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  • Differential involvement of germline pathogenic variants in breast cancer genes between DCIS and low-grade invasive cancers

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Cancer genetics
Original research
Differential involvement of germline pathogenic variants in breast cancer genes between DCIS and low-grade invasive cancers
  1. D Gareth Evans1,
  2. Siva Sithambaram2,
  3. Elke Maria van Veen3,
  4. George J Burghel4,
  5. Helene Schlecht5,
  6. Elaine F Harkness3,
  7. Helen Byers6,
  8. Jamie M Ellingford7,
  9. Ashu Gandhi8,
  10. Sacha J Howell2,9,
  11. Anthony Howell10,
  12. Claire Forde11,
  13. Fiona Lalloo12,
  14. William G Newman13,
  15. Miriam Jane Smith14,
  16. Emma Roisin Woodward15
  1. 1 Division of Evolution and Genomic Science, The University of Manchester School of Health Sciences, Manchester, UK
  2. 2 Manchester Univerities Hospital NHS Foundation Trust, Manchester, UK
  3. 3 Division of Evolution and Genomic Sciences, The University of Manchester, Manchester, UK
  4. 4 Genomic Diagnostic Laboratory, MFT, Manchester, UK
  5. 5 North West Genomic Laboratory Hub, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  6. 6 Genomic Medicine, The University of Manchester School of Health Sciences, Manchester, UK
  7. 7 Institute of Human Development, The University of Manchester School of Health Sciences, Manchester, UK
  8. 8 Prevent Breast Cancer Centre, Wythenshawe Hospital Manchester Universities Foundation Trust, Manchester, UK
  9. 9 Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
  10. 10 Manchester Foundation Trust, Prevent Breast Cancer Centre, Manchester, UK
  11. 11 Clinical Genetics Service, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  12. 12 Clinical Genetics Service, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  13. 13 Genetics, The University of Manchester School of Health Sciences, Manchester, UK
  14. 14 Genetic Medicine, The University of Manchester School of Health Sciences, Manchester, UK
  15. 15 Manchester Centre for Genomic Medicine, MFT, Manchester, UK
  1. Correspondence to Professor D Gareth Evans, Division of Evolution and Genomic Science, The University of Manchester School of Health Sciences, Manchester, M13 9WL, UK; gareth.evans{at}mft.nhs.uk

Abstract

Purpose To investigate frequency of germline pathogenic variants (PVs) in women with ductal carcinoma in situ (DCIS) and grade 1 invasive breast cancer (G1BC).

Methods We undertook BRCA1/2 analysis in 311 women with DCIS and 392 with G1BC and extended panel testing (non-BRCA1/2) in 176/311 with DCIS and 156/392 with G1BC. We investigated PV detection by age at diagnosis, Manchester Score (MS), DCIS grade and receptor status.

Results 30/311 (9.6%) with DCIS and 16/392 with G1BC (4.1%) had a BRCA1/2 PV (p=0.003), and 24/176-(13.6%) and 7/156-(4.5%), respectively, a non-BRCA1/2 PV (p=0.004). Increasing MS was associated with increased likelihood of BRCA1/2 PV in both DCIS and G1BC, although the 10% threshold was not predictive for G1GB. 13/32 (40.6%) DCIS and 0/17 with G1BC <40 years had a non-BRCA1/2 PV (p<0.001). 0/16 DCIS G1 had a PV. For G2 and G3 DCIS, PV rates were 10/98 (BRCA1/2) and 9/90 (non-BRCA1/2), and 8/47 (BRCA1/2) and 8/45 (non-BRCA1/2), respectively. 6/9 BRCA1 and 3/26 BRCA2-associated DCIS were oestrogen receptor negative-(p=0.003). G1BC population testing showed no increased PV rate (OR=1.16, 95% CI 0.28 to 4.80).

Conclusion DCIS is more likely to be associated with both BRCA1/2 and non-BRCA1/2 PVs than G1BC. Extended panel testing ought to be offered in young-onset DCIS where PV detection rates are highest.

  • Genetics, Medical

Data availability statement

Data are available upon reasonable request. Data available on request.

https://doi.org/10.1136/jmg-2022-108790

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    Data availability statement

    Data are available upon reasonable request. Data available on request.

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    Footnotes

    • Twitter @BurghelG, @ER_Woodward

    • Contributors Conception and design: DGE; acquisition of data: DGE, ERW, MJS, EMvV and SS; analysis and interpretation of data and drafting of the manuscript: DGE and ERW; manuscript review and approval of the manuscript for final submission: all authors.

    • 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 and Care Research or the Department of Health.

    • Competing interests None declared.

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