1. Lynch Syndrome and Colorectal Cancer Steven G. Proshan, M.D. Annapolis Colon and Rectal Surgeons Anne Arundel Medical Center November 8, 2014 1

2.  Familial Predisposition to Colorectal and other cancers  Autosomal Dominant  Henry Lynch, MD 1966  Hereditary Nonpolyposis Colorectal Cancer (HNPCC) 2 Lynch Syndrome (LS)

3.  Cancers more frequently  Cancers at younger age (40’s)  Right sided cancers  Adenoma to carcinoma sequence more rapid  Synchronous and Metachronous Cancers  Lifetime Risk 10-74% (vs. 5.5% without)  Better Prognosis 3 Colorectal Cancer in LS

4. Genetics of CRC Sporadic (65 %– 85%) Familial (10 %– 30%) Lynch syndrome (3%) Familial adenomatous polyposis (FAP) (1%) Rare CRC syndromes (<0.1%) MYH associated polyposis (MAP) (1%)

5. CancerIncidence (%)Incidence LS (%) Endometrium2.714-71 Stomach<10.2-13 Ovary1.64-20 Hepatobiliary Tract<10.02-4 Urinary Tract<10.2-25 Small Bowel<10.4-12 Brain/CNS<11-4 Sebaceous Neoplasm<11-9 Pancreas1.50.4-4 Prostate16.29-30 Breast12.45-18 Other LS Cancers

6. A Classic HNPCC/Lynch Family CRC dx 50s CRC dx 45 CRC dx 61 CRC dx 75 Ovarian Ca, dx 64 CRC dx 48 CRC dx 52 Endometrial Ca, dx 59 CRC dx 42 45

7. 1. Three or more relatives with histologically verified colorectal cancer, 1 of which is a first-degree relative of the other two. Familial adenomatous polyposis should be excluded. 2. Two or more generations with colorectal cancer. 3. One or more colorectal cancer cases diagnosed before the age of 50 years. Clinical Diagnosis of LS Amsterdam I Criteria (1991)

8. 1. Three or more relatives with histologically verified HNPCC-associated cancer (colorectal cancer, cancer of the endometrium, small bowel, ureter, or renal pelvis), 1 of which is a first-degree relative of the other 2. Familial adenomatous polyposis should be excluded. 2. Cancer involving at least 2 generations. 3. One or more cancer cases diagnosed before the age of 50 years. Clinical Diagnosis of LS Amsterdam II Criteria (1999)

9. 1. CRC diagnosed at younger than 50 years. 2. Presence of synchronous or metachronous CRC or other LS-associated tumors. * 3. CRC with MSI-high pathologic-associated features (Crohn-like lymphocytic reaction, mucinous/signet cell differentiation, or medullary growth pattern) diagnosed in an individual younger than 60 years old. 4. Patient with CRC and CRC or LS-associated tumor * diagnosed in at least 1 first-degree relative younger than 50 years old. 5. Patient with CRC and CRC or LS-associated tumor * at any age in 2 first-degree or second-degree relatives. * LS-associated tumors include tumor of the colorectum, endometrium, stomach, ovary, pancreas, ureter, renal pelvis, biliary tract, brain, small bowel, sebaceous glands, and kerotoacanthomas. Clinical Diagnosis of LS Revised Bathesda Guidelines (2004)

10.  Microsatellite Instability (MSI)  MSI - High  MSI - Low  MS - Stable  MSI – High Better Prognosis  Most MSI Colorectal Cancers are not LS (12% of sporadic CRC) 10 LS Genetic Alterations

11. Microsatellite Instability -CG--CGCGCGCG-CG--CGCGCGCG -CG--CGCGCGCG -CG-CGCGCGCG- -CG- -CGCGCGCGCG- -CG- -CGCGCG- -CG- -CGCG- -CG--CGCG--CGCGCG--CGCGCGCGCG- Normal Cells Tumor Cells Microsatellite Instability Normal Microsatellites

