Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 May 8;30(5):oyaf052.
doi: 10.1093/oncolo/oyaf052.

Exploring the promoter regions of cancer predisposition genes in patients with triple-negative breast cancer reveals the presence of rare germline variants

Michela Palleschi  1 , Alessandra Virga  2 , Emanuela Scarpi  3 , Eugenio Fonzi  3 , Antonino Musolino  1   4 , Filippo Merloni  1 , Samanta Sarti  1 , Rita Danesi  5 , Mila Ravegnani  5 , Chiara Casadei  1 , Marianna Sirico  1 , Caterina Gianni  1 , Roberta Maltoni  1 , Sara Bravaccini  2 , Daniele Calistri  2 , Valentina Arcangeli  5 , Valentina Zampiga  2 , Ilaria Cangini  2 , Erika Bandini  2 , Francesca Mannozzi  3 , Fabio Falcini  5   6 , Giovanni Martinelli  7 , Ugo De Giorgi  8 , Paola Ulivi  2 , Gianluca Tedaldi  2
Affiliations

Exploring the promoter regions of cancer predisposition genes in patients with triple-negative breast cancer reveals the presence of rare germline variants

Michela Palleschi et al. Oncologist. .

Abstract

Background: Current genetic screening for predisposition to breast cancer (BC) is limited to BRCA1/2 exons and intron/exon boundaries, and limited information exists about the impact of variants in BRCA1/2 non-coding regions. The majority of alterations identified in these regions remain unclassified, but evidence of the impact of variants in the regulatory regions on cancer risk and response to treatment is emerging.

Patients and methods: This project aimed to investigate the prevalence of germline variants in the non-coding regulatory regions of BRCA1/2 and other BC predisposition genes in patients with triple-negative BC (TNBC) selected for age at cancer diagnosis and/or family history of cancer. The study also aims to investigate the relationship between these variants and clinical outcomes such as overall survival, disease-free survival (DFS), and response to treatment. We analyzed a Next-Generation Sequencing (NGS) custom panel of promoter regions of 28 genes involved in BC predisposition on 144 patients with TNBC previously tested wild type for coding regions of BRCA1/2.

Results: The NGS analysis identified 635 rare variants in promoter regions of the 28 genes. Among the 144 patients, for 75 with available clinical data, rare germline variants in BRCA2 promoter were statistically significantly related to worse overall survival (OS) (P-value = .017). No differences in DFS and OS were found for the other genes. Rare variants in the CDH1 promoter were related to the highest percentage of non-pathological complete response after neoadjuvant chemotherapy (P = .0273); MLH1 and PALB2 rare non-coding variants were found to be both related to bilateral BC (P = .0146 and P = .0005, respectively) and ATM promoter variants were associated with a positive family history (P = .041).

Conclusion: Our results underscore the importance of searching for rare germline variants in regulatory regions of cancer predisposition genes in patients with TNBC, since these variants can be associated with an increased cancer risk.

Keywords: cancer predisposition; hereditary breast cancer; promoter variants; regulatory regions; triple-negative breast cancer.

PubMed Disclaimer

Conflict of interest statement

U.D.G.: Consultant: Janssen, AstellasPharma, Sanofi, Bayer, Pfizer, Bristol-Myers Squibb, Novartis, Ipsen, Merck; Institutional funding: Roche, Sanofi, AstraZeneca. M.P.: reports honoraria for educational events/materials from Novartis, Daiichy-Sankyo, Gilead and travel, accommodations, and/or expenses from Grant from Novartis, Astrazeneca and Lilly. A.M.: reports research funding: Lilly, Roche, Pfizer Scientific Advisory Board: Lilly, Roche, MSD, Daiichi.

Figures

Figure 1.
Figure 1.
The explanatory figure illustrating the role and structure of enhancers, promoters, and regulatory regions in human genes.
Figure 2.
Figure 2.
Lolliplots showing the position of alterations identified in regulatory regions of BRCA1, BRCA2, CDH1 and PALB2. The plot range is the promoter region of each gene (see Table 1), with a downstream padding of 300 bp.
Figure 3.
Figure 3.
(A) Disease-free survival (DFS) according to BRCA1/2 non-coding regions status: on the left DFS and BRCA1non-coding regions: on the right DFS and regulatory regions of BRCA2. (B) Overall survival (OS) according to BRCA1/2 non-coding regions status on the left relationship between alterated non-coding regions of BRCA1 and OS, on the right relationship between regulatory regions of BRCA2 and OS (C) DFS according to non-coding regions of CDH1 status and pathological complete response (pCR): on the left pCR, on the right no pCR. (D) DFS according to ATM status in regulatory regions and family history: on the left Positive family history; on the right Negative family history.
See this image and copyright information in PMC

References

    1. Lips EH, Mulder L, Oonk A, et al. Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers. Br J Cancer. 2013;108:2172-2177. https://doi.org/ 10.1038/bjc.2013.144 - DOI - PMC - PubMed
    1. Mavaddat N, Rebbeck TR, Lakhani SR, Easton DF, Antoniou AC.. Incorporating tumour pathology information into breast cancer risk prediction algorithms. Breast Cancer Res. 2010;12:R28. https://doi.org/ 10.1186/bcr2576 - DOI - PMC - PubMed
    1. Palleschi M, Tedaldi G, Sirico M, et al. Moving beyond PARP Inhibition: current state and future perspectives in breast cancer. Int J Mol Sci. 2021;22:7884. https://doi.org/ 10.3390/ijms22157884 - DOI - PMC - PubMed
    1. Jia X, Wang K, Xu L, et al. A systematic review and meta-analysis of BRCA1/2 mutation for predicting the effect of platinum-based chemotherapy in triple-negative breast cancer. Breast. 2022;66:31-39. https://doi.org/ 10.1016/j.breast.2022.08.012 - DOI - PMC - PubMed
    1. Sun W, Wu Y, Ma F, Fan J, Qiao Y.. Efficacy of PARP inhibitor, platinum, and immunotherapy in BRCA-mutated HER2-negative breast cancer patients: a systematic review and network meta-analysis. J Clin Med. 2023;12:1588. https://doi.org/ 10.3390/jcm12041588 - DOI - PMC - PubMed