
131f0df0-6a80-45b4-9b92-f3cdc3f20304
Pereira, Marta
15e782c3-1eec-4c3a-bfb9-d0de5dc644d4
Wallace, Andrew J.
38f0ecf3-11ec-4fda-8360-42c7b30efe7d
Howell, Sasha J.
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Howell, Anthony
b8669677-35cf-4120-bd1d-895e8a14c3c7
Lalloo, Fiona
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Newman, William G.
423ab943-5e28-410e-83dd-9fcbebfac401
Smith, Miriam Jane
82abd44c-cf4c-468a-ad64-df8656df2527
Evans, D. Gareth, van Veen, Elke M., Byers, Helen J., Evans, Sarah J., Burghel, George J., Woodward, Emma R., Harkness, Elaine F., Eccles, Diana, Greville-Haygate, Stephanie L., Ellingford, Jamie M., Bowers, Naomi L., Pereira, Marta, Wallace, Andrew J., Howell, Sasha J., Howell, Anthony, Lalloo, Fiona, Newman, William G. and Smith, Miriam Jane
(2022)
High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer.
Journal of Medical Genetics, 59 (2), .
(doi:10.1136/jmedgenet-2020-107347).
Abstract
Background: while the likelihood of identifyingconstitutional breast cancer-associated BRCA1, BRCA2and TP53 pathogenic variants (PVs) increases with earlierdiagnosis age, little is known about the correlation withage at diagnosis in other predisposition genes. Here,we assessed the contribution of known breast cancerassociated genes to very early onset disease.
Methods: sequencing of BRCA1, BRCA2, TP53 andCHEK2 c.1100delC was undertaken in women withbreast cancer diagnosed ≤30 years. Those testingnegative were screened for PVs in a minimum of eightadditional breast cancer-associated genes. Rates ofPVs were compared with cases ≤30 years from theProspective study of Outcomes in Sporadic vs Hereditarybreast cancer (POSH) study.
Results: testing 379 women with breast cancer aged≤30 years identified 75 PVs (19.7%) in BRCA1, 35(9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%)CHEK2 c.1100delC. Extended screening of 184 PVnegative women only identified eight additionalactionable PVs. BRCA1/2 PVs were more common inwomen aged 26–30 years than in younger women(p=0.0083) although the younger age group had ratesmore similar to those in the POSH cohort. Out of 26women with ductal carcinoma in situ (DCIS) alone,most were high-grade and 11/26 (42.3%) had a PV(TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yieldis similar to the 61 (48.8%) BRCA1/2 PVs identified in125 women with triple-negative breast cancer. The POSHcohort specifically excluded pure DCIS which may explainlower TP53 PV rates in this group (1.7%).
Conclusion: the rates of BRCA1, BRCA2 and TP53PVs are high in very early onset breast cancer, withlimited benefit from testing of additional breast cancerassociated genes.
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jmedgenet-2020-107347.full
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More information
Accepted/In Press date: 31 October 2020
e-pub ahead of print date: 23 March 2021
Published date: 1 February 2022
Additional Information:
Funding Information:
Competing interests JME is funded by a postdoctoral research fellowship from
Funding Information:
Funding This work was supported by the Manchester National Institute for Health Research Biomedical Research Centre (IS-BRC-1215-20007 to DGE, EFH, ERW, MJS, EMvV, HB, WGN and SH) and Prevent Breast Cancer (GA17-001).
Publisher Copyright:
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.
Keywords:
genetic testing, genetics, human genetics
Identifiers
Local EPrints ID: 444888
URI: http://eprints.soton.ac.uk/id/eprint/444888
ISSN: 0022-2593
PURE UUID: 6e5b72b1-c722-4682-81f8-00ec0fb639fd
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Date deposited: 10 Nov 2020 17:30
Last modified: 17 Mar 2024 02:36
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Contributors
Author:
D. Gareth Evans
Author:
Elke M. van Veen
Author:
Helen J. Byers
Author:
Sarah J. Evans
Author:
George J. Burghel
Author:
Emma R. Woodward
Author:
Elaine F. Harkness
Author:
Stephanie L. Greville-Haygate
Author:
Jamie M. Ellingford
Author:
Naomi L. Bowers
Author:
Marta Pereira
Author:
Andrew J. Wallace
Author:
Sasha J. Howell
Author:
Anthony Howell
Author:
Fiona Lalloo
Author:
William G. Newman
Author:
Miriam Jane Smith
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