The role of testing for BRCA1 and BRCA2 mutations in cancer prevention.

摘要: In May 2013, Angelina Jolie,1 the actress and director, announced in an op-ed New York Times that she carried a BRCA1 mutation had preventive double mastectomy. Jolie’s message was striking–by identifying cancer susceptibility gene, one of most famous actresses our generation dramatically reduced her risk dying from cancer. Widely available for more than decade, clinical testing mutations breast ovarian genes, BRCA2, remains prominent example use human genetic variation to reduce disease risk. BRCA2 are tumor suppressor genes involved DNA repair, therefore defective copy either gene sensitizes cells development. BRCA1/2 substantially increase risks cancer. The average US woman has 12% lifetime cancer, whereas carriers have 50% 60% is even greater–from 1.4% without over 40% among nearly 20% carriers.2 The benefit comes linking test results interventions For women who found carry mutation, dramatic–and also effective–risk reduction intervention prophylactic surgery, which Jolie chose. Prophylactic mastectomy reduces by 90%. oophorectomy similar effect on do not undergo yearly screening with mammography magnetic resonance imaging biannual pelvic ultrasonography antigen 125 (CA-125) often used,3 although definitive evidence mortality lacking. oral medications tamoxifen raloxifene developing included current recommendations management mutations.3 BRCA1/2 implications other settings. families hereditary and/or where found, individuals negative may be spared increased surveillance anxiety. newly diagnosed identification can influence extent such as choice contralateral or breast-conserving surgery. Poly ADP-ribose polymerase (PARP) inhibitors new class drugs target repair pathway different targeted BRCA1/2. PARP particularly effective whose already lack mechanism. being studied trials involving patients mutations. It surprising decision raised interest BRCA testing, including potential role population-based programs. Public response story overwhelmingly positive. Genetic centers reported influx interested patients–a phenomenon could termed effect. reality, however, far complicated elevated serum cholesterol levels high blood pressure, mammography. very rare general population, prevalence 2 3 per 1000 individuals.4 Even if finding variant unknown significance (where there enough data determine whether sequence change associated risk) common. Variants about 10% 15% tests. None strategies fully eliminate all complications. Removing breasts ovaries healthy fertility body image. When performed young women, causes immediate menopause, lead weight gain, cardiovascular diseases, bone loss, sexual problems. Tamoxifen but serious adverse effects, uterine clots, stroke. addition, individual’s family members; require additional counseling facilitate communication within these implications. BRCA1/2 expensive. charge full sequencing $3000. That likely decrease now Supreme Court invalidated Myriad Genetics’ patents opened market companies.5 Nonetheless, low-risk health care utilization costs, physician visits, studies, when variants found. Given considerations, how should used? It clear greatest value populations at carrying mutation. Current guidelines recommend considered probability defined personal history, Ashkenazi Jewish ancestry, whom 1 40 mutation.3 possible, information obtained first member been having cancer; does further unlikely useful. If relatives tested specific familial This approach less expensive whole genes. The higher recently led debates Israel institute program.6 Three “founder mutations” comprise 80% 95% mutations, respectively, populations,7,8 Jews 3-variant sequencing. However, Israel, because woman’s respond positive result difficult.6 Some feel empowered knowing they mutation; others, find this knowledge great burden prefer know. used uncomfortable options reducing risk, makes sense. Underuse substantial concern. Limited uptake high-risk cancer,9 it difficult prevent members. Relevant history collected primary practices, strong advised counselors expertise experience. assessment routine component Access services vital, requiring investment training counselors, continued development long distance, telehealth approaches, expansion insurance coverage. By raising public awareness preventing service. challenges impede appropriate genomic