Outline. Colon Cancer Lynch Syndrome Tumor Testing. Colorectal Cancer. Epidemiology of Colorectal Cancer 9/25/2012 LYNCH SYNDROME REVIEW

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1 Outlie Cacer Lych Sydrome Tumor Testig Daa Zakalik, M.D. Beaumot Cacer Geetics Program OUWB Medical School September 19, 01 Molecular Pathology Symposium Lych sydrome/crc overview Geetics of LS Cliical characteristics/cacer risks Maagemet of risk Tumor testig MSI IHC Case examples Colorectal Cacer 3 rd most commo cacer i the U.S. 145,000 ew cases per year 3 rd most commo cause of cacer-related death Most commo form of hereditary CRC is Lych Sydrome (LS) Stepwise progressio Beig mucosa polyp cacer Effective screeig prevetio Epidemiology of Colorectal Cacer Rare Sydromes ~4% Sporadic 60% MUTYH Associated Polyposis (MAP) ~1% Familial Adeomatous Polyposis (FAP) ~1% Familial/ Multifactorial 30% Lych Sydrome ~-4% Cacer 1996;78: Am J Med 1999;107:68-77 Gastroeterology 000;119: Am J Path 003;16: LYNCH SYNDROME REVIEW Lych Sydrome (formerly HNPCC: Hereditary polyposis Colorectal Cacer) KEY FEATURES: CRC (usually dx <50 y) Usually RT-sided, siget-rig, mucious, poorly differetiated, Microsatellite Istability-High (MSI-H) Edometrial cacer <50 y Ca preset prior to CRC dx i wome Other cacers: Ovaria, stomach, uriary tract, pacreatic, small bowel, bile duct, brai, sebaceous cysts AD iheritace 0 to very few polyps GENES: MLH1, MSH, MSH6, PMS mismatch repair gees Slides Courtesy of WBH Cacer Geetics Program 1

2 Lych Sydrome Amsterdam I Criteria, 1991 Three or more relatives with CRC, which oe case is a first degree relative of the other two At least two successive geeratios Oe or more cacers diagosed before age 50 FAP excluded Colorectal cacers i LS Distict histologic features Tumor ifiltratig lymphocytes Croh s-like lymphocytic ifiltrate Mucious histology Adeoma to carcioma rapid progressio Metachroous cacer risk 16% at 10 yrs, 41% at 0 yrs Defect i mismatch repair (MMR) system **Revised i 1999 Amsterdam II Mismatch Repair Gees Chr MSH6 (10%) MSH (40%) Chr 3 MLH1 (45%) Chr 7 PMS (5%) EPCAM (TACSTD1) TACSTD1 lies upstream of MSH promoter Icluded i LS testig schema Deletio i the 3 exos of TACSTD1 gee leads to hypermethylatio of MSH promoter Leads to silecig of MSH Accouts for 5% of cases i which MSH abset Absece of MSH expressio o IHC ca be caused by either: MSH mutatio or EPCAM mutatio (leadig to methylatio of MSH) Slide courtesy of Moica Marvi, MS; CGC. MMR System ad LS DNA MMR system maitais geomic itegrity by correctig DNA errors durig replicatio Recogizes base-pair mismatches ad repairs them Failure to repair DNA mismatches leads to geomic istability Occurs i regios of repetitive ucleotide sequeces - microsatellites

3 Red Flags for Lych Sydrome CLINICAL PRESENTATION Lych Sydrome / uterie cacer uder age 50 Presece of > oe LS-associated cacer i same idividual Specific pathological features Amsterdam Criteria 3-3 relatives with a LS associated tumor - Two successive geeratios affected 1- At least oe diagosed uder age Polyposis sydrome ruled out *LS cacers: colorectal, edometrial, gastric, ovaria, ureter/real pelvis, biliary tract, small bowel, pacreas, brai, sebaceous adeoma Lych Sydrome- Cacer Risks Lych Sydrome- Cacer Risks Cacer Risks Avg age dx = 4-61 EC Avg age dx = Lych Sydrome- Cacer Risks 3

