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Universal Screening for Lynch Syndrome. Cecelia Bellcross, PhD, MS, CGC Emory University School of Medicine Department of Human Genetics. Genetics of CRC. Sporadic (65 %– 85%). Familial (10 %– 30%). Rare CRC syndromes (
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Universal Screening for Lynch Syndrome
Cecelia Bellcross, PhD, MS, CGCEmory University School of Medicine
Department of Human Genetics
Genetics of CRC
Sporadic (65%–85%)
Familial (10%–30%)
Lynch syndrome (aka Hereditary
nonpolyposis colorectal cancer -
HNPCC) (3%)Familial adenomatous polyposis (FAP) (1%)
Rare CRC syndromes
(<0.1%)
MYH associated polyposis (MAP) (1%)
Clinical Features of Lynch/HNPCC• Early but variable age at
CRC diagnosis (~45 years)
• Tumor site in proximal colon predominates
• Metachronous/synchronous CRCs
• Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile duct, pancreatic, sebaceous skin tumors; brain tumors
A Classic HNPCC/Lynch Family
CRCdx 50s
CRCdx 45
CRCdx 61
CRCdx 75
OvarianCa, dx 64
CRCdx 48
CRCdx 52
EndometrialCa, dx 59
CRCdx 42
45
Other Features of Lynch Syndrome
• Autosomal dominant inheritance• Genes belong to DNA mismatch repair
(MMR) family • Genetic heterogeneity (MLH1, MSH2,
MSH6, PMS2)• CRC lifetime risk 30-80%• Endometrial cancer lifetime risk 30-60%
18-29 30-39 40-49 50-59 60-69 70-790
102030405060708090
100
Male MLH1Male MSH2Female MLH1
Age (years)
Cum
ulat
ive
Ris
k C
olor
ecta
l Can
cer
(%)
CRC RISK
*Barrow, Clin Genet 2008
Extra-colonic/Extra EndometrialLifetime Cumulative Incidence to age 70 yo:• Urologic tract (8.4% overall)
– MLH1: female =1.1%, Male = 3.7% – MSH2: female =11.9%, Male = 27.8%
• Ovary = 6.7%• Gastric = 5.8%• Small Bowel = 4.3%• Biliary/Pancreatic = 4.1%
Watson, Int. J. Cancer, 2008
Cancer Site Surveillance/ Prevention Frequency Begin Age:
Colon Rectum
Colonoscopy Every 1-2 years 20-25 (30)(Colectomy)
Uterus Transvaginal Ultrasound / Endometrial Biopsy
Every year 30-35
Hysterectomy 30+Ovary Transvaginal Ultrasound / CA-125 Every year 30-35
Oral contraceptives > 5 yearsOophorectomy 30+
Stomach Small Bowel
Upper Endoscopy Every 2 years 30-35
Pancreas Biliary
Liver function tests & Abdominal Ultrasound
Every year 30-35
Urinary Tract Urinalysis cytology Every year 30-35Renal Ultrasound Every 1-2 years 30-35
Skin Lesions Dermatology Exam Every year 20-25
Surveillance/Prevention Options for Lynch syndrome (Lindor JAMA, 2006;296:1507)
Impact of Screening
Incidence Mortality05
1015202530354045 Screened Group
(n=44)Control Group (n=46)
Perc
ent
Jarvinen, Gastroent, 2000
Jarvinen, JCO, 2009: 242 mutation +, 367 mutation - : >95% screening compliance, no difference in cancer or all cause mortality rates
Amsterdam II Criteria 3 or more relatives with verified HNPCC
associated tumor (CRC, endometrial, ovarian, gastric, small bowel, urinary tract) in family
One case a first-degree relative of the other two
Two or more generations involved One or more cancer diagnosed by age 50 FAP excluded
Failure to meet these criteria does not exclude HNPCC
Revised Bethesda Guidelines:• CRC < age 50• Patient with 2 HNPCC related tumors• Patient with CRC < age 60 with MSI-H
histology• Patient with CRC with 1st degree relative with
HNPCC related cancer; one of the cancers at < 50 years
• Patient with CRC and 2 or more relatives with HNPCC-related cancer regardless of age
Umar, JNCI, 2004
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
Abnormal or missing MSH2 protein
Immunohistochemistry
Abnormal Gene (MSH2)
MSH2-Lack of MSH2 expression, negative IHC staining for MSH2 protein
Normal tissue Tumor tissue
MSH2+
Testing for Lynch/HNPCCFamily/Medical history meets screening criteria
Amsterdam/Bethesda
MSI/IHCon tumor tissue MSI normal
IHC normal
No further testingRisks & screeningbased on history
MSI-High IHC – loss of protein expression
Genetic Testingon blood
Mutation Identified
No mutation Identified
1. Consider additional genetic testing2. Risks & screening based on test results and family/medical history
Lynch/HNPCC screening & managementFamily members offered testing
Rationale for HNPCC/Lynch Syndrome Screening of Newly Diagnosed CRC
• Common: ~ 3% of all CRC• Age/screening criteria miss up to 25%• Accurate methods (MSI/IHC) using easily
accessible tumor tissue• Benefits of medical intervention
– Cascade testing of family members– Surveillance/prevention– CRC treatment decisions
• Evidence of cost-effectiveness
EGAPP Lynch RecommendationGenetics in Medicine January 2009
May, 2007www.ahrq.gov/downloads/pub/evidence/pdf/hnpcc/hnpcc.pdf
GIM, 2009;1:42
GIM, 2009;1:35
Summary Statement
“The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer (CRC) to reduce morbidity and mortality in relatives.
