Cecelia Bellcross PhD MS CGC Emory University School of Medicine Department of Human Genetics Genetics of CRC Sporadic 65 85 Familial 10 30 Lynch syndrome aka Hereditary ID: 294206
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Slide1
Universal Screening for Lynch Syndrome
Cecelia Bellcross, PhD, MS, CGCEmory University School of MedicineDepartment of Human GeneticsSlide2
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%)Slide3
Clinical Features of Lynch/
HNPCCEarly 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 tumorsSlide4
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
45Slide5
Other Features of Lynch Syndrome
Autosomal dominant inheritanceGenes belong to DNA mismatch repair (MMR) family Genetic heterogeneity (
MLH1, MSH2, MSH6, PMS2
)
CRC lifetime risk 30-80%
Endometrial cancer lifetime risk 30-60%Slide6
CRC RISK
*Barrow, Clin
Genet 2008Slide7
Extra-colonic/Extra Endometrial
Lifetime 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, 2008Slide8
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 years
Oophorectomy
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
30-35
Renal 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)Slide9
Impact of Screening
Percent
Jarvinen
,
Gastroent
, 2000
Jarvinen
, JCO, 2009: 242 mutation +, 367 mutation - : >95% screening compliance, no difference in cancer or all cause mortality ratesSlide10
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 HNPCCSlide11
Revised Bethesda Guidelines:
CRC < age 50Patient 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, 2004Slide12
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 MicrosatellitesSlide13
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+Slide14
Testing for Lynch/HNPCC
Family/Medical history meets screening criteriaAmsterdam/Bethesda
MSI/IHC
on
tumor tissue
MSI
normal IHC normal
No further testingRisks & screeningbased on historyMSI-High IHC – loss of protein expression
Genetic Testingon bloodMutation Identified
No mutation Identified1. Consider additional genetic testing
2. Risks & screening based on test results and family/medical history
Lynch/HNPCC screening & managementFamily members offered testingSlide15
Rationale for HNPCC/Lynch Syndrome
Screening of Newly Diagnosed CRCCommon: ~ 3% of all
CRC
Age/screening criteria miss up to 25%
Accurate methods
(MSI/IHC) using
easily accessible tumor tissue
Benefits of medical interventionCascade testing of family membersSurveillance/preventionCRC treatment decisions
Evidence of cost-effectivenessSlide16
EGAPP Lynch Recommendation
Genetics in Medicine January 2009May, 2007www.ahrq.gov/downloads/pub/evidence/pdf/hnpcc/hnpcc.pdf
GIM, 2009;1:42
GIM, 2009;1:35Slide17
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.”Slide18
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% MSH213.6% MSH613.6% PMS2
Columbus-area HNPCC study (1999-2005)
Hampel et al.
New Engl J Med 2005; 352:1851 Hampel
et al. J Clin Oncol 2008; 26:5783Slide19
35 CRC
probands have had genetic counselingDegree of Kinship Tested Positive
First 99 52
Second 64 28
> Second 86 29
Total 249
109
Family Studies of 35/44 CRC ProbandsHampel et al. NEJM 2005;352:1851-60.; Hampel et al. JCO 2008.Slide20
Theoretical Population Health Benefit
Bellcross, Genet Med, 2012Slide21
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”Slide22
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
Mutations14.3% MLH1 21.4% MSH264.3% MSH6No PMS2
2.5 % with deleterious mutations (n=14)Slide23
12/14 EC
probands have had genetic counselingDegree of Kinship Tested Positive
First 28 16
Second 12 3
> Second 8 2
Total 48 21
Columbus HNPCC study Family studies of 14 EC probandsSlide24
EGAPP Data Interpretation Concerns“To reduce morbidity and mortality in relatives”Implies no benefit to
probandIncreasing evidence of impact on CRC management – chemotherapy, surgeryKnown increased risk for 2nd primary colorectal cancers and other tumors impacts medical managementDoes not take into account current practice and insurance coverage (including Medicare)Slide25
Potential Impact on CRC treatmentMSI-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 carriersExtensive colectomy – 0/50 metachronous
tumors vs. Segmental resection – 74/322 (22%)
Cumulative risk of
metachronous
CRC at 10, 20, & 30 yrs = 16%, 41% & 62% respectivelySlide26
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 casesSlide27
Business Analysis by a Healthcare SystemEvidence review & computerized simulation models – Intermountain Healthcare
Cost of screening all (unselected) CRC patients for Lynch syndrome <$25,000/LYSIHC with methylation studies, reflexing to BRAF most efficientGudgeon, Am J Managed Care, 2011;17:e288Slide28
Universal IHC screening for CRC: OSU experience
Began March 1, 2006270 cases of CRC in first 2 years57 (21.1%) absent for one or two MMR proteins54 contacted by genetics with physician consent5 deceased, reported to next of kin7 prisoners34 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; 11:812-817Slide29
Challenges to Implementation
Lack of provider knowledge of Lynch syndrome and testing issuesQuestion of informed consentAvailability of genetic servicesCost and coverage Psychosocial impact
Informing relatives – who is responsible?
Patient and provider compliance
Infrastructure needs
Testing limitations (e.g. IHC accuracy by site)
Slide30
It takes a team
SurgeryPathologyOncologyGastroenterologyGeneticsGynecologyPatientsFamiliesHealthcare systemSlide31
http://
www.lynchscreening.net Slide32
LSSN Vision and MissionLSSN 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 malignanciesSlide33
Membership DataSlide34
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/
Onc
Namita
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 InternSlide35
Emory LS Screening ProtocolSlide36
IHC Result Interpretation
IHC ResultFrequencyImplications
Follow