4 Lych Sydrome: Maagemet Lych Sydrome: Maagemet Cacer Surveillace oscopy every 1- y startig at age 0-5 y Surgery Prophylactic Colectomy Cosider if: Cacer diagosis Large polyp burde Pt uwillig to udergo surveillace Edometrial /Ovaria Cacer Surveillace (o clear evidece to support) Trasvagial U/S Edometrial samplig Startig at age y Surgery Hysterectomy RRSO Gastric ad Small Bowel cacer (?) clear evidece supportig screeig but may cosider: EGD with exteded duodeoscopy Capsule edoscopy for small bowel cacer At -3 y itervals startig at age y Uroepithelial cacer Cosider aual urialysis startig at 5-30 y CNS cacer Aual physical examiatio starig at 5-30 y Pacreatic cacer recommedatio, limited data Chemoprevetio of LS (Bur at al Lacet 10/1) CAPP Trial largest LS itervetio trial 861 pts with LS (UK) ASA 600 mg vs placebo > 4 y f/u (mea 56 mos) 63% reductio i CRC (HR 0.41, p=0.0) Also decrease i o-crc LS cacers protectio if < y of itervetio icrease i ulcers, GI bleed, aemia LYNCH SYNDROME TUMOR TESTING Lych Sydrome Evaluatio Germlie Testig Molecular geetic testig of the germlie gees MLH1, MSH, MSH6, PMS for a deleterious mutatio Tumor screeig Microsatellite Istability (MSI) Immuohistochemistry (IHC) Lych Sydrome Testig Germlie Testig Molecular geetic testig of the germlie gees MLH1, MSH, MSH6, PMS for a deleterious mutatio Tumor screeig Microsatellite Istability (MSI) Immuohistochemistry (IHC) 4

5 Germlie Testig Mismatch Repair Gees MLH1 ad MSH (EPCAM) ~90% MSH6 ~7-10% PMS <5% Tumor screeig (MSI/IHC) allows for targeted germlie testig Lych Sydrome Testig Germlie Testig Molecular geetic testig of the germlie gees MLH1, MSH, MSH6, PMS for a deleterious mutatio Tumor screeig Microsatellite Istability (MSI) Immuohistochemistry (IHC) Tumor Tests to Scree for Lych Sydrome Microsatellite Istability (MSI) testig Performed o DNA extracted from tumor ad ormal tissue 15% of sporadic CRC cases are MSI-H Epigeetic silecig of MLH1 due to hypermethylatio Test is positive (MSI-H) i 77-89% of LS cases 5-10% false egative rate Immuohistochemistry staiig Abormal (absece of MMR protei) i 10-15% of sporadic CRC 5-10% false egative rate Microsatellite Istability (MSI) MSI testig i LS MSI-H is associated with Lych sydrome MSI-stable ad MSI-low is ot 5

6 Lych Sydrome Revised Bethesda Bethesda Criteria, Guidelies, Tumors from idividuals should be be tested for for MSI MSI i i the the followig situatios: 1. Colorectal cacer diagosed i a patiet who is less tha 50 years of 1. CRC age. dx < 50 y.. Presece. Presece of sychroous of multiple colorectal, or metachroous or other LS associated Lych sydrome associated tumors, regardless tumors,* regardless of age. of age. 3. CRC 3. Colorectal with MSI H cacer histology with the i pt MSI H < 60 y. histology diagosed i a patiet 4. CRC who i is pt less with tha oe 60 or years more of first degree age. relatives with a LS related tumor, 4. Colorectal with oe cacer of the diagosed cacers < i 50 oe y or more first degree relatives 5. CRC with a Lych sydrome related tumor, ad with oe of the cacers beig dx diagosed i pt with two uder or age more 50 firstyears. or secod degree relatives with a LS related cacers, regardless of age. 5. Colorectal cacer diagosed i two or more first or secod degree relatives, regardless of age. * Lych sydrome (HNPCC)-related tumors iclude colorectal, edometrial, stomach, ovaria, pacreas, ureter ad real pelvis, biliary tract, ad brai (usually glioblastoma as see i Turcot sydrome) tumors, sebaceous glad adeomas ad keratoacathomas i Muir Torre sydrome, ad carcioma of the small bowel. Immuohistochemistry (IHC) Patiet 1: Abset MLH1/PMS Patiet : Abset MSH/MSH6 Patiet #1 Patiet # IHC results Iterpretatio rmal : staiig preset or positive staiig of MMR protei Abormal : Staiig abset or egative staiig for MMR protei Five Possible Results of IHC test: 1. rmal All 4 Stais Preset. Abormal MLH1 & PMS Abset 80% of the time will get this result May eed geetics evaluatio if suspect LS, patiet dx <45, patiet has had multiple CRC primaries (meets Amsterdam II criteria) 80% acquired methylatio of MLH1 BRAF testig 0% will be LS MLH1 MSH MSH6 PMS 6

