Elsevier

Seminars in Cancer Biology

Volume 72, July 2021, Pages 27-35
Seminars in Cancer Biology

Genetics and Genomics of Breast Cancer: update and translational perspectives

https://doi.org/10.1016/j.semcancer.2020.03.013Get rights and content

Abstract

In the recent years the rapid scientific innovation in the evaluation of the individual’s genome have allowed the identification of variants associated with the onset, treatment and prognosis of various pathologies including cancer, and with a potential impact in the assessment of therapy responses. Despite the analysis and interpretation of genomic information is considered incomplete, in many cases the identification of specific genomic profile has allowed the stratification of subgroups of patients characterized by a better response to drug therapies. Individual genome analysis has changed profoundly the diagnostic and therapeutic approach of breast cancer in the last 15 years by identifying selective molecular lesions that drive the development of neoplasms, showing that each tumor has its own genomic signature, with some specific features and some features common to several sub-types. Several personalized therapies have been (and still are being) developed showing a remarkable efficacy in the treatment of breast cancer.

Section snippets

Driver and Passenger Mutations

Numerous landscape studies have explored the number and the types of somatic and germinal mutations in breast cancer [5]. Driver mutations are often somatic, however, germline driver mutations (e.g. BRCA1 and BRCA2) are frequently detected in breast cancer.

The most frequently implicated cancer genes across a study involving 500 breast cancers examined, were TP53, PIK3CA, MYC, PTEN, CCND1, ERBB2, FGFR1, and GATA3 with a frequency of 41%, 30%, 20%, 16%, 16%, 13%, 11%, 10% respectively [12].

Genometype and Gene Expression Signatures in Breast Cancer

Breast cancer is not a single entity but rather several diseases with distinct patterns of genomic alterations, which are often subtype-specific [[20], [21], [22]]. The molecular subtypes are recognized mainly on the expression of estrogen receptor (ER), progesterone receptor (PgR) and the overexpression or amplification of oncogenic human epidermal growth factor receptor 2 (HER2).

The different molecular subtypes are:

1 luminal A: ER-positive, PgR positive, HER2 negative

2 luminal B: ER-positive,

Tumoral Heterogeneity and Mutational Signatures

Breast cancer tumor heterogeneity is one of the hallmarks of malignancy, which includes inter-tumor heterogeneity observed in breast cancers from different individuals and intra-tumor heterogeneity caused by the presence of heterogeneous cell populations within an individual tumor [[31], [32], [33]]. Several studies indicate that most tumor samples are a heterogeneous mixture of cells, including noncancerous cells and subpopulations of cancerous cells with different somatic aberrations [34,35].

Germline Mutations in Different Cancer Phenotype

Germline mutations in BRCA1 and BRCA2 (BRCA1/2) genes are present in about 50% of cases of hereditary breast cancer [48]. Progresses in next generation sequencing and the use of multigene panels for breast cancer testing [49] have generated a large amount of data on gene variants implicated in hereditary breast cancer, particularly in genes such as PALB2, ATM, CHEK2, RAD51, MSH2, and BARD1 [50] [Table1].Early onset diagnosis and family history of breast cancer are generally considered

Epigenetic deregulation

Epigenetics was used to describe the heritable changes in gene expression without causing any change in the DNA sequence itself. Epigenetics in breast cancer similarly to other cancers, have been well documented [84]. DNA methylation, histone acetylation, differentially expressed miRNAs, abnormal expression of lncRNAs, are the major epigenetic mechanisms observed in breast cancer. [16,85] (Fig. 1). It is known that different patterns of methylation are useful to distinguish breast cancer

Treatment Strategy According to the Cancer Genotype

Precision oncology start a new epoch two decades ago with two targeted therapies: trastuzumab to treat patients with HER2-amplified metastatic breast cancer and imatinib to treat patients with BCR–ABLfusion-positive chronic myelogenous leukaemia (CML) [94,95].Currently, genotype-directed therapies approved by different medicines agencies such as FDA, EMA, PMDA [[96], [97], [98]] are available for many different tumor types. Inhibitors of EGFR, ALK, and ROS1 are administered to patients with

Conclusions and Outlook

This review has focused on genome changes that lead the cell to become a tumor cell. However, it is clear that breast cancer represents a complex of diseases that require an integrated approach including pathological characterization, epigenetic, in addition to the genomics. Cross-talk genetic screening by incorporating germline mutations to stratify people with higher risk of cancer and somatic mutations to profiling the tumor genome for the right therapy can aid patient care. This is a clear

Funding Source

NO funding

Declaration of Competing Interest

No conflicts of interest

Acknowledgements

This work was supported in part by Italian Ministry of Health grant reference CUPE83C17000880001 to M.B. We are indebted to Graziano Bonelli for the kind help in the realization of the figure and Francesca Pisanu for the technical support. We thank the physicians and clinical staff of the PTV Breast Unit for their cooperation in patient’s management.

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