breast cancer inheritance

The involvement of a parent with a similar diagnosis is a frequent finding in the histories of people diagnosed with breast cancer. However, several researchers have shown that genetic mutations are responsible for 10% or fewer breast cancer cases (Foulkes). Mutations in the breast cancer susceptibility genes (BRCA 1 and BRCA 2) are the most common pathogenic genetic mutations in inherited breast cancer. These genes are classified as tumor suppressor genes, which is a catch-all name for a group of genes. The occurrence of mutations in the BRCA1 and BRCA2 genes in the general population is estimated to be between 1:800 and 1:1000. (Risch et al.). The prevalence figures are higher, however, in individuals with a positive family history of breast and/or ovarian cancer, diagnosis of breast cancer in young relatives or a male relative exacerbates the risk further (Malone et al.). Ford et al. found that hereditary breast and ovarian cancer (HBOC) syndrome, which is associated with mutations in genes BRCA1/2,accounts for 5% annual breast cancer cases in the United States. HBOC was also linked with 90 percent of families with multiple cases of breast and ovarian cancer (O’Donovan and Livingston).

Mutations in other tumor suppressor genes such as P53 has also been associated, albeit less commonly, with breast cancer along with other hereditary cancer syndromes such as Li-Fraumeni syndrome.

BRCA1 and BRCA 2 Genes

Structure of the BRCA1Gene

The BRCA1 gene on chromosome 17q21 was first described by Miki et al in 1994.It was identified to contain 22 exons spanning about 80kb of DNA, encoding 1863 amino-acid proteins.The structure of coded protein possess has recognized motifs. The BRCA1 gene contains RING finger domain near the N-Terminal. On the other hand, the C-Terminal there is a BRCT domain. An interaction of protein-DNA or protein-protein transmission is mainly maintained by hystidines and cysteines, whereby the ring finger is characterized by zinc-binding domains (Chen 1754s).

The BRCA1 RING domain facilitates ubiquitin ligase activity and associations/interactions of BRCA1 with other proteins (Clark et al.). BRCA1 closely associates with cell cycle regulating proteins and other tumor suppressor genes such as BRCA2, p53, RAD51 in response to DNA-damage (Bork et al.; Brose et al.). Encoded phosphoprotein binds with other suppressor genes and intrinsic DNA damage sensors forming a larger protein complex called a BRCA1- associated genome surveillance complex (BASC). BASC interacts with RNA polymerase and histidine deacetylase complexes to enact DNA double strand break repairs and recombination as well as facilitating transcription (“BRCA1, DNA Repair Associated [Homo Sapiens (human)] - Gene - NCBI”).BRCA1 consists of two NLSs (nuclear localized signals which are situated on the Exon 11.Exon 11 is found to be enormous as it codifies about 60% of the coding region of BRCA 1 protein. Exon 11 contains the highest numbers of mutations , whereby some of the mutations are frame shift which lead to nonfunctional proteins.

Fig 1. BRCA1 protein

(Image adapted from: Breast cancer genetics: What we know and what we need May 2001, vol. 7)

Structure of the BRCA2 Gene

The BRCA2 is a larger gene than BRCA1. The gene is located on chromosome 13q12-q13. It has 27 exons, encodes a 384 KD nuclear protein(Rosen et al.). studies by Wong et al and Bork, Blomberg, and Nilges have demonstrated 39 repeat amino acid patterns that are essential in the interaction of BRCA2 withtumor suppressor genes RAD51 to confer resistance to methyl associated genetic mutations.

Fig 2. BRCA2 protein

(Image adapted from: Breast cancer genetics: What we know and what we need May 2001, vol. 7)

Functions

BRCA1 and BRCA2 as tumor suppressor genes are cardinal in the maintaining the integrity of DNA. The genes are integral in controlling of cell cycle checkpoint responses (Brose et al.), chromosomal segregation and repairing breaks in the DNA strand as well as transcription (Huen, Sy, and Chen; O’Donovan and Livingston).BRCA 1 functions well in both repairing the DNA and checkpoint activation. BRCA 2 acts a mediator in the core mechanisms involving homologous recombination. Both proteins work harmoniously in protecting the genome from double strand DNA damage. During replication of the DNA.BRCA2 interacts with RAD51, while binding with the single strand DNA in the stimulation of strand invasion. Localization of the RAD51 to the double strand DNA, needs the formation of BRCAI-PALB2-BRCA2 complex.PALB2 incorporates with BRCA2 chimera and functions synergistically to promote the strand invasion. The double strand breaks are associated with natural and environmental exposures and during meiosis. The double strand breaks, are also generated during repair of the DNA. The BRCA1 AND BRCA2 protein maintains stability of human genome and prevents some form of gene rearrangement that causes other types of cancer. BRCA2, regulates activities of other genes and helps in embryo development.

