*This is the only report that comments on a putative novel breast cancer gene BRCAX (genes other than BRCA1 and BRCA2).
**Genetic alteration in the p53 gene leads to different types of cancer. P53 expression in breast cancer can be either sporadic or germline. When inherited as germline mutation, it leads to Li-Fraumeni syndrome.
The following topics are discussed in detail.
Germline Mutations:
Hereditary breast cancer results from germline mutations in the breast cancer genes. It is characterized by
- Onset at a young age
- Strong family history
- Involvement of tumours in other organs, particularly ovary and prostate gland
- Bilateral occurence
BRCA1 was first identified by Miki etal in 1994.
The gene locus for BRCA1 is 17q21. BRCA1 is a large gene, with 24 exons encoding a 220 kD nuclear protein (1863 amino acids). Two recognizable motifs are found. The amino terminus contains a RING finger domain and the C-terminus contains a BRCT domain. The RING finger in BRCA1 specifically interacts with another RING finger protein known as BARD1.[45] Both BRCA1 and BARD1 consists of an acidic C-terminus known as the BRCT domain which is a shared conserved feature and thus they are homologous to each other. The BRCT domain is involved in DNA repair, transcriptional co-activation and cell cycle regulation [46]. Recently, the crystal structure of the BRCT repeat region for BRCA1 was identified. [pubmed].
The BRCA1 protein also interacts with RAD51 protein, acting as a
gatekeeper in maintaining genome integrity. When there is DNA damage, BRCA1 causes transcriptional
activation of a growth suppressor protein known as P21 cyclin dependent
kinases. This enables cell cycle arrest at G1/S checkpoint.Therefore, any
loss of function in BRCA1 protein will result in accumulation of genetic defects
leading to cancer.
BRCA1 binds to BRCA2, p53, RAD51 and many other proteins involved in
cell cycle and DNA-damage response. A large number of
mutations (HGMD link) have been sequenced and described for BRCA1 in
Human Gene Mutation Database. Similarly, an online database - BIC
is available
that gives extensive information on BRCA1 & BRCA2 mutations. Exon 11 is
the largest exon and comprises
60% of the coding region for BRCA1 protein. It has been reported that
exon11 contains majority of the mutations and several of these are
frameshift mutations resulting in
missing or nonfunctional proteins.
The cumulative risk by age in BRCA1 predisposing mutations are shown by Easton et al. [table] [49]
| AGE (years) | Cumulative Risk (%) |
|---|---|
| 30 yrs | 3.2% |
| 40 yrs | 19.1% |
| 50 yrs | 50.8% |
| 60 yrs | 54.2% |
| 70 yrs | 85% |
| BRCA1 | OMIM | GDB | GenAtlas | GenCards | Locuslink | PDB structure | protein sequence | Gene sequence | Mutation map |
BRCA2 (13q12.3) was identified by Wooster et al in 1995. It encodes for 384 kD nuclear protein (3418 amino acids). BRCA2 bears no homology to any known tumour supressor genes. BRCA2 contains 27 exons spread over 70 kb of genomic DNA.
BRCA2 consists of eight BRC repeats consisting of 30-80 aminoacids which interact with RAD51 maintaining genome integrity [50]. RAD51 domain binds to eight BRC repeats. Similarly, the frameshift mutations reported for BRCA2 are mostly deletions, insertions, or nonsense mutations leading to premature truncation of protein. Furthermore, BRCA2 mutations are also associated with an increase in colon, prostate and pancreatic cancers, gallbladder and bile duct cancer, stomach cancer and malignant melanoma. BRCA2 accounts for 21% of male breast cancer.[cancerlit]
The cumulative risk by age in BRCA2 predisposing mutations are shown by Krainer et al [51]
| AGE (years) | Cumulative Risk (%) |
|---|---|
| 30 yrs | 4.6% |
| 40 yrs | 12% |
| 50 yrs | 46% |
| 60 yrs | 61% |
| 70 yrs | 86% |
| BRCA2 | OMIM | GDB | GenAtlas | GenCards | Locuslink | Gene sequence | Mutation map |
It has been found that BRCA2 is remarkably similar to BRCA1 in the following aspects :
- A large exon 11
- Translational start sites in exon 2
- Coding sequences rich in A-T
- Both span approximately 70 kb of genomic DNA and
- Expressed at high levels in testis and
- Both function as tumour suppressor genes.
Mutations in Sporadic Breast Cancer:
Approximately, 5% of the breast cancer occurs due to germline mutation in BRCA1 and BRCA2. The remaining 95% is due to genetic changes that takes place in a women's life. Somatic mutations are unique events as they occur only in tumour cells. The genes which undergo sporadic mutation are mostly the tumour suppressor genes (P53,RB1) and oncogenes ( ras,myc,neu ) as well as the genes that are involved in cell-cycle inhibition, cell-cell adhesion, angiogenesis, DNA repair and apoptosis.
One of the processes involved in this non-hereditary form of cancer is 'Methylation'. It is a biochemical process that alters the function of cancer-related genes by turning them off and on. Normal methylation allows the gene to function normally, but when the gene is ‘hyper’ methylated, it turns off inhibiting tumor-suppressing activities, thus leading to the initiation of cancer. Such an alteration is associated with 10% to 15% of breast cancers.[52] p53 stands for Tumour Protein with a molecular weight of 53 kD and
it's gene is located on the short arm of chromosome 17 (17p13.1). It
accounts for 12-46%
of sporadic breast cancer. When there is a
DNA damage, p53 acts as a negative regulator of cell growth in binding to
DNA sequences. When p53 protein
binds DNA, it stimulates another gene to produce a protein called p21 that
interacts with a cell division-stimulating protein (cdk2). If there is
any mutation in the p53 tumour suppressor gene, p21 protein cannot bind
the cdk2 protein and as as a result of this, the p21 protein is not made
available to
function as the
'stop signal' for cell division. Therefore, cells divide uncontrollably,
and
result in cancers [53]. A flowchart depicting the
function of p53 is given below:
| OMIM | GDB | GeneCards | PDB structure | Protein sequence |