Family History Of Breast Cancer An Genetic Factors

GENETIC FACTORS

In the development of breast cancer there are two genes involved almost total probability:

BRCA1 gene

The BRCA1 gene is located on the long arm of chromosome 17 (17q21). The entire gene consists of approximately 100 kb and is composed of 24 exons (sequences that code for protein) of which 22 are transcribed, resulting in an mRNA of 7.8 kb in length which translates into a protein of 1863 amino acids.

The BRCA1 gene is a tumor suppressor function: this is shown because the tumor cells of female carriers show loss of heterozygosity (ie, while non-cancerous cells only one copy of the gene is mutated in tumor cells both copies are mutated) Additionally, when you enter the normal BRCA1 gene to breast tumor cell lines and ovarian cancer, inhibits tumor development. This gene could also play a role in the development of apoptosis or programmed cell death.

It has been postulated that the BRCA1 protein can activate transcription through different mechanisms. One of them is through a command of type "zinc fingers", close to the C-terminal. The zinc ring region of BRCA1 interacts with the zinc ring close to the N-terminal protein BARD1 (BRCA1 ring domain1), creating a heterodimer. BRCA1 and BARD1 probably cooperate in the recognition of specific DNA sequences, as is well known that many transcription factors bind to DNA only after forming heterodimers. Other mechanisms are activation of transcription through its union with: BAP1 (activator protein-1 BRCA1) and probably by binding to p53 through its BRCT domain (BRCA1 C-Terminal)

It has also been observed that BRCA1 has three nuclear localization signal sequences that allow the protein to move from the cytoplasm to the nucleus. The most recent evidence that BRCA1 is the core function is its ability to bind to RAD51, a protein that is involved both in the process of meiotic recombination and in repair of chromosome breaks.

BRCA2 gene

After the discovery of BRCA1 was observed that many of the families with a clearly hereditary pattern of breast cancer showed no mutations in this gene, which was suspected the existence of a second susceptibility gene for breast cancer.

The BRCA2 gene was discovered in 1994 and cloned and sequenced in 1995, with a risk profile similar but not identical to the gene BRCA1. The risk of breast cancer, ovarian cancer and male breast cancer is increased for carriers and BRCA2 mutation carriers. In addition, high risk for developing prostate cancer, pancreas, colon and others have been associated with BRCA2 gene. Families that have mutations in a region of 3.3 kb in exon 11 have a higher frequency of ovarian cancer . For that reason this region is known as OCCR, suggesting that this region is important for regulating specific tissue in the ovary.

The BRCA2 gene mutational spectrum is becoming better known, more than 100 mutations have been identified.Mutations in BRCA2 are spread along the coding sequence and have not been detected regions that mutate more frequently. Most mutations produce truncated proteins, mainly due to insertions and deletions.

This gene is expressed in most tissues at very low levels, with high expression in testis. Al igual que ocurre con BRCA1, presenta altos niveles de expresión en células epiteliales mamarias en rápida proliferación. As with BRCA1, has high levels of expression in mammary epithelial cells rapidly proliferating. Also this expression is highest around the transition from G1-S. Its expression is increased by glucocorticoids and decreased by deprivation of growth factors. Ongoing studies suggest that BRCA2 probably also has nuclear localization signals.

BRCA2 protein appears to interact directly with RAD51 through two binding sites, one in the center and another in the BRC terminal region of the protein, suggesting a role in recombination and in repairing double-strand breaks in DNA, processes in which RAD51 participates.

The BRCA2 gene is involved in DNA repair process. It has been a marked sensitivity of BRCA2-deficient cells to various genotoxic agents but the mechanisms of apoptosis and cell cycle regulation remain intact. In these cells also show a moderate sensitivity to radiation typical range of a defective repair of double-stranded breaks in DNA. . Sensitivity to ionizing radiation could mean that BRCA2 is involved in other different repair pathways to repair double-stranded. . The karyotype of these cells shows both chromatid breaks, chromatid simple, triradiate and cuadrirradios, suggesting that BRCA2 is involved in the process of repair throughout the cell cycle.

Although the sequences of the BRCA1 and BRCA2 genes are very different, both genes are very similar in structure and function, which has been proposed that both genes may have a joint or coordinated cellular function.

SYNDROMES OF HEREDITARY BREAST CANCER

There are different syndromes that include an increase in the incidence of breast cancer The study of several pedigrees has resulted in the recognition of different syndromes in which predominates the existence of hereditary breast cancer.

Li-Fraumeni Syndrome

Is inherited as an autosomal dominant with high penetrance. Includes the association of breast cancer, soft tissue sarcomas, brain tumors, leukemia and adrenal carcinomas. Of the women with Turner syndrome who have breast cancer, 77% are diagnosed between 22 and 45 years and 25% had bilateral tumors.
About 30% of the tumors described in these families are diagnosed before the age of 15 years.The basic genetic defect is a mutation in the p53 gene, located on chromosome 17p13.1 (Li FP, et al, 1988).

The prevalence of germline alterations of p53 among women diagnosed with breast cancer younger than 40 years is estimated to be around 1%. Therefore, this alteration is not a common explanation for the occurrence of breast cancer in this population.

Cowden disease

Also known as multiple hamartoma syndrome including mucocutaneous lesions, benign tumors of the thyroid, colon polyps, uterine leiomyomas and breast cancer. Breast cancer affects 90% of women with a mean age at diagnosis of 40 years. It has autosomal dominant inheritance with low expression. So far there has found the gene responsible for this syndrome.

Breast-ovarian syndrome or Lynch syndrome

The association between breast and ovarian cancer was described by Lynch and subsequently endorsed by other researchers. It is estimated that the cumulative risk of breast cancer or ovarian cancer in the daughters of mothers affects of this syndrome is 46%, which corresponds with autosomal dominant high penetrance. In these families often coexist ovarian cancer association with breast cancer diagnosis at a young age.

Existe una relación inequívoca entre el marcador genético D17S74 en 17q21 y la aparición de cáncer de ovario en los miembros de la familia. There is a clear relationship between the genetic marker D17S74 in 17q21 and the occurrence of ovarian cancer in family members.

Of hereditary breast cancer not associated with other malignancies

These are families where the age at diagnosis is higher than in other inherited forms, although the average age is below 45 years (heterogeneity in the age distribution). A younger age at diagnosis and more often bilateral, it is smaller the probability that the association is due to chance. Linkage studies performed for the marker gene located DS17S74 hereditary breast cancer early onset on chromosome 17q21, although some subsequent studies have failed to confirm.

There are some families with hereditary pattern of breast cancer late onset, in postmenopausal women, which is being investigated polymorphic markers linkage to the estrogen receptor gene.

Breast cancer and its association with other malignancies with familial aggregation

Gastrointestinal tract neoplasms are tumors that occur more frequently in families with breast cancer. We have not confirmed a clear inheritance pattern, the association may be due to the high incidence of these tumors among the general population.

Barnes and colleagues describe a family with a history of multiple cancers (breast, endometrial, brain, colon, nasopharynx) does not fit into the above syndromes, in which mother and daughter patients complaining of breast cancer have a normal p53 protein accumulation both mesenchymal tissue and in the tumor itself, suggesting that it could be a new syndrome.

By: Jock Bigotes

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