7 3. Abormal MSH & MSH6 Abset 4. Abormal MSH6 Abset Most likely LS due to either MSH or MSH6 gee mutatio Most likely LS due to a MSH6 gee mutatio Posible EPCAM mutatio MLH1 MSH MLH-1 MSH- MSH6 PMS MSH-6 PMS- 5. Abormal PMS Abset Most likely LS due to a PMS gee mutatio Older age of cacer MLH1 MSH LS is uder-recogized Amsterdam criteria too restrictive ~5-50% of idividuals with LS do ot meet Amsterdam or Bethesda criteria Accuracy of family history poor Estimated 1.% of all idividuals with LS are aware of their LS diagosis (Hampel et al 011) MSH6 PMS Solutio Uiversal Tumor Screeig for LS The Search for Uaffected Idividuals with LS: Do the Eds Justify the Meas? (Hampel 11) Uiversal Tumor Screeig Populatio icidece of LS: 1 i 370 LS:.8% of all ewly dx CRC Estimated 89,747 of the 307,006,550 people i U.S. could have LS < 10,000 LS cases curretly diagosed i US 1.% (10,000/89,747) of all idividuals with LS are aware of their diagosis Reduce the morbidity ad mortality from LS-related cacer i at-risk affected ad uaffected relatives Sufficiet evidece to recommed offerig Lych sydrome tumor screeig to all idividuals with ewly diagosed colorectal cacer Justified from a atioal health care system perspective ICER is $,5 (aythig below $50K cosidered cost-effective) The Evaluatio of Geomic Applicatios ad Prevetio Practice (EGAPP) Guidelies, 009 7

8 EGAPP Guidelies Edorsed tumor testig of all patiets with CRC (cost-effective) May (71%) NCI desigated Cacer Ceters have adopted reflex IHC/MSI to scree for LS Commuity hospitals less ofte (15%) LSSN Lych sydrome screeig etwork Beaumot a member Lych Sydrome Testig The most cost effective strategy ivolves IHC testig first ad subsequet targeted gee testig (Mvudura et al 010) MLH1, MSH, MSH6, ad PMS aalysis = $ MSI & IHC = $ IHC aloe = $ Sigle Gee Aalysis = $ Beamer et.al. JCO 4/1/1 Cost-effectiveess data Uiversal tumor testig of all CRC Preferred approach: IHC followed by BRAF mutatio testig Icremetal cost-effectiveess ratio (ICER) $36,00 per life-year gaied Requires participatio of at-risk relatives (3 or more) Uiversal Tumor Screeig for LS: The Beaumot Experiece Myudura et.al. 010 The Beaumot Experiece IHC for the four Lych associated proteis iitiated Jauary 1, 01 for ALL ewly diagosed colorectal cacer resectios ONLY Biopsies may ot provide eough ormal tissue for iteral cotrol Ifrastructure i place to hadle screeig results ad isure commuicatio ad proper follow-up (Cacer Geetics) The Beaumot Testig Schematic CRC > 50 yo & o family hx o persoal hx STOP IHC rmal CRC 50 or FDR w/ CRC or multiple primaries Refer to Geetics IHC Abormal Abset Staiig MSH & MSH6, or PMS abset MLH1& PMS abset Somatic tumor testig STOP 8