12.  Proofread Replicated DNA  Problem will be most obvious in repetitive sequences  Defect in both copies leads to cancer  If already carries one defect, at high risk to develop a second defect – Lynch Syndrome  LS is Autosomal Dominant Mismatch Repair (MMR) Genes and Proteins

13. Carrier Parent Non-carrier Parent Autosomal Dominant Inheritance Aa aa Aa aa Carrier Non-carrier 1/2

14.  MLH1  MSH2  MSH6  PMS2  EPCAM (Promotor for MSH2) 14 Mismatch Repair (MMR) Genes

15. MLH1 MSH2 MSH6 PMS2

16.  MSI Testing  Inexpensive  Prognostic and Treatment Information  MMR Protein Testing  Inexpensive  Directs which gene to look at  Confirm Positive Results with Gene Analysis 16 Universal Tumor Testing for LS

17.  Genetic Counseling  Gene Testing Appropriate Family Members  Familial Colorectal Cancer Type X (FCRCTX) 17 Followup

18.  Partial Colectomy  Risk of Metachronous Cancer 16-19% at 10 years  Total or Subtotal Colectomy with Ileorectal/Ileosigmoid Anastomosis  Risk of Metachronous Cancer 0-3.4% at 10 years  Diarrhea  Need to consider age and sphincter function 18 Treatment of Colon Cancer in LS Patients

19.  Resection of Rectum with Anastomosis  Risk of Metachronous Cancer 69% at 30 years with colonoscopy every 1.6 years  Total Proctocolectomy with Ileal Pouch-Anal Anastomosis (IPAA)  Standard of Care for cancer with UC or FAP  LS patients older  Total Proctocolectomy with End Ileostomy 19 Treatment of Rectal Cancer in LS Patients

20.  Colonoscopy every 1-3 years leads to fewer CRC and at a later age than unscreened  Colonoscopy every 1-3 years leads to similar CRC mortality compared to those without LS, although more CRC diagnosed  More frequent colonoscopy (≤ 2 years) better 20 CRC Screening in LS Patients

21. Guideline: Screening for CRC by colonoscopy is recommended in persons at risk (first-degree relatives of those affected) or affected with LS every 1 to 2 years, beginning between ages 20−25 years or 2−5 years before the youngest age of diagnosis of CRC in the family if diagnosed before age 25 years. May need to adjust based on exact family history and which gene is mutated. 21 CRC Screening in LS Patients

22.  Second most common cancer  75% Stage I and 88% 5 year survival  Hard to prove screening helps  Annual Pelvic Exam and Endometrial Sampling Offered Starting at Age 30-35 22 Endometrial Cancer in LS

23.  No data as to screening  Transvaginal Ultrasound and CA-125 Screening does not seem to help with BRCA1 and BRCA2 patients  Annual Transvaginal Ultrasound Offered Starting at Age 30-35 23 Ovarian Cancer in LS

24.  Retrospective analysis of 315 women with MMR mutations  33% Uterine cancer without surgery  No uterine cancer with surgery  5.5% Ovarian cancer without surgery  No ovarian cancer with surgery  Guideline: Hysterectomy and Oophorectomy after childbearing or at age 40 24 Prophylactic Hysterectomy and Oophorectomy in LS

25.  Lifetime Risk 0.2-13%  EGD every 2-3 years beginning age 30-35  Treat H.pylori if found  Modify based on family history and gene mutation 25 Gastric Cancer in LS

26.  Not much data screening (urinalysis, urine cytology) helps  Inexpensive  Noninvasive  Easy  Consider annually starting age 30-35 26 Urinary Cancers in LS

27.  No screening or no increased screening beyond that for usual population  Pancreatic  Small Intestine  Prostate  Breast  Either no clear increased risk or no good screening test 27 Other Cancers in LS

28. Questions? 28