Ovarian cancer (Ovarian Cancer) - Genes BRCA1, BRCA2, MLH1, MSH2 and TP53
Ovarian cancer is a disease that affects women, in which certain cells in the ovaries become abnormal and multiply uncontrollably to form a tumor. In about 90% of cases, ovarian cancer occurs after age 40, and most cases occur after 60 years.
The most common form of ovarian cancer starts in the epithelial cells of the fimbriae at the end of one of the fallopian tubes and subsequently cancer cells migrate to the ovary. However, such cancer can also arise in epithelial cells in the surface of the ovary and peritoneal epithelial cells. This latter form of cancer called primary peritoneal cancer, similar to that of epithelial ovarian cancer in its origin, symptoms, progression and treatment. The primary peritoneal cancer often spreads to the ovaries, even in their absence. Because cancers that begin their development in the ovaries, fallopian tubes, and peritoneum are so similar and are easily spread from one of these structures to other, often difficult to distinguish. In approximately 10% of cases, ovarian cancer does not develop in epithelial cells but in germ cells or granulosa cells.
Usually in its early stages, ovarian cancer is asymptomatic. As it progresses, signs and symptoms may include pain or feeling of heaviness in the pelvis or lower abdomen, bloating, early satiety when eating, back pain, vaginal bleeding between menstrual periods or after menopause, or changes in urinary or bowel habits. However, these changes can occur as part of many different disorders. Having one or more of these symptoms does not mean that a woman has ovarian cancer. In some cases, cancerous tumors can develop into metastatic cancers. If ovarian cancer spreads, cancerous tumors appear most frequently in the abdominal cavity or surfaces nearby organs such as the bladder or colon. Because usually diagnosed at an advanced stage ovarian cancer can be difficult to treat. However, when diagnosed and treated early, the survival rate at 5 years is high.
This process is due to mutations in critical genes that control growth and cell division or DNA repair damaged, allowing the cells to grow and divide uncontrollably to develop a tumor. These genes are critical: TP53, BRCA1, BRCA2, MLH1 and MSH2.
TP53, located on the short arm of chromosome 17 (17p13.1), encodes a protein called p53 acts as a tumor suppressor. This protein is located in the nucleus of cells throughout the body, where it binds directly to DNA. When DNA in a cell is damaged by agents such as toxic chemicals, radiation or ultraviolet sunlight (UV), this protein plays a critical role in determining whether the DNA is repaired or damaged cell undergoes apoptosis. To date, 261 have been described in the TP53 gene mutations: missense mutations (176), and cutting mutations -splicing- junction (27), regulatory mutations (2), small deletions (30), small insertions (12) , small indels (5), larger deletions (8), and complex rearrangements (1) .The TP53 somatic mutations are common in ovarian cancer because they occur in about half of ovarian tumors. Most of these mutations change the amino acids in the protein p53, which reduces or eliminates the tumor suppressor protein function. Because the altered protein is less able to regulate cell growth and division, you can develop a cancerous tumor.
BRCA1, located on the long arm of chromosome 17 (17q21) and BRCA2, located on the long arm of chromosome 13 (13q12.3), encode proteins that act as tumor suppressors. These proteins are involved in repairing damaged DNA. Breaks in DNA can be caused by natural and medical radiation or other environmental exposures, and also occur when chromosomes exchange genetic material in preparation for cell division. To help repair DNA, BRCA1 and BRCA2 proteins play a critical role in maintaining the stability of the genetic information of a cell. In addition, it is believed that the BRCA1 and BRCA2 protein also regulate the activity of other genes and play an essential role in embryonic development. To perform these functions, these proteins interact with many other proteins, including tumor suppressors and other proteins that regulate cell division.
