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Latest breast cancer news
No Increased Risk Of Breast Cancer With Estrogen Alone HRT 4/15/2006
Breast cancer genetics
In the last few decades, marked advancement and progress was made in our understanding of molecular basis of breast cancer. Most researchers hold a two hit hypothesis for the causation of breast cancer in patients who have inherited a genetic defect. This means that although the patient is born with a genetic defect that would predispose them to higher risk of breast cancer, additional insults from the environment may be actually required to cause the initiation of breast cancer.
In early 1990s scientist identified mutations in the p53 gene (located on the chromosome 17) to be responsible for the causation of Li-Fraumeni syndrome. Li-Fraumeni syndrome is associated with increased risk of breast cancer, sarcomas and other tumor types. In 1997 mutations in the PTEN gene on chromosome 10 have been shown to be associated with Cowdens syndrome. Cowdens syndrome is associated with increased risk of breast cancer, and skin lesions. Recently it has been shown that mutations in the STK11/LKB1 gene on chromosome 19 are associated with Peutz-Jeghers syndrome. This syndrome is associated with increased risk of breast cancer, gastro-intestinal system cancers and hamartomas. Mutations in MLH1 and MLH2 are associated with Muir-Torre syndrome which is associated with increased risk of breast cancer, genitourinary system and gastro-intestinal system tumors.
A major breakthrough in our understanding of molecular basis of breast cancer came with the discovery of breast cancer associated genes 1 and 2 known as BRCA1 and BRCA2. Identification and characterization of these two genes has revolutionized our understanding of breast cancer genetics. BRCA1 and BRCA2 mutations are associated with increased risk of breast cancer and the carriers of these mutations also have an increased risk of development of breast cancer even at a younger age. Apart from increased risk of breast cancer, BRCA1 and BRCA2 are associated with increased risk of ovarian cancer, and various other types of cancers. When a young woman develops breast cancer the possibility of BRCA1 or BRCA2 mutation should always be explored. BRCA1 associated breast cancer is usually of higher-grade compared to breast cancer that develop without BRCA1 mutation. BRCA1 associated breast cancer also tend to be hormone receptor negative, however it is not clear if the overall out come is different from breast cancer not associated with BRCA mutations. On the other hand BRCA2 associated breast cancer tends to resemble the regular breast cancer, which is not associated with any genetic mutations.
The exact incidence of BRCA1 and BRCA2 mutations in the general population is not very clear. The general estimate of BRCA1 in the general population ranges from 1 in 500 and 1 in 800. The estimated incidence of BRCA2 mutations in the general population is smaller than BRCA1. However certain ethnic groups are associated with a very high risk of these mutations. Most of the information that we have on these genes have come from studies on high risk populations. BRCA1 and BRCA2 mutations are very common in the Ashkenazi Jews. The incidence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish population may be as high as 1 in 40. Most common mutation in BRCA1 is designated as185delAG. About a quarter of all patients with Ashkenazi background who develop 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 the 17th chromosome and has a very complex structure and function. Mutations on the BRCA1 gene can occur in various parts of the large gene and so far more than 500 different types of mutations are identified. BRCA1 mutations are inherited in an autosomal dominant pattern, which means the manifestations of the mutated gene can be seen even with the inheritance of one copy of the mutated gene from any one of the parents. As mentioned above BRCA1 mutations are associated with increased risk of breast cancer. A woman carrying BRCA1 mutation has about 56 to 85 percent chance of developing breast cancer in her lifetime. Apart from the risk of development of breast cancer, BRCA1 mutations are associated with increased risk of ovarian cancers and prostate cancer in the male carrier of the gene. The association of BRCA1 mutation and ovarian cancer is very strong and a woman carrying BRCA1 mutation has of 15 percent to 45 percent chance of developing ovarian cancer in her lifetime. By comparison only about 1.8 percent of women without an inherited BRCA abnormality get ovarian cancer. The association of prostate cancer with male carriers of BRCA1 is not as strong compared to breast cancer and ovarian cancer risk, but evidence suggest there is a close relationship between the two.
BRCA2
BRCA2 is again a large gene located on the 13th chromosome. BRCA2 is about twice the size of BRCA1 gene and has a complex structure and function. Male carriers of BRCA2 gene also have an increased risk of development of breast cancer. The incidence of male breast cancer is very small and is about 1/100 of the incidence of breast cancer in women. Hence all male patients with breast cancer should be evaluated for the possibility of BRCA2 gene mutations, especially if they have other family members who had breast cancer in the past. BRCA2 carrier men have about 6 percent chance of breast cancer development in his lifetime. In contrast BRCA1 mutation in a male carrier does not significantly increase the risk of breast cancer. BRCA2 mutations are also associated with increased risk of ovarian cancer, pancreatic cancer and malignant melanoma. Together BRCA1 and BRCA2 account for the most of the genetic breast cancers.
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