Last few decades have witness significant advancement in our understanding of the genetic and molecular basis of breast cancer. Most researchers believe in a "two hit theory" for the causation of breast cancer in patients who have inherited a genetic abnormality that causes an increased risk of breast cancer. This theory assumes that eventhough these women are born with a specific a genetic abnormality with high risk of breast cancer development, additional insults induced by the environment may be actually mandatory to cause the process of breast cancer development.

In early part of 1990s, scientists have discovered mutations for the gene that is responsible for p53 protein, (located on the chromosome 17) to be responsible for causing Li-Fraumeni syndrome. Li-Fraumeni syndrome is responsible for increased breast cancer risk, sarcomas and other tumor types. In 1997, genetic mutations in the PTEN gene, which is located on the 10th chromosome, have been shown to be associated with Cowden's syndrome. Cowden's syndrome is correlation to higher risk of developing breast cancer, and characteristic skin lesions. Cowden's syndrome is correlated with elevated risk of breast malignancy and skin lesions. Recently it has been shown that mutations involving STK11/LKB1 gene, which is located on the 19th chromosome, is associated with Peutz-Jeghers syndrome. This syndrome is linked with breast cancer, gastrointestinal malignancies and hamartomas. Mutations in MLH1 and MLH2 are associated with Muir-Torre syndrome, which has been shown to be linked to elevated risk of breast malignancy, and tumors involving the genitourinary system and gastrointestinal systems.

A major breakthrough in unraveling of the mysteries of breast cancer genetics was achieved with the identification of BRCA1 and BRCA2 also known as breast cancer associated gene 1 and 2. Identification and analysis of these two breast cancer associated genes had very significant impact on our understanding of breast cancer genetics. BRCA1 and BRCA2 mutations are linked to higher risk levels of breast cancer. Carriers of these mutations also have a higher risk of development of breast malignancy even at a younger age. Apart from increased risk of breast malignancy, BRCA1 and BRCA2 carriers are at high risk for develpment of ovary cancer, and various other types of cancers. Whenever a young woman presents with breast cancer the chance of that being BRCA1 or BRCA2 mutation should always be explored. BRCA1 associated breast cancer is commonly more aggressive in comparison to garden variety breast cancer that develop without BRCA1 mutation. BRCA1 associated breast cancer also tend to be hormone negative, however it is known if the overall out come is different from breast cancer, which is not linked to BRCA1 mutations. Conversely BRCA2 associated breast cancer are likely to resemble the regular garden variety breast cancer, which is not linked to any genetic mutations.

The exact occurence rate of BRCA1 and BRCA2 mutations in the larger population is not very clear. The general estimate of BRCA1 in the population ranges from 1 in 500 and 1 in 800. The estimated occurence rate of BRCA2 mutations in the general population is lower than BRCA1. However certain ethnic groups like Ashkenazi Jews have very high risk of harboring these mutations. Most of the information that we know on these genes came from studies on high risk populations. The occurence rate of BRCA1 and BRCA2 mutations in Ashkenazi Jewish women may be as much as 1 in 40. Most common mutation in BRCA1 is called as 185delAG. About a quarter of all women with Ashkenazi background, who are diagnosed with breast cancer at or below age of 40-years may have a mutation in one of these genes.

BRCA1
BRCA1 is a large gene, located on chromosome 17 and has a very complex structure and unclear function. Mutations on the BRCA1 gene can happen in various areas of the large gene and so far more than 500 different types of mutations are identified. Siblings inherit BRCA1 mutations as an autosomal dominant pattern, which would mean the manifestations of the abnormal gene can be seen even with the inheritance of one copy of the mutated gene from any one of the two parents.

BRCA1 mutations are linked to higher risk of breast cancer during the lifespan of the person carrying the abnormal gene. A woman carrying BRCA1 mutation has approximately 56 to 85 percent risk of developing breast cancer in her lifetime. Apart from the risk of having breast cancer, mutations of BRCA1 gene are also linked to increased risk of ovary cancers and prostate cancers in carrier of the abnormal gene. The association of BRCA1 mutation and cancer of the ovaries is very strong and a woman harboring BRCA1 mutation has about 15 percent to 45 percent chance of developing ovary cancer in her lifetime. By comparison only about 1.8 % of women without an demonstrable BRCA abnormality get ovary cancer. The association between prostate cancer and males who harbor of BRCA1 mutations is not as strong compared to breast cancer and ovary cancer risk, seen in women, but evidence shows there is a close relationship between the two.

BRCA2
Breast cancer Associated gene 2 or BRCA2 is a large gene found on the 13th chromosome. BRCA2 is about twice the size of BRCA1 gene and has a complex structure and unclear function. In contrast to to BRCA1, male carriers of BRCA2 gene are found to have an increased risk of having of breast cancer. The occurence rate of male breast cancer is very low and is about 1/100 of the of breast cancer rates in women. Hence all male breast cancer patients should be assessed for the possibility of BRCA2 gene abnormalities, particularly if they have other family members who had breast cancer in the past. BRCA2 carrier men have about 6 % chance of developing breast cancer in his lifetime. In contrast to BRCA2, men who carry BRCA1 do not appear to have any significantly increased risk in the development of breast cancer. Mutations in the BRCA2 gene are also linked to higher risk of ovary cancer, pancreatic cancer and cancerous melanoma. Taken together BRCA1 and BRCA2 account for most of the genetic breast cancers that occur in women.

Posted by: Loraine

---