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Review
. 2024 Feb 8;15(2):219.
doi: 10.3390/genes15020219.

Genetic Basis of Breast and Ovarian Cancer: Approaches and Lessons Learnt from Three Decades of Inherited Predisposition Testing

Valeria Barili  1 , Enrico Ambrosini  2 , Beatrice Bortesi  3 , Roberta Minari  3 , Erika De Sensi  1 , Ilenia Rita Cannizzaro  1 , Antonietta Taiani  1 , Maria Michiara  3   4 , Angelica Sikokis  3   4 , Daniela Boggiani  3   4 , Chiara Tommasi  1   3   4 , Olga Serra  3   4 , Francesco Bonatti  3 , Alessia Adorni  3 , Anita Luberto  1 , Patrizia Caggiati  2 , Davide Martorana  2 , Vera Uliana  2 , Antonio Percesepe  1   2 , Antonino Musolino  1   3   4 , Benedetta Pellegrino  3   4
Affiliations
Review

Genetic Basis of Breast and Ovarian Cancer: Approaches and Lessons Learnt from Three Decades of Inherited Predisposition Testing

Valeria Barili et al. Genes (Basel). .

Abstract

Germline variants occurring in BRCA1 and BRCA2 give rise to hereditary breast and ovarian cancer (HBOC) syndrome, predisposing to breast, ovarian, fallopian tube, and peritoneal cancers marked by elevated incidences of genomic aberrations that correspond to poor prognoses. These genes are in fact involved in genetic integrity, particularly in the process of homologous recombination (HR) DNA repair, a high-fidelity repair system for mending DNA double-strand breaks. In addition to its implication in HBOC pathogenesis, the impairment of HR has become a prime target for therapeutic intervention utilizing poly (ADP-ribose) polymerase (PARP) inhibitors. In the present review, we introduce the molecular roles of HR orchestrated by BRCA1 and BRCA2 within the framework of sensitivity to PARP inhibitors. We examine the genetic architecture underneath breast and ovarian cancer ranging from high- and mid- to low-penetrant predisposing genes and taking into account both germline and somatic variations. Finally, we consider higher levels of complexity of the genomic landscape such as polygenic risk scores and other approaches aiming to optimize therapeutic and preventive strategies for breast and ovarian cancer.

Keywords: BRCA1 and BRCA2; hereditary breast and ovarian cancer (HBOC) syndrome; homologous recombination deficiency (HRD); poly (ADP-ribose) polymerase (PARP) inhibitors.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 3
Figure 3
Homologous recombination repair deficiency (HRD) detection is based on various methods based on germline or somatic analysis.
Figure 1
Figure 1
Polygenic risk scores (PRSs) in breast cancer risk. (A) Generation of PRSs by genome-wide association studies (GWASs) which identify SNV with various effect sizes on disease penetrance, to create numerous PRSs. (B) The various PRSs are then examined through different correlation testing, and the most accurate PRS is identified and then implemented in an independent-subject cohort. (C) Forest plot showing BC risk for specific breast cancer subtypes associated with 313- and 77-SNP PRSs from Mavaddat et al., 2019 [142].
Figure 2
Figure 2
Benefits, limitations, and future perspectives of PRS in breast cancer management.
See this image and copyright information in PMC

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