9 Beaumot Data 1/1/1 6/1/1 Reflex IHC for MMR proteis (MLH1,MSH,MSH6,PMS) 109 IHC performed o colorectal cacer resectios 10 curretly pedig 75 of 99 IHCs were ormal (76%) Expected 80-85% 4 / 99 IHCs were abormal (4%) Expected 15-0% Beaumot Data 1/1/1 6/1/1 Abormal results: showed abset MLH1 ad PMS (%) Expected 15% 0% of those expected to have LS 80% Sporadic etiology (somatic hypermethylatio MLH1/BRAF mutatio) showed abset MSH6 ad MSH (%) Expected 3% Most will likely have LS 0 MSH6 or PMS oly abset Expected % IHC Results Expected Observatio rmal CASE EXAMPLES MLH1/PMS Abset MSH/MSH6 Abset MSH6 Abset PMS Abset Case Example 1 1-year-old male preseted with a bowel obstructio due to carciomatosis Foud to have adeocarcioma of the colo with liver metastases Treatmet icluded a left hemicolectomy ad palliative chemotherapy Patiet was referred to cacer geetics due to his early age of diagosis of CRC Ifo d. 65 d. 80s 80s d. 56 d.70 d. Ca Type Ifo Lymphoma Breast Uterie Lug Ukow dx 60 dx 30s (Smoker) Pacreatic dx? 60s 60 d. 40 d Uterie Ovaria Polyps? dx 7 Ovaria dx 40 d. late 70s Lymphoma dx 60-70s 60 1 dx Materal Acestry: Polish Pateral Acestry: Irish AJ: 9

10 Ifo Ca Type Ukow d. 65 d. 80s 80s Ifo Lymphoma Breast dx 60 d. 56 d.70 d. Uterie Lug dx 30s (Smoker) Pacreatic dx? d. late 70s Lymphoma dx 60-70s Ifo Ca Type Ukow d. 65 d. 80s 80s Ifo Lymphoma Breast dx 60 d. 56 d.70 d. Uterie Lug dx 30s (Smoker) Pacreatic dx? d. late 70s Lymphoma dx 60-70s 60s 60 d. 40 Uterie dx 40 d. 38 Ovaria dx 7 Ovaria Polyps? 60 60s 60 d. 40 Uterie dx 40 d. 38 Ovaria dx 7 Ovaria Polyps? 60 1 dx 1 IHC Loss of MSH 4 6 Materal Acestry: Polish Pateral Acestry: Irish AJ: d. dx 1 MSH IVS4+1G>T 4 6 Materal Acestry: Polish Pateral Acestry: Irish AJ: Case Example d year-old male preseted for a routie screeig colooscopy Polyp i right colo Pathology revealed a high grade adeocarcioma Tumor screeig performed followig colo resectio: IHC loss of MSH6 expressio MSI-H 3/6 markers Patiet preseted to cacer geetics d. 89 d. 68 d. 54 Possible Cervical d Materal Acestry: Irish Pateral Acestry: Polish 5 d. 86 d. 77 d. 7 CHF Bladder dx d. 71 d. 5 AJ: d. 37 d. 37 d. 89 d. 68 d. 54 Possible Cervical d. 86 d. 77 d. 7 CHF Bladder d. 71 d. 89 d. 68 d. 54 Possible Cervical d. 86 Gastric Tumor dx 68 d. 77 CHF d. 7 Bladder d d dx 51 MSH6+ p.r1005x 50 d. 5 d dx 51 MSH6+ p.r1005x 50 d. 5 Materal Acestry: Irish Pateral Acestry: Polish 4 Materal Acestry: Irish Pateral Acestry: Polish 4 AJ: AJ: 10

11 Materal acestry: Irish / Germa / Eglish Pateral acestry: Germa d. 80 d. old age dx? d. 80s d. 67 Prostate dx? old age heart d.? d. 58 d. 80s d. 70 d. 7 ifo 93 Cacer Stomach Lug Type dx? dx? dx? dx 60s ukow 68 MLH1+ 61 dx 40 / 68 Real dx 64 Key: Bladder dx 59 cacer Stomach cacer 4 46 polyps Other cacer MLH1 eg dx 34 Real cacer Bladder cacer 5 - Preca Appedix cells Summary Lych Sydrome is the most commo iherited colorectal cacer sydrome Itese cacer surveillace ad/or prophylactic surgery decreases morbidity ad mortality from LS-related cacers Family history ad testig criteria aloe are isufficiet i idetifyig idividuals at risk Tumor screeig is a cost-effective approach to icreasig the detectio rate of Lych Sydrome Beaumot Cacer Geetics Program Daa Zakalik, MD Geetic Couselors: Lidsay Dohay, MS, CGC Heidi Dreyfuss, MS Jeifer Fulbright, MS, CGC Ashley Reeves, MS lidsay.dohay@beaumot.edu 11