Overview of the Genetic Basis Toward Early Detection of Breast Cancer

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Breast cancer is the most common type of cancer in women worldwide, and it affects women of all ages. As an important part of any community, a disease that disproportionately targets women can cause significant socioeconomic burdens on a community.

In this review, the authors report on genome, genetics, and epigenetics of cancer overall. They then turn the spotlight to breast cancer: nongenetic risk factors, genetic risk factors, hereditary syndromes, and how these influence screening and early detection, especially of disease recurrence; and the role of clinical, laboratory, and radiologic testing, especially in younger women, in mitigating the burdens of breast cancer.

Breast Cancer: Targets and Therapy
Breast Cancer: Targets and Therapy

Abstract: Cancer is a socioeconomical burden in any nation. Out of that, breast cancer is identified as the most common malignancy worldwide among women irrespective of age. As women are an important segment in a community, the weakening of their strength toward the development of a nation is a critical problem in each nation. In this review, it was aimed to discuss the characteristics of cancer genome, cancer genetics, and cancer epigenetics in general and then focus on discussing both genetic and nongenetic factors responsible for the predisposition of breast cancer in humans. More emphasis was placed on genes responsible for the early onset of the disease and which can be used as genetic tools in the identification of the disease at an early stage. Then the context of genetic involvement toward the breast cancer occurrence before age of 40 years was highlighted accordingly. In addition to genetic testing, the review paid adequate attention to mention novel liquid biopsy techniques and other clinical, laboratory, and radiologic assessments. These techniques can be used in early detection and recurrence as well as the surveillance of the patients after primary therapies.

Keywords: breast cancer, genetic predisposition, early onset, recurrence  


Cancer can be defined as a complex human disease where growth of a group of abnormal cells occurs uncontrollably, disregarding the normal rules of cell division. With a few exceptions, cancers are derived from single somatic cells and their progeny. The cells in emerging neoplastic clone accumulate a series of genetic and epigenetic alterations that tend to modify gene activities of a number of genes and their products causing various phenotypic changes.1

Normal cells are subjected to signals that regulate whether the cell should divide, differentiate into another cell, or die. However, cancer cells develop a degree of autonomy for these signals and lead to uncontrolled cell growth and proliferation without regulation. As a result, six “hallmark features” of the cancer cell phenotype have been identified by Hanahan and Weinberg, namely self-sufficiency in growth, insensitivity to antigrowth signals, evading apoptosis, limitless replicative potential, sustained angiogenesis and tissue invasion, and metastasis.2 Due to theoretical progression in cancer field in the last decade, another two emerging hallmarks have been added to the list, namely reprogramming of energy metabolism and evading immune destruction.3 Apart from these, genomic instability and inflammation have been identified as two enabling characteristics of cancers. In hereditary cancers, genomic instability occurs as a result of mutations in DNA repair genes and leads to cancer development, which is predicted by the mutator hypothesis.4 Inflammation promotes multiple hallmark functions by supplying bioactive molecules to the tumor microenvironment, including growth factors. Thus, inflammation is a critical component in tumor progression.3,5

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Cancer genome

Cancers are thought to share a common pathogenesis. Similar to Darwinian evolution of origins of species, cancer evolution and development are based on two constituent processes. These are continuous acquisition of heritable genetic variation (inherited mutation) in individual cells by more-or-less random mutation and natural selection acting on the resultant phenotypic diversity. The natural selection may promote cells carrying alterations that confer the capability to proliferate and survive more effectively than their neighboring cells or eradicate those cells that acquired the mutations. A single cell occasionally acquires a set of sufficiently advantageous mutations that allow a cell to proliferate autonomously, invade tissues, and metastasize during the selection.6

The DNA sequence of a cancer cell genome as well as most normal cell genomes has acquired a set of differences from its progenitor fertilized egg. These are collectively termed somatic mutations to distinguish them from germline mutations that are inherited from parents and transmitted to offsprings.6 Somatic mutations namely driver and passenger mutations in a cancer cell genome are acquired from several different sources such as substitution of bases, deletions and insertions of DNA fragments, and rearrangement and amplification of DNA sequence. Furthermore from exogenous sources where completely new DNA sequences are acquired from viruses such as human papilloma virus, Epstein–Barr virus, and hepatitis virus.7,8

Driver mutations are positively selected during the evolution of the cancer that gives growth advantage, tissue invasion and metastasis, angiogenesis, and evasion of apoptosis, whereas passenger mutations do not give growth advantage and therefore do not contribute to cancer development. By definition, driver mutations reside in a subset of genes known as “cancer genes”, whereas passenger mutations are mutations that were present in the progenitor cell of the final clonal expansion of the cancer and are biologically neutral.9 Thus, identification of driver mutations and the cancer genes is the main goal in cancer genome analysis. Systematic sequencing of more than 25,000 cancer genomes at the genomic, epigenomic, and transcriptomic level revealed the evolutionary diversity of cancers and implicated a larger range of cancer genes than previously anticipated.10 The Cancer Genome Project is utilizing the human genome sequence and high-throughput mutation detection methods to identify somatically acquired sequence variants and thereby identify critical genes in the development of cancers in humans.11

The cancer genome will also be able to acquire epigenetic changes that alter chromatin structure and gene expression when compared to the fertilized egg. Then it is manifested at DNA sequence level by changing the level of methylation of some cytosine residues.6 The epigenetic changes are stably heritable from the mother to the daughter cell and they generate phenotypic effects for selection to act on. Furthermore, somatic mitochondrial DNA mutations have been identified in primary human cancer types but their roles in the development and progression of cancer are not yet established by means of possible diagnostic and therapeutic implications.12

Mutations in a cancer cell genome have accumulated over the lifetime of the cancer patient. Due to internal and external mutagens, a cell is continuously damaged but most of the damage is repaired. However, due to low intrinsic error rate in the DNA replication process, a small fraction of damage may be retained as fixed mutations. Mutation rates increase in the presence of exogenous mutagenic factors such as tobacco, some carcinogens, naturally occurring chemicals like aflatoxins from fungi, or harmful radiations like ultraviolet radiation.

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