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Distinct breast cancer phenotypes in BRCA 1/2 carriers based on ER status

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Abstract

Purpose

BRCA1/2 genes are the two main genes associated with hereditary breast cancers (BC). In the present study, we explore clinical and molecular characteristics of BRCA-associated BC in relation to estrogen receptor (ER) status.

Methods

Three BC databases (DB) were evaluated: (i) Hadassah oncogenetics (n = 4826); (ii) METABRIC (n = 1980), and (iii) Nick-Zainal (n = 560). We evaluated age at diagnosis in BRCA positive (BP) and BRCA negative (BN) patients, and tested for mutational signature differences in cohort iii. mRNA differential expression analysis (DEA) and pathway analysis were performed in cohort ii.

Results

Age at diagnosis was lower in BP vs. BN tumors in all cohorts in the ER- group, and only in cohort i for the ER + group. Signature 3 was universal in BP BC, whereas several signatures were associated with ER status. Pathway analysis was performed between BP&BN, and was significant only in ER- tumors: the major activated pathways involved cancer-related processes and were highly significant. The most significant pathway was estrogen-mediated S-phase entry and the most activated upstream regulator was ERBB2.

Conclusion

Signature 3 was universal for all BP BC, while other signatures were associated with ER status. ER + BP& BN show similar genomic characteristics, ER- BP differed markedly from BN. This suggests that the initial carcinogenic process is universal for all BRCA carriers, but further insults lead to the development of two genomically distinct subtypes ER− and ER + . This may shed light on possible mechanisms involved in BP and carry preventive and therapeutic implications.

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Data availability

We analyzed published available databases.

Code availability

Not applicable.

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Funding

This work was partially supported by the Institutional Women's health foundation and the joint research fund between the Hebrew University faculty of Medicine and Hadassah University Hospital.

Author information

Author notes

  1. Shai Rosenberg and Michal Devir have contributed equally to this work.

Authors and Affiliations

  1. Gaffin Center for Neuro-Oncology, Sharett Institute for Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Shai Rosenberg & Michal Devir

  2. The Wohl Institute for Translational Medicine, Hadassah-Hebrew University Medical Center, Kiryat Hadassa, 91120, Jerusalem, Israel

    Shai Rosenberg & Michal Devir

  3. Sharett Institute for Oncology, Hadassah-Hebrew University Medical Center, Kiryat Hadassa, 91120, Jerusalem, Israel

    Luna Kaduri, Albert Grinshpun, Avital Granit, Ofra Maymon & Tamar Peretz

  4. Department of Human Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Vardiella Miner

  5. R&D Division, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Tamar Hamburger

  6. Department of General and Oncological Surgery - Surgery C, Sheba Medical Center, Ramat Gan, Israel

    Aviram Nissan

  7. Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

    Tamar Peretz

Authors
  1. Shai Rosenberg
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  2. Michal Devir
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  3. Luna Kaduri
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  4. Albert Grinshpun
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  5. Vardiella Miner
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  6. Tamar Hamburger
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  7. Avital Granit
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  8. Aviram Nissan
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  9. Ofra Maymon
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  10. Tamar Peretz
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Corresponding authors

Correspondence to Shai Rosenberg or Tamar Peretz.

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Supplementary Information

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10549_2022_6851_MOESM1_ESM.tif

Supplementary file1 (TIF 245 kb)—Distribution of age at diagnosis grouped by BRCA1/2 and ER status. Histograms shown separately for each of the three databases

10549_2022_6851_MOESM2_ESM.tif

Supplementary file2 (TIF 1411 kb)—Ingenuity Pathway Analysis for ER positive: BRCA positive vs. BRCA negative tumors. Orange – pathways overrepresented in BRCA positive tumors, Blue – pathways underrepresented in BRCA positive tumors. Only pathways for which the direction of the enrichment could be determined are shown

10549_2022_6851_MOESM3_ESM.tif

Supplementary file3 (TIF 9547 kb)—Ingenuity Pathway Analysis for ER-negative tumors after exclusion of Her2 positive tumors BRCA positive vs. BRCA negative tumors. Orange – pathways overrepresented in BRCA positive tumors, Blue – pathways underrepresented in BRCA positive tumors pathways for which the direction of the enrichment could be determined are shown in gray.

10549_2022_6851_MOESM4_ESM.tif

Supplementary file4 (TIF 11149 kb)—Ingenuity Pathway Analysis for ER-positive tumors after exclusion of Her2 positive tumors BRCA positive vs. BRCA negative tumors. Orange – pathways overrepresented in BRCA positive tumors, Blue – pathways underrepresented in BRCA positive tumors pathways for which the direction of the enrichment could be determined are shown in gray.

10549_2022_6851_MOESM5_ESM.tif

Supplementary file5 (TIF 1669 kb)—Number of genetic aberrations for the BRCA and ER status groups. A. single nucleotide substitutions, B. indels, C. rearrangements. The number of aberrations is given in log 10 scale.

Supplementary file6 (XLSX 92 kb)

Supplementary file7 (XLSX 11 kb)

Supplementary file8 (XLSX 11 kb)

Supplementary file9 (XLS 93 kb)

Supplementary file10 (XLS 91 kb)

Supplementary file11 (XLSX 11 kb)

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Rosenberg, S., Devir, M., Kaduri, L. et al. Distinct breast cancer phenotypes in BRCA 1/2 carriers based on ER status. Breast Cancer Res Treat 198, 197–205 (2023). https://doi.org/10.1007/s10549-022-06851-6

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  • DOI: https://doi.org/10.1007/s10549-022-06851-6

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