Comprehensive IHC Screening for Lynch Syndrome: What You Need to Know Andrea Lewis, MS, CGC January 14, 2010

Overview Lynch syndrome review Norton Comprehensive IHC Screening Program Interpreting IHC results

What is Lynch Syndrome? Hereditary cancer syndrome associated with an increased risk for:  Colon cancer 80%  2 nd colon cancer40-50%  Uterine cancer 60%  Gastric cancer11-19%  Ovarian cancer9-12%  Urinary tract4-7%  Hepatobiliary tract2-7%  Small bowel1-4%  CNS/Brain1-3%

Immunohistochemistry Screening for Lynch syndrome IHC staining for the 4 mismatch repair gene proteins is performed on tumor tissue  MLH1, MSH2, MSH6, and PMS2 genes  Proteins are normally present  Absence of one or more of the proteins could indicate Lynch syndrome  Can direct genetic testing  Can be done in house  Approximately 94% detection rate

Importance of IHC Screening Columbus area Lynch syndrome study  500 patients with CRC screened for Lynch syndrome 18 had Lynch syndrome (3.6%) Age range from Only 44% were diagnosed under age 50 Only 72% met Amsterdam or Bethesda Criteria An average of 3 family members tested per proband Average age of colon cancer diagnosed in patients with Lynch syndrome is 61.2 years Hampel, et al. JCO 2008, Hampel, et al. Gastroent 2005

Importance of IHC Screening Proper screening reduces cancer risks 15 year colonoscopy screening ScreenedNot Screened n=133n=119 Colorectal cancer8 19 p=0.014 Death from CRC09p<0.001 Overall deaths1026P<0.001 Colonoscopy screening decreases overall mortality in Lynch syndrome families by 65% Jarvinen, et al. Gastroent. 2000

Norton Comprehensive IHC Program Launched October 1, 2009 IHC for Lynch sx performed on all colorectal cancers resected at Norton Healthcare All results sent to Genetic Counseling Service Process for abnormal results  Surgeon is contacted to discuss follow-up plan  Patient is offered genetic counseling appointment  Gene specific testing for Lynch syndrome performed

Program Statistics 31 colorectal resections performed in the Norton Healthcare system 10/1/09-present 7 abnormal IHC results (22.6%)  6 MLH1/PMS2  1 MSH2/MSH6 Surgeons of all 7 patients have been contacted 1 patient underwent testing (neg) 2 patients have scheduled appointments

Interpreting IHC Results

MLH1Protein Expressed MSH2Protein Expressed MSH6Protein Expressed PMS2Protein Expressed This test result indicates that ALL four genes are likely functioning normally. Patients with this test result are very unlikely to have Lynch Syndrome. ***Patients with a significant family history or indication of a different hereditary cancer syndrome should still be referred to Genetic Counseling Services***

Interpreting IHC Results MLH1 Protein Not Expressed MSH2Protein Expressed MSH6Protein Expressed PMS2 Protein Not Expressed This test result indicates that the MLH1 gene (or rarely the PMS2 gene) is NOT functioning in the colon tumor. Patients have a 20% chance to have Lynch syndrome due to a deleterious mutation in the MLH1 gene and an 80% chance to have loss of expression due to somatic hypermethylation of the MLH1 gene. MLH1Protein ExpressedMSH2 Protein Not Expressed MSH6 PMS2Protein Expressed This test result indicates that the MSH2 gene (or rarely the MSH6 gene) is NOT functioning in the colon tumor. Patients with this test result have nearly a 100% chance to have Lynch syndrome due to a deleterious mutation in the MSH2 gene.

Interpreting IHC Results MLH1Protein Expressed MSH2Protein Expressed MSH6 Protein Not Expressed PMS2Protein Expressed This test result indicates that the MSH6 gene is NOT functioning in the colon tumor. Patients with this test result have nearly a 100% chance to have Lynch syndrome due to a deleterious mutation in the MSH6 gene. MLH 1 Protein Expressed MSH 2 Protein Expressed MSH 6 Protein Expressed PMS 2 Protein Not Expressed This test result indicates that PMS2 is NOT functioning in the colon tumor. Patients with this test result have nearly a 100% chance to have Lynch syndrome due to a deleterious mutation in the PMS2 gene.

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