We found insufficient evidence to recommend a specific genetic testing strategy among the several examined.”
2.8% of CRC probands with deleterious mutations (n=44)
• Age at diagnosis – 51.4 (range 23-87)• 50% diagnosed over age 50• 25% did not meet either Amsterdam or Bethesda criteria• Mutations
– 20.5% MLH1 – 52.3% MSH2– 13.6% MSH6– 13.6% PMS2
Columbus-area HNPCC study (1999-2005)
Hampel et al. New Engl J Med 2005; 352:1851 Hampel et al. J Clin Oncol 2008; 26:5783
35 CRC probands have had genetic counseling
Degree of Kinship Tested PositiveFirst 99 52Second 64 28> Second 86 29Total 249 109
Family Studies of 35/44 CRC Probands
Hampel et al. NEJM 2005;352:1851-60.; Hampel et al. JCO 2008.
Theoretical Population
Health Benefit
Bellcross, Genet Med, 2012
Healthy People 2020 Approved Genomics Objective
(Developmental)
“Increase the proportion of persons with newly diagnosed colorectal cancer who receive genetic testing to identify
Lynch syndrome”
Endometrial cancer
Hampel H et al. Cancer Res. 2006; 66:7810 Hampel H et al. Cancer Res. 2007;67:9603
• Age at diagnosis – 54.1 (range 39-69)• 65% diagnosed over age 50• 65% did not meet either Amsterdam or Bethesda
criteria• Mutations
– 14.3% MLH1 – 21.4% MSH2– 64.3% MSH6– No PMS2
2.5 % with deleterious mutations (n=14)
12/14 EC probands have had genetic counseling
Degree of Kinship Tested PositiveFirst 28 16Second 12 3> Second 8 2 Total 48 21
Columbus HNPCC study Family studies of 14 EC probands
EGAPP Data Interpretation Concerns
• “To reduce morbidity and mortality in relatives”– Implies no benefit to proband
• Increasing evidence of impact on CRC management – chemotherapy, surgery
• Known increased risk for 2nd primary colorectal cancers and other tumors impacts medical management
• Does not take into account current practice and insurance coverage (including Medicare)
Potential Impact on CRC treatment
• MSI-H tumors– Better prognosis (Popat, JCO 2005;23:609) – Lack of impact of 5FU on RFS/OS (DesGuetz, Eur J
Cancer 2009;45:1890)• Surgical (Gut 2011;60:950 – 382 LS gene mutation carriers
– Extensive colectomy – 0/50 metachronous tumors vs. Segmental resection – 74/322 (22%)
– Cumulative risk of metachronous CRC at 10, 20, & 30 yrs = 16%, 41% & 62% respectively
Cost effectiveness Data
Mvundura M, et al. Genet Med. 2010;12:93-104
Targeting screening only to CRCs < age 50 would miss over 50% of LS cases
Business Analysis by a Healthcare System
• Evidence review & computerized simulation models – Intermountain Healthcare
• Cost of screening all (unselected) CRC patients for Lynch syndrome <$25,000/LYS
• IHC with methylation studies, reflexing to BRAF most efficient
Gudgeon, Am J Managed Care, 2011;17:e288
Universal IHC screening for CRC: OSU experience
• Began March 1, 2006• 270 cases of CRC in first 2 years
– 57 (21.1%) absent for one or two MMR proteins– 54 contacted by genetics with physician
consent• 5 deceased, reported to next of kin• 7 prisoners
– 34 appropriate for consultation– 18 scheduled appointment/9 completed appt– 7/9 tested
• 2 confirmed Lynch, 3 with MLH1 methylation
South et al, Genet Med 2009; 11:812-817
Challenges to Implementation
Lack of provider knowledge of Lynch syndrome and testing issues
Question of informed consent Availability of genetic services Cost and coverage Psychosocial impact Informing relatives – who is responsible? Patient and provider compliance Infrastructure needs Testing limitations (e.g. IHC accuracy by site)
It takes a teamSurgeryPathologyOncologyGastroenterologyGeneticsGynecologyPatientsFamiliesHealthcare system
LSSN Vision and Mission• LSSN Vision:
– to reduce the cancer burden associated with Lynch syndrome.
