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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
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
0022-2593
Evans, D. Gareth
141c5f82-b4c6-4d79-a5b4-ed24e98c4979
van Veen, Elke M.
24692869-c7e5-44f9-b99d-682f38c13fc6
Byers, Helen J.
bd8b9d81-a692-4534-8bce-b152553d6995
Evans, Sarah J.
daee7e6b-a621-4354-9e18-8b00ec01c620
Burghel, George J.
0288eca6-9ca5-4806-bfeb-2f963643d326
Woodward, Emma R.
ab892641-74f3-4713-8f5d-b3033d468f02
Harkness, Elaine F.
928d851e-2284-49ee-a738-01750c8cbbde
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
et al.,
96c90377-641f-4276-9d09-6968e3f36258
Evans, D. Gareth
141c5f82-b4c6-4d79-a5b4-ed24e98c4979
van Veen, Elke M.
24692869-c7e5-44f9-b99d-682f38c13fc6
Byers, Helen J.
bd8b9d81-a692-4534-8bce-b152553d6995
Evans, Sarah J.
daee7e6b-a621-4354-9e18-8b00ec01c620
Burghel, George J.
0288eca6-9ca5-4806-bfeb-2f963643d326
Woodward, Emma R.
ab892641-74f3-4713-8f5d-b3033d468f02
Harkness, Elaine F.
928d851e-2284-49ee-a738-01750c8cbbde
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
et al.,
96c90377-641f-4276-9d09-6968e3f36258

Evans, D. Gareth, van Veen, Elke M., Byers, Helen J., Evans, Sarah J., Burghel, George J., Woodward, Emma R., Harkness, Elaine F., Eccles, Diana and et al., (2021) High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer. Journal of Medical Genetics.

Record type: Article

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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More information

Accepted/In Press date: 31 October 2020
Published date: 23 March 2021
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
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

Catalogue record

Date deposited: 10 Nov 2020 17:30
Last modified: 26 Nov 2021 02:34

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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: Diana Eccles ORCID iD
Author: et al.

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