Described to date 1424 mutations in the BRCA1 gene, of which: missense mutations (468), and cutting mutations -splicing- junction (117), regulatory mutations (6), small deletions (434), small insertions (151), small indels (25), deletions higher (171), insertions / higher duplications (32), complex rearrangements (19) and variations of repetition (1). On the other hand, have been described hitherto 1165 mutations in the BRCA2 gene: missense mutations (378), and cutting mutations -splicing- junction (85), regulatory mutations (1), small deletions (461), small insertions ( 166), small indels (25), deletions older (32), insertions / higher duplications (10) and complex rearrangements (7). Mutations in these genes alter DNA repair, allowing potentially deleterious mutations in DNA persist. As these defects accumulate, they can cause cells to grow and divide without control or order to develop a tumor. Germline mutations are involved in more than one fifth of cases of ovarian cancer. Between 65% and 85% of these mutations they are in the BRCA1 gene or BRCA2. These mutations of genes are described as "mutations high penetrance" because they are associated with a high risk of developing ovarian cancer. Compared with a lifetime risk of 1.6% of ovarian cancer in women in the population, the lifetime risk in women with a BRCA1 gene is 30% to 60%, and lifetime risk in women with a BRCA2 gene mutation is 12% to 25%. Men with mutations in these genes also have a higher risk of developing various forms of cancer.
MLH1 genes, located on the short arm of chromosome 3 (3p21.3) and MSH2, located on the short arm of chromosome 2 (2p21), encode proteins that play an essential role in DNA repair. These proteins help repair errors that occur in DNA copying in preparation for cell division. Repairs are made by removing a section of DNA containing errors and the replacement section with a DNA sequence corrected. A significantly increased risk of ovarian cancer is also a feature of certain rare genetic syndromes, including Lynch syndrome. Lynch syndrome is associated more with mutations in the MSH2 or MLH1 gene and represents between 10% and 15% of ovarian cancers hereditary. Other rare genetic syndromes may also be associated with an increased risk of ovarian cancer.
To date, 864 have been described mutations in the MLH1 gene: missense mutations (283), and cutting mutations -splicing- junction (146), regulatory mutations (8), small deletions (193), small insertions (80) , small indels (17), deletions higher (114), insertions / higher duplications (15) and complex rearrangements (8). Meanwhile, they have been described hitherto 839 MSH2 gene mutations: missense mutations (263), and cutting mutations -splicing- junction (91), regulatory mutations (2), small deletions (170), small insertions ( 83), small indels (13), deletions higher (189), insertions / higher duplications (20) and complex rearrangements (8) .The mutations in either gene may allow cells to grow and divide without control, which It leads to the development of a cancerous tumor. Like BRCA1 and BRCA2 genes, these genes are considered "high penetrance" because mutations greatly increase the likelihood of developing cancer of a person.
Germline mutations in dozens of other genes have been identified as potential risk factors for developing ovarian cancer. These genes are described as "low penetrance" or "moderate penetrance" because changes in each of these genes appear to have only a small or moderate contribution to the overall risk of ovarian cancer. Some of these genes encode proteins which interact with the proteins encoded by the BRCA1 or BRCA2 genes. In addition to genetic changes they have been identified many personal and environmental factors that contribute to the risk of developing ovarian cancer in women. These factors include age, ethnicity, and hormonal and reproductive factors. A history of ovarian cancer closely related members of the family is also an important risk factor, especially if the cancer occurred in early adulthood.
Most cases of ovarian cancer are sporadic and are not due to inherited genetic factors. These cancers are associated with somatic mutations acquired during a person 's life. In general, a cancer predisposition due to a germline mutation is inherited in an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to increase the probability of developing cancer. Although ovarian cancer occurs only in women, the mutated gene can be inherited from the mother or father. It is important to note that people inherit a greater chance of developing cancer, not the disease itself. Not all people who inherit mutations in these genes develop cancer.
Tests in IVAMI: in IVAMI perform detection of mutations associated with ovarian cancer, by the complete PCR amplification of the exons of TP53, BRCA1, BRCA2, MLH1 and MSH2 genes, respectively, and subsequent sequencing.
Samples recommended: for being in most cases are not inherited somatic mutations is recommended to send tissue biopsy. In the case of inherited mutations extracted blood with EDTA for separating blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).