• LSSN Mission:
– to promote universal Lynch syndrome screening on all newly diagnosed colorectal and endometrial cancers; to facilitate the ability of institutions to implement appropriate screening by sharing resources, protocols and data through network collaboration; and to investigate universal screening for other Lynch syndrome related malignancies
Membership Data
Emory LS Screening TeamN. Volkan Adsay, MD PathologyCecelia A. Bellcross PhD, MS, CGC GeneticsAmanda Eppolito, MS, CGC GeneticsAlton B. Farris, III, MD PathologyNatalyn N. Hawk, MD Hem/OncIra R. Horowitz, MD Gyn/OncJohn Kauh, MD Hem/OncNamita Khanna, MD Gyn/OncDana M. Meaney-Delman, MD High Risk Gyn Virginia O. Shaffer, MD Colorectal SurgeryChristine Stanislaw, MS, CGC GeneticsPatrick S. Sullivan, MD Colorectal Surgery
Miranda Chergosky – GC Student Focus Intern
Emory LS Screening Protocol
IHC Result InterpretationIHC Result Frequency Implications Follow-up
MLH1 & PMS2 Absent
15%
80% acquired
20% LS due to MLH1 mutation
BRAF (V600E +) and/or MLH1 hypermethylation Genetics referral & MLH1 DNA analysis
MSH2 & MSH6 Absent
3% Most LS due to MSH2 mutation
Genetics referral & MSH2 DNA analysis
MSH6 or PMS2 Absent
2% Most LS due to MSH6 or PMS2 mutation
Genetics referral & MSH6/PMS2 DNA analysis
Genetics Follow-up• Access to CoPath – automatic search for all
CRC specimens– Monitor if IHC being done – interface with GI
path fellows– Review IHC/BRAF results
• Enter into LSSN database• Abnormal IHC results
• Follow-up letter to MD via EMR• Coordination with RN staff to ensure genetics referral• Subset of IHC positive screens to be seen at point of
care (post-op or oncology appt)• Enter follow-up/outcome data into LSSN db
What Is Cancer Genetic Counseling?
• Cancer genetic counseling is NOT genetic testing!
• It is a process of information gathering, risk assessment and education.
• The goal of cancer genetic counseling is to provide the individual, family and their health care providers with accurate cancer risk information to facilitate personal management decisions.
Initial Genetic Counseling Visit
• Review medical history and family history• Assess risk for hereditary cancer• Discuss cancer biology and genetics• Discuss genetic testing options and/or referrals
for additional evaluation if appropriate• Discuss implications of testing for the patient
and their family• Coordinate testing including review of
insurance issues
Informed Consent:Potential Benefits of Genetic Testing
• Improved cancer risk management– Prevention– Early detection– Avoidance of unnecessary and costly screening and
surgery
• Relief from uncertainty and anxiety about cancer risk
• Information for individual and family members• Lifestyle decision making
Informed Consent:Limitations of Genetic Testing
• Not all mutations are detectable• Uncertain significance of some mutations • Negative result is fully informative only if
mutation has been identified in family • Results indicate probability, not certainty, of
developing cancer • Management/screening strategies continually
evolving as new data collected
Ideally, Begin Testing With an Affected Person
If a mutation is found in an affected person, testing will be more informative for other family members.
Colon Ca, 42
Colon Ca, 38d.45
Colon Ca, 45 Person seeking
counseling (proband)
Test first, if possible
Understanding Possible Test Results
Positive
Negative
Uncertain Variant
Increased Cancer Risk
Has a mutation been found in the
family?
Y
N
NO Increased Cancer Risk
Cancer Risk Not Altered
(individualized empiric risk based on family
history)
Impact of Genetic TestingFamily with known mutation
True negative: no increased risk beyond general population
Colon Ca, 52
Endometrial Ca, 47
Colon Ca, 45
MSH2 +37
MSH2 -
d. 50MSH2?
*30
MSH2+
Mutation Positive: initiate screening
Informed Consent:Potential Risks of Genetic Testing
• False sense of security if test negative• Psychological distress• Change in family dynamics• ?? Insurance discrimination
The Myth of Genetic Discrimination• No well-documented cases of health
insurance loss, denial, or rate increase based on cancer genetic testing • State and Federal laws exist which address health insurance and employment• GINA – Genetic Information Non-
discrimination Act (May, 2008)• Life/disability/long-term care not
protected
Result Disclosure and Post-test Counseling
• Assess cancer risk based on test results• Discuss any additional testing recommendations• Review of implications for family members• Present screening and management options• Discuss risk reduction strategies• Explore psychosocial adjustment to cancer risk and/or
genetic risk
QuestionsCommentsThoughts
Suggestions
?Thank You