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Cancer genetics
Original research
Detection of pathogenic variants in breast cancer susceptibility genes in bilateral breast cancer
  1. D Gareth Evans1,2,
  2. George J Burghel3,
  3. Helene Schlecht4,
  4. Elaine F Harkness5,
  5. Ashu Gandhi6,
  6. Sacha J Howell7,8,
  7. Anthony Howell9,
  8. Claire Forde10,
  9. Fiona Lalloo10,
  10. William G Newman11,
  11. Miriam Jane Smith12,
  12. Emma Roisin Woodward13
  1. 1 Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  2. 2 Genomic Medicine, Manchester Academic Health Science Centre, Manchester, UK
  3. 3 Genomic Diagnostic Laboratory, Manchester University NHS Foundation Trust, Manchester, UK
  4. 4 North West Genomic Laboratory Hub, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  5. 5 Genomic Medicine, The University of Manchester, Manchester, UK
  6. 6 Prevent Breast Cancer Centre, Wythenshawe Hospital Manchester Universities Foundation Trust, Manchester, UK
  7. 7 Genomic Medicine, Wythenshawe Hospital Manchester Universities Foundation Trust, Wythenshawe, UK
  8. 8 Genomic Medicine, The Christie NHS Foundation Trust, Manchester, UK
  9. 9 Genomic Medicine, Prevent Breast Cancer Centre, Manchester, UK
  10. 10 Clinical Genetics Service, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  11. 11 Genetics, Central Manchester University foundation Trust, Manchester, UK
  12. 12 Genetic Medicine, University of Manchester, Manchester, UK
  13. 13 Manchester Centre for Genomic Medicine, Central Manchester NHS Foundation Trust, Manchester, UK
  1. Correspondence to Professor D Gareth Evans, Manchester University Hospitals NHS Foundation Trust, Manchester, UK; gareth.evans{at}mft.nhs.uk

Abstract

Purpose To investigate the frequency of germline pathogenic variants (PVs) in women with bilateral breast cancer.

Methods We undertook BRCA1/2 and CHEK2 c.1100delC molecular analysis in 764 samples and a multigene panel in 156. Detection rates were assessed by age at first primary, Manchester Score, and breast pathology. Oestrogen receptor (ER) status of the contralateral versus first breast cancer was compared on 1081 patients with breast cancer with BRCA1/BRCA2 PVs.

Results 764 women with bilateral breast cancer have undergone testing of BRCA1/2 and CHEK2; 407 were also tested for PALB2 and 177 for ATM. Detection rates were BRCA1 11.6%, BRCA2 14.0%, CHEK2 2.4%, PALB2 1.0%, ATM 1.1% and, for a subset of mainly very early onset tumours, TP53 4.6% (9 of 195). The highest PV detection rates were for triple negative cancers for BRCA1 (26.4%), grade 3 ER+HER2 for BRCA2 (27.9%) and HER2+ for CHEK2 (8.9%). ER status of the first primary in BRCA1 and BRCA2 PV heterozygotes was strongly predictive of the ER status of the second contralateral tumour since ~90% of second tumours were ER− in BRCA1 heterozygotes, and 50% were ER− in BRCA2 heterozygotes if the first was ER−.

Conclusion We have shown a high rate of detection of BRCA1 and BRCA2 PVs in triple negative and grade 3 ER+HER2− first primary diagnoses, respectively. High rates of HER2+ were associated with CHEK2 PVs, and women ≤30 years were associated with TP53 PVs. First primary ER status in BRCA1/2 strongly predicts the second tumour will be the same ER status even if unusual for PVs in that gene.

  • genetic predisposition to disease
  • genetic research

Data availability statement

Data are available upon reasonable request. Please email Prof Evans.

https://doi.org/10.1136/jmg-2023-109196

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    Data availability statement

    Data are available upon reasonable request. Please email Prof Evans.

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    Footnotes

    • Twitter @BurghelG, @ER_Woodward

    • Contributors Conception and design: DGE; acquisition, analysis and interpretation of data and drafting of the article: DGE and ERW; manuscript review and approval of the final submission: all. DGE accepts overall responsibility for content

    • Funding This research was funded by the Manchester National Institute for Health Research Biomedical Research Centre (IS-BRC-1215-20007).

    • Disclaimer The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.