**6. Conclusion**

Lynch Syndrome (hereditary nonpolyposis colorectal cancer ) is an autosomal dominant disorder that is caused by germline mutations in one of several DNA-MMR genes (*MLH1, MSH2, MSH6, PMS2,* and *EPCAM*). The syndrome is characterized by an approximate lifetime risk of EC and CRC of 40% to 60% in affected individuals. Other LS-associated cancers (gastric, ovarian, urothelial, pancreas, hepatobiliary tract, brain, small bowel, skin) as well as, synchronous and metachronous cancers, may present in these patients and their families. Identification of these individuals meeting AC II and/or Bethesda guidelines should have their tumors tested for MSI and for MMR protein expression by IHC. Further genetic counseling and direct MMR gene testing of those at-risk individuals should be done in the context of an established high risk genetics/cancer clinic. Post-test genetic counseling regarding the risks and benefits of LS-associated cancer surveillance and prophylactic surgery strategies, should be performed with consideration of the informed consent, completed childbearing, autonomy, cost-effectiveness and quality of life, for each individual patient.

#### **7. References**

Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltoner LA, de la Chapelle A, Peltomaki P, Meclin JP, Jarvinen HJ. Cancer Risk in Mutation Carriers of DNA-Mismatch Repair Genes. *International Journal of Cancer*. 1999;81:214-18.

compared with 69 of 210 (33%) of the controls (no hysterectomy). Further, no women who underwent a BSO developed ovarian cancer compared with 12 of 233 (5%) of the controls (no BSO). One ovarian cancer was diagnosed in a woman who underwent a hysterectomy. Risk-reducing surgery may take place at the time of CRC diagnosis or once child-bearing is completed. In addition, there are no recommendations for chemopreventive strategies in LS to decrease gynecologic cancer risks. Studies from Lu et al., suggest oral contraceptive pills or medroxyprogesterone acetate (Depo-Provera) may have the potential to prevent EC

Counseling regarding prophylactic surgery of this kind should include not only the risks inherent in surgery, but also premature menopause and its associated risks; menopausal vasomotor symptoms, estrogen therapy, osteoporosis, urogenital atrophy, and less clear, heart disease (Chen et al., 2007; Schmeler et al., 2006). Preoperative assessment should include colonoscopy, endometrial sampling, TVUS and a CA125 tumor marker. Preparation

Cost-effectiveness decisions must be reviewed with the patient when embarking on a management strategy for surveillance or prevention of LS-associated cancers. One study compared different strategies in a hypothetical cohort of women with LS: 1) no prevention, 2) prophylactic hysterectomy and BSO at age 30, 3) prophylactic surgery at age 40, 4) annual screening with endometrial biopsy, TVUS and CA125 from age 30, and 5) annual screening from age 30 until prophylactic surgery at age 40 (combined strategy) (Kwon et al., 2008). The authors found that annual screening followed by prophylactic surgery at age 40 was the most effective gynecologic cancer prevention strategy, but the incremental benefit over riskreducing surgery alone came with a substantial cost. Thus, a careful review of different strategies to improve the effectiveness and decrease the lifetime costs of these interventions

Lynch Syndrome (hereditary nonpolyposis colorectal cancer ) is an autosomal dominant disorder that is caused by germline mutations in one of several DNA-MMR genes (*MLH1, MSH2, MSH6, PMS2,* and *EPCAM*). The syndrome is characterized by an approximate lifetime risk of EC and CRC of 40% to 60% in affected individuals. Other LS-associated cancers (gastric, ovarian, urothelial, pancreas, hepatobiliary tract, brain, small bowel, skin) as well as, synchronous and metachronous cancers, may present in these patients and their families. Identification of these individuals meeting AC II and/or Bethesda guidelines should have their tumors tested for MSI and for MMR protein expression by IHC. Further genetic counseling and direct MMR gene testing of those at-risk individuals should be done in the context of an established high risk genetics/cancer clinic. Post-test genetic counseling regarding the risks and benefits of LS-associated cancer surveillance and prophylactic surgery strategies, should be performed with consideration of the informed consent, completed child-

bearing, autonomy, cost-effectiveness and quality of life, for each individual patient.

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**6. Conclusion** 

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