Roles of BRCA1 and BRCA 2 in DNA repair

Image retrieved from http://www.cancer-biomarkers.com/2012/06/hereditary-breast-and-ovarian-cancer.html

The above model describes the functions of macromolecular complex

(BRCA1,BRCA2, BARD1 and Rad51 functions in repairing the damaged DNA.

Most Common Gene Mutations that Cause Breast Cancer

BRCA1 and BRCA2 Mutations

Mutations can occur throughout the coding region in the BRCA1 and BRCA2 genes, however, most lead to truncated protein when translated. Most pathogenic mutations in these genes are deletions, which facilitates manifestation of features due to tumor suppression roles. Mutations often occur in 3 major regions of BRCA1 gene-encoded proteins; the amino-acid (N) terminal RING domain, at exons 11(where majority of exon associated mutations occur) through 13 and the BRCT domain. (Clark et al.).

Rebbeck et al. found that Mutations were can be grouped by type and function as frame shift, nonsense, missense, and splice site. In BRCA1- mutation associated tumors, additional genetic abnormalities in other tumor suppressor genes, and microdeletions has been observed (Saal et al.). Thompson and Easton reported variations in risk of breast and ovarian cancer depending on theposition of mutation at exon 11. Increased risk for ovarian vs breast cancer was reported in individuals with germline mutations in central portions of exon 11.

Consequences of BRCA1 and BRCA2 mutations

70% of ovarian cancers are of the serous subtype, with about 16-21 %of these found to have BRCA1 or BRCA2 mutations (Press et al.). It has been observed, however, high grade serous ovarian cancers are associated with BRCA1 and BRAC2 mutations in addition to mutations in other tumor suppressor genes; TP53, RAD51C. Primary fallopian tube and peritoneal cancers are also closely associated with these mutations (Liu et al.)

Mutations in BRCA1 and BRCA2 genes are inherited in an autosomal dominant pattern and are highly penetrant. Women with BRCA1 and BRCA2 mutations have markedly increased susceptibility to breast cancer, with a lifetime risk of 50 to 85 percent (Chen and Parmigiani). Males with BRCA gene mutations are 5 to 10% more likely to develop breast cancer than men without the gene mutation. A 50 percent chance of passing on the abnormal gene to children exists be both males and females who are carriers (Liede et al.).

Inheritance of the mutation gene

Mutations can be inherited by the parents and can be passed on to the children. Regardless of the sex, each child who is of genetic carrier is at risk of acquiring and inheriting the mutated gene. Half of the people with BRCA gene mutations are male who are capable of passing on the mutation to 50% of the offspring, whether male or female. Only about 5-10% of breast cancer cases are attributed to both types of mutations with BRCA1 being the most common. However, a high risk mutation is not a guarantee that the woman will contract cancer

Other Genes Related to Breast Cancer

The BRCA1 associated RING doman1 (BARD1) gene is a growing interest in screening for breast cancer susceptibility genes. Both BARD1 and BRCA1 possesses structural and functional similarities; amino-acid (N) terminal RING-finger motif. BARD1 is composed of 11exons spanning 85kb region of DNA and encodes a 777 amino acid protein (Klonowska et al.). These proteins form a heterodimer with BRCA1 that stabilizes both proteins that are essential for tumor suppression and been discovered involved in DNA repair and cell cycle regulation (Karppinen et al.).

The Cys557Ser allele variant of the BARD1 gene that arises from missense alteration was noted to be predominant in women with increased risk of breast cancer, thence implicated as well (Stacey et al.).The BARD 1 cysteine 557 is a conserved amino acid that is found between the ankyrin repeats and the domain of the protein(BRCT).

The relationship of BARD and BRCA

Retrieved from

http://flipper.diff.org/app/pathways/Ubiquitination

The above diagram shows the interaction of BARD1 with the N terminal region of BRCA (BRCA1-associated RING domain 1)

Breast Cancer Gene Mutations Diagnostic Methods

BRCA1 and BRCA2 testing

A gene panel for BRCA1 and BRCA2 genes involves sequence analysis performed alongside deletion/duplication analysis (Petrucelli, Daly, and Pal). Owing to the large numbers and different mutations that have been identified in the BRCA genes, targeted analysis for three pathogenic variants (BRCA1 c.68_69delAG (BIC: 185delAG) BRCA1 c.5266dupC (BIC: 5382insC), and BRCA2 c.5946delT) predominant in up to 99% of individuals of Ashkenazi decent has been suggested at initial test (Palma et al.).

BARD1 gene testing

Diagnosis of BARD1 gene mutation is diagnosed through theuse of exome sequencing (Churpek et al.)

Conclusion

The importance of identifying and appreciating theinfluence of genetics as a critical risk factor for breast cancer cannot be overstated. With the ever emerging and broadening data and testing of susceptibility genes BRCA1/2, the relatively newly researched BARD1 genes, better screening opportunities are being forged for individuals at risk. It is essential to encourage genetic screening in individuals, both male and female, hence, deemed at risk of being carriers or inheriting the mutated genes.

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