Ovarian Cancer In Carriers Of Brca 1 example essay topic

Genetics and the Predisposition to Breast Cancer: BRCA 1 & BRCA 2 I.A. The genetics of Cancer a. Some Interesting Facts i. Cancer is one of the most common and severe diseases on earth ii. It is responsible for 20% of all deaths. One-third of the world's population will develop some form of cancer iv.

Cancer is responsible for more than 10% of the total cost of all medical care in developed countries b. Cancer is a virulent form of neoplasia, or uncontrolled cellular proliferation leading to a malignant mass or tumor capable of metastasizing. c. Three main forms of cancer: Lymphoid / hematopoietic, sarcoma, carcinoma. B. Molecular basis of cancer a. Mutations in the genes responsible for controlling cell proliferation and apoptosis cause cancer. b. Damage to the DNA of a somatic cell rarely has an effect beyond that cell unless the mutation contributes to a malignant transformation (cancer). c. Cancer results from a series of mutations. d.

Cancer evolves from an accumulation of additional mutations in the genes that encode DNA -repair and tumor-suppressors. C. Predisposition to Cancer a. Mutations that occur in germ-line cells and are then fertilized pass down the mutation to offspring. b. These offspring now have a "predisposition" to cancer, with the mutation found in every cell of their body. II.

Part II: Breast and Ovarian Cancer a. Some Interesting Facts About Breast Cancer i. Over 150,000 women each year are diagnosed with breast cancer, and over 40,000 of them die. ii. Lifetime risk for the average woman is a 1 in 9 chance of developing breast cancer..

Only about 5 to 10% of these patients have a strong family history of disease, and can be attributed to BRCA 1 and BRCA 2 mutations. b. Oncogenes i. Mutated proto-oncogenes, alleles of normal cellular genes ii. Mutations are dominant, require only one mutated allele.. Can encode telomerase genes that block apoptosis iv. Usually are gain-of-function mutations that facilitate malignant transformation by mechanisms such as: vs. Stimulating cell proliferation vi.

Increasing blood supply to tumors vii. Inhibit apoptosis c. Tumor-Suppressor Genes i. Loss-of-function mutation, leads to the inability to suppress the growth of tumors. ii. Leads to uncontrolled cell division, abnormal growth, and defective apoptosis.. There is a strong selective advantage for these mutations due to increased proliferation and survival rates. iv.

Action of tumor-suppressor genes is recessive, both alleles must be mutated or lost. d. Molecular Genetics of Breast Cancer i. Damage to the DNA of a somatic cell rarely has an effect beyond that cell unless the mutation contributes to a malignant transformation (cancer) ii. Damage to a germ-line cell so that the change is passed on to all the cells in the organisms offspring. Genetic predisposition does not imply genetic inevitability iv. Both men and women are all born with 2 normal copies of the BRCA 1 and BRCA 2 genes. vs. The "two hit" model for genetic predisposition assumes that a carrier is born with a mutation in one of the two BRCA genes, but that the normal BRCA gene imparts its protective effects until such time that the normal gene undergoes a mutation for what ever reason (e.g. environmental factor). vi.

At that point, the tumor suppressor protein is no longer encoded properly and a cancer develops. vii. This is called "Loss of heterozygosity" (LOH) Part. Breast Caner Genes a. BRAC 1 a. Autosomal Dominant Inheritance b.

Located on chromosome 17 q 21 c. Estimated to be 1 to 1.5 Mb long d. Putative role in double-stranded DNA repair, Isolated in 1994 e. Primary mutation responsible for familial breast and ovarian cancer f. Cumulative lifetime risk of breast cancer for women who carry the BRCA 1 mutation is approximately 92%, and a 40-60% lifetime risk of developing ovarian cancer. b. Gene Function i.

Gene product is 220-kD nuclear phosphoprotein localized in the ER-Golgi complex. ii. BRCA 1 coexists along with BRCA 2 to participate in a pathway (s) associated with the activation of double-strand break repair and / or homologous recombination.. Has been found to be a probable component of the RNA polymerase II holoenzyme, acting as a transcriptional co activator. iv. May function to suppress estrogen-dependent pathways related to cell proliferation, functioning as a tumor suppressor. vs. More than 235 mutations have been identified in BRCA 1 c. BRCA 2 vs. Autosomal Dominant Inheritance ix. Located on chromosome 13 q 12 x.

Estimated to be 3.3 kb xi. Putative role in double-stranded DNA repair, Isolated in 1995 xii. Cumulative lifetime risk of breast cancer for women who carry the BRCA 2 mutation is approximately 85%, and a lifetime risk of 10-20% for ovarian cancer. x. Also is associated with 6% chance of male breast cancer. xiv. Elevated risk for other cancers like pancreatic, prostate, stomach, & thyroid. d. Gene Function xv.

Associated with the activation of double-strand break repair and homologous recombination xvi. BRCA 2 and RAD 51 (a homolog of the bacterial recombination protein RecA) both co-localize to nuclear foci thought to be sites of DNA damage xvii. Loss of BRCA 2 leads to error prone repair of double strand DNA breaks and in dividing cells can lead to chromosomal abbe rations and loss of genetic information. xv. About 100 mutations have been identified in BRCA 2.. Part IV: Diagnosis and treatments a.

