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  • Germline testing of BRCA1, BRCA2, PALB2 and CHEK2 c.1100delC in 1514 triple negative familial and isolated breast cancers from a single centre, with extended testing of ATM, RAD51C and RAD51D in over 400

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Cancer genetics
Original research
Germline testing of BRCA1, BRCA2, PALB2 and CHEK2 c.1100delC in 1514 triple negative familial and isolated breast cancers from a single centre, with extended testing of ATM, RAD51C and RAD51D in over 400
  1. Emma R Woodward1,2,3,
  2. Fiona Lalloo1,
  3. Claire Forde1,
  4. Sarah Pugh1,
  5. George J Burghel1,
  6. Helene Schlecht1,
  7. Elaine F Harkness4,
  8. Anthony Howell3,5,6,
  9. Sacha J Howell3,5,6,
  10. Ashu Gandhi5,6,
  11. D Gareth Evans1,2,3,4
  1. 1 Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  2. 2 Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
  3. 3 Manchester Breast Centre, The Christie NHS Foundation Trust, Manchester, UK
  4. 4 Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
  5. 5 Prevent Breast Cancer Unit, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK
  6. 6 Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
  1. Correspondence to Professor D Gareth Evans, The University of Manchester, Manchester, M13 9WL, UK; gareth.d.evans{at}manchester.ac.uk

Abstract

Background The identification of germline pathogenic gene variants (PGVs) in triple negative breast cancer (TNBC) is important to inform further primary cancer risk reduction and TNBC treatment strategies. We therefore investigated the contribution of breast cancer associated PGVs to familial and isolated invasive TNBC.

Methods Outcomes of germline BRCA1, BRCA2 and CHEK2_c.1100delC testing were recorded in 1514 women (743—isolated, 771—familial), and for PALB2 in 846 women (541—isolated, 305—familial), with TNBC and smaller numbers for additional genes. Breast cancer free controls were identified from Predicting Risk Of Cancer At Screening and BRIDGES (Breast cancer RIsk after Diagnostic GEne Sequencing) studies.

Results BRCA1_PGVs were detected in 52 isolated (7.0%) and 195 (25.3%) familial cases (isolated—OR=58.9, 95% CI: 16.6 to 247.0), BRCA2_PGVs in 21 (2.8%) isolated and 67 (8.7%) familial cases (isolated—OR=5.0, 95% CI: 2.3 to 11.2), PALB2_PGVs in 9 (1.7%) isolated and 12 (3.9%) familial cases (isolated—OR=8.8, 95% CI: 2.5 to 30.4) and CHEK2_c.1100delC in 0 isolated and 3 (0.45%) familial cases (isolated—OR=0.0, 95% CI: 0.00 to 2.11). BRCA1_PGV detection rate was >10% for all familial TNBC age groups and significantly higher for younger diagnoses (familial: <50 years, n=165/538 (30.7%); ≥50 years, n=30/233 (12.9%); p<0.0001). Women with a G3_TNBC were more likely to have a BRCA1_PGV as compared with a BRCA2 or PALB2_PGV (p<0.0001). 0/743 isolated TNBC had the CHEK2_c.1100delC PGV and 0/305 any ATM_PGV, but 2/240 (0.83%) had a RAD51D_PGV.

Conclusion PGVs in BRCA1 are associated with G3_TNBCs. Familial TNBCs and isolated TNBCs <30 years have a >10% likelihood of a PGV in BRCA1. BRCA1_PGVs are associated with younger age of familial TNBC. There was no evidence for any increased risk of TNBC with CHEK2 or ATM PGVs.

  • Genetic Counselling
  • Genetics
  • Genetic Testing
  • Mutation
  • DNA Repair

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/jmg-2023-109671

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • Twitter @ER_Woodward, @BurghelG

    • Contributors ERW and DGE conceptualised the study. HS and GJB interpreted the sequencing analyses. ERW and DGE interpreted the data and wrote the manuscript. All authors reviewed the manuscript. DGE is guarantor of the study.

    • Funding The genotyping work was supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007) and Prevent Breast Cancer (GA19-002).

    • Competing interests None declared.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.