OVERVIEW
The establishment of a clear relationship between BRCA genes and their roles in breast cancer formation has been a great leap in the development of oncology, providing a link between genetics and cancer in a time when cancer was thought to be only viral. In this article, we’ll discuss how the inactivation of the BRCA1 genes may lead to breast cancer and other risks.
WHAT ARE BRCA GENES?
BRCA1 and BRCA2 are genes commonly called tumor suppressors, responsible not only for producing proteins to repair damaged DNA, but also transcriptional regulation, and are therefore critical for the prevention of cancer. In simple words, transcriptional regulation is the control of the conversion of DNA to RNA for gene expression, whereas DNA repair is a much more complicated process. On the occurrence of DNA damage, BRCA proteins in healthy cells form part of a complex in a repair mechanism called homologous recombination. This complex utilises a homologous sequence from a sister chromatid, or a homologous chromosome as a template to correct the DNA.
Through studying cultured embryonic stem cells with BRCA deficiency(Ralph Scully & David M. Livingston, 2000), scientists found that they displayed chromosomal abnormalities including severe aneuploidy (having an abnormal number of chromosomes) and centrosome amplification (a condition in which centrosomes appear larger than normal). These are often closely linked to cancer, which suggests BRCA genes’ role as tumor suppressors.
BRCA genes contain an unusually high density of repetitive elements, building a basis for the mutation of the said genes. For instance, the BRCA1 genomic region consists of 42% Alu sequences and 5% non-Alu repeats, while the BRCA2 region has 47% repetitive DNA, with 20% Alu sequences and 27% other repetitive DNA. (Piri L. Welcsh & Mary-Claire King, 2001) Alu sequences, being transposable elements, are commonly called the “jumping gene”. They have a special “copy and paste” mechanism, which allows them to move to new positions within the genome of a single cell. As a result of the high density of repetitive elements in BRCA1 and BRCA2, Alu-mediated genomic arrangements, in which somatic genetic alteration can occur, are often observed within these genes.
RISKS
The relationship between BRCA mutation and breast cancer was uncovered by Mary Claire King, who later received a Shaw Prize in 2018 for her great discovery. Her research, combined with recent epidemiological studies on families with evidence of linkage to BRCA1, suggests that BRCA1 and
BRCA2 mutation carriers have up to 81% lifetime risk of breast cancer, while individuals with normal BRCA function have a low 8%. (Meilin Zhu, 2017)
WHY BREAST CANCER SPECIFICALLY?
Although there may not be a solid answer, it is most likely that the crucial link is estrogen. In the University of Texas Health Science Center at San Antonio, 2017, a group of researchers conducted a study to explain BRCA1’s tissue specificity. (UT Health San Antonio, 2017) After collecting human breast tissue specimens from oncologists, the team compared those of BRCA1 mutation carriers and non-carriers, providing fascinating findings. They proposed that gene expression- related stress is higher in BRCA mutation carriers, and only in luminal epithelial cells where breast cancer originates. In those luminal epithelial cells, the stress is the highest in estrogen responsive genes.
Gene expression can be understood as the process of cells “switching on” genes to carry out functions. It is possible that changes of expression in certain genes can cause damage to DNA, resulting in formation of abnormal structures labelled as “stress”. The breast, being one of the biggest estrogen responsive sites in the human body, is thus largely affected by BRCA gene expression. Upon mutation or inactivation of the BRCA genes, it is also the most susceptible to cancer.
MUTATIONS AND INACTIVATION
Now let’s move on to how changes within BRCA genes, namely mutations and inactivation, increases cancer susceptibility. Mutations are “mistakes” made during DNA replication, rearrangements between repetitive elements, or during large genomic rearrangements. However, inherited BRCA mutations are more commonly seen, which can be identified as heterozygous germline pathogenic variants. BRCA mutations are carried in an autosomal dominant pattern, which means one copy alone is enough to increase the possibility of breast tumorigenesis greatly. Due to its heterozygous nature, offspring of mutation carriers have 50% chance of inheriting the mutated allele. Mutated BRCA genes may not produce effectively functioning proteins, for example, and result in more DNA mutations and eventually uncontrollable cell division, which lead to cancer.
On the other hand, inactivation of an allele can be caused by the deletion of a chromatin loop containing a large portion of BRCA1 or BRCA2 through homologous recombination between repeat sequences. Besides, mutations can also be due to somatic inactivation. An inactivating allele can bring about BRCA deficiency, which results in chromosomal instability because they are not able to repair DNA efficiently. Hence, forming the pathogenic basis for breast tumor formation.
TO CONCLUDE
All in all, the high density of repetitive elements in BRCA genes, responsible for tumor suppression, is a factor contributing to its somatic alteration and inactivation. Mutations can also be inherited in an autosomal dominant pattern. Through the production of dysfunctioning proteins, such mutated or inactivated alleles can cause breast cancer due to it being one of the body’s biggest estrogen responsive sites. Lastly, looking into the future, we can hope for the creation of new methods for the detection and treatment for women with BRCA1 and BRCA2 mutations.
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