Am I at Risk? i. Has any woman in your family had both breast and ovarian cancer? ii. Have more than 3 women from the same side of your family had breast or ovarian cancer? Has any woman in your family had breast or ovarian cancer before the age of 40? iv. Have any men in your family had breast cancer? vs. Are you of Ashkenazi Jewish decent? (1 in 40 chance) vi.

Are you of Dutch, Icelandic, or Norwegian decent? b. Characteristics of Familial Breast Cancer i. Multiple affected individuals in the family ii. Early age of onset (Before age 35) .

Frequent bilateral disease iv. Occurrence of breast cancer in men. vs. Distinct histological appearance of BRCA mutated tumors B. BRCA 1- excess of medullary histopathology, are of higher histological grade, and are more likely to be estrogen receptor-negative and progesterone receptor-negative. At the molecular level there is a higher frequency of p 53 mutations C. BRCA 2- do not seem to have a characteristic histopathology, and are at least as likely to be hormone receptor-positive c. Genetic Testing i.

BRCA 1 and BRCA 2 are the only two genes that have genetic tests available. ii. Cost B. Can vary from several hundred to several thousand dollars. C. Genetic counseling without testing cost on average $213, whereas counseling, testing, and disclosure of results totaled $2057 . Accuracy B. "For a patient with at least a 10% probability of a positive test based on a personal or family history of cancer, the chance of an incorrect test result is less than 1%". -MDS Laboratory Services iv. Time B. Test results typically take 3 to 6 weeks d. Implications of Test Results Implications of Test Results vs. Positive Test Result vi.

Will I actually develop disease? vii. Should I tell my family? vs. Should I have children? ix. Should I adopt? x. Should I buy more insurance? xi. Will I qualify for insurance or be dropped from my current policy? xii. Should I undergo invasive prophylactic surgery to prevent cancer? x.

Negative Test Result xiv. Basically inconclusive xv. May still carry an unknown mutation xvi. Still has general population risk for breast cancer xvii.

Relief xv. Survivor guilt IV. What Can I do if I Have a Positive Test Result? a. Surveillance- Careful monitoring to catch the disease at an early stage i.

Mammography - Yearly after age 30 ii. Breast Self-exams - Monthly after age 18 . MRI b. Prophylactic Surgery- Removal of the breasts or ovaries before disease develops i. Mastectomy - Reduces risk for carriers by 90% ii. OOphorectomy - Genetic Counselors recommend carriers complete their families by age 35, followed by bilateral prophylactic oophorectomy Reduces risk by at least 90% c.

Oral contraceptive use protects against ovarian cancer in carriers of BRCA 1 or BRCA 2 mutations, reducing risk by 50%. d. Chemoprevention -utilization of a drug or a chemical to prevent the development of cancer V. Chemoprevention a. Tamoxifen i. An anticancer drug that belongs to the family of drugs called anti estrogens. Tamoxifen blocks the effects of the hormone estrogen in the body. It is used to prevent or delay the return of breast cancer or to control its spread. ii.

Has been shown to reduce the occurrence of breast cancer by 50% when taken daily for 4-5 years. b. Side Effects i. endometrial cancer (cancer of the lining of the uterus) ii. uterine sarcoma (cancer of the connective tissue of the uterus) . pulmonary embolism (a blood clot in the lung) iv. deep vein thrombosis (a blood clot in a major vein). c. Raloxifene i. Similar to Tamoxifen, marketed by Eli Lily as Evista (R) to treat Osteoporosis, not FDA approved to prevent breast cancer ii. Study was designed to look at osteoporosis, after an average of more than three years researchers observed a significant reduction in the number of breast cancers in those women taking the drug compared to the placebo. VI.

Healthcare for Carriers a. The Unfortunate Truth i. A positive genetic test result may affect a person's health insurance coverage. ii. A person with a positive result may be denied coverage for medical expenses related to their genetic condition, dropped from their current health plan, or unable to qualify for new insurance. b.

Partial Protection i. The Health Insurance Portability and Accountability Act (HIPAA) of 1996 provides some protection for people who have employer-based health insurance. B. Prohibits group health plans from using genetic information as a basis for denying coverage if a person does not currently have a disease. C. Does not prohibit employers from refusing to offer health coverage as part of their benefits, or prevent insurance companies from requesting genetic information. ii. In 2000, HIPAA National Standards to Protect Patients' Personal Medical Records B. This regulation covers medical records maintained by health care providers, health plans, and health care clearinghouses. C. Not specific to genetic information, they provide the first comprehensive Federal protection for the privacy of health information. VII. Preventative Measures for Those At High Risk a. Healthy Diet i.

Low in fat ii. High in anti-oxidants like betacarotine, vitamin C & E, and selenium. b. Maintain a healthy weight c. Exercise d. Avoid alcohol e. Do not smoke f.

Drink plenty of water V. Prognosis a. Cure rates for breast cancer exceed 90% when confined to breast tissue. b. Metastases to visceral organs and the brain have 5-year survival rates of less than 20%. c. There is no clear evidence of a survival rate difference between BRCA 1 and BRCA 2 carriers with breast cancer or ovarian cancer. d. There is no difference in survival rates between breast / ovarian cancer that is spontaneous and cancers caused by BRCA mutations when they are diagnosed at the same age and same stage. BRCA 1 and BRCA 2: Genetics and Predisposition to BReast Cancer.