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Insights into Breast Cancer Genetics
During the early part of 1990s, scientists have discovered mutations in the p53 gene which is present on the 17th chromosome to be responsible for causing Li-Fraumeni syndrome. The mutation in Li-Fraumeni syndrome is associated with increased breast cancer risk, sarcomas and various other types of tumors including brain tumors. In the year 1997, mutations in the PTEN gene, on chromosome 10 have been linked to Cowden's syndrome. Presence of Cowden's syndrome is associated with higher risk of breast cancer, and lesions in the skin. Cowden's syndrome may be associated with elevated risk of breast cancer, and lesions on the skin. Recent research has demonstrated that mutation in the STK11/LKB1 gene, which is located on the 19th chromosome, is associated with Peutz-Jeghers syndrome. Peutz-Jeghers syndrome has been associated with gastrointestinal malignancies, breast cancers and hamrtomas. Gene mutations in MLH1 and MLH2 are associated with Muir-Torre syndrome, which has been shown to be associated with increased risk of genitourinary system tumors, gastrointestinal system abnormalities and breast cancer.
A major milestone in our understanding of molecular basis of breast cancer was achieved with the discovery of breast cancer associated genes 1 and 2 known as BRCA1 and BRCA2. Discovery and characterization of these two breast cancer associated genes have revolutionized our understanding of genetic factors involved in the breast cancer development. Mutations of BRCA1 and BRCA2 are associated with higher risk levels of breast cancer. Women who carry these mutations also have a higher risk of development of breast malignancy starting at a younger age. In addition to the increased risk of breast malignancy, BRCA1 and BRCA2 carriers are at high risk for having ovarian cancer, and various other types of malignancies. When a young woman presents with breast cancer the chance of that being BRCA1 or BRCA2 related breast cancer should always be explored. Breast cancer that develops because of BRCA1 mutation is usually more aggressive compared to garden variety breast cancer that a woman may develop without BRCA1 mutation. Breast cancer that develops because of BRCA1 mutation also tend to be hormone negative, however it is known if the overall survival is different from breast cancer, which is not associated with BRCA1 mutations. In contrast to BRCA1, 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. An educatedl estimate of BRCA1 in the population ranges from 1 in 500 and 1 in 800. BRCA2 mutations rates in the general population is lower than BRCA1. However some ethnic groups like Ashkenazi Jews have very high risk of harboring these mutations. Much of the information that we know on these genes came from population 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 women. Most common site of mutation in BRCA1 is called as 185delAG. Approximately a quarter of all women with Ashkenazi background, who are diagnosed with breast malignancy at or below age of 40-years might have a mutation in one of these genes.
BRCA1
BRCA1 is located on chromosome 17 and has a very complex structure and unclear function. Aberrations on the BRCA1 gene can happen in various areas of this big sized gene and so far more than 500 different kinds of mutations are identified. BRCA1 mutations are inherited in an autosomal dominant pattern, which would mean the manifestations of the abnormal gene could be seen even with the passing of one copy of the abnormal gene from any one of the two parents.
Mutations in the BRCA1 gene are associated with higher risk of breast cancer during the lifespan of the woman carrying the abnormal gene. A woman possessing BRCA1 mutation has approximately 56 to 85 percent risk of having breast cancer in her lifetime. In addition to the risk of having breast cancer, mutations of BRCA1 gene are also linked to increased risk of ovarian cancers and prostate cancers in the carrier of the mutated gene. The link between BRCA1 mutation and cancer of the ovaries is very strong and a woman harboring a mutation in the BRCA1 gene has about 15 percent to 45 percent risk of developing ovarian cancer diagnosis in her lifetime. In comparison only about 1.8 % of women without an demonstrable abnormalities in the BRCA genes get ovarian cancer. The link between prostate cancer and males who harbor of BRCA1 mutations is not as strong in comparison to breast cancer and ovarian cancer risk levels, seen in women, but evidence shows there is a close link between the two.
BRCA2
BRCA2 is a large tumor suppressor gene, which encodes for a 384 kD protein with 3418 amino acids. BRCA2 gene is about twice the size of BRCA1 gene and has a complex structure and unclear function. Unlike BRCA1, male carriers of BRCA2 gene are found to have an increased risk of having of a diagnosis of breast cancer. Prevalence rate of male breast cancer is very low and is about 1/100 of the of breast cancer rates in women. Because of this all male patients with breast cancer should be assessed for the possibility of BRCA2 gene abnormalities, particularly if they have other family members who had a diagnosis of breast cancer in the past. Men who carry BRCA2 gene have about 6 % chance of developing breast cancer during 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. BRCA2 mutations are also associated with higher risk of ovarian cancer, pancreas cancer and malignant melanoma of the skin. When combined together BRCA1 associated breast cancers and BRCA2 associated breast cancers would account for most of the genetic breast cancers that occur in women.
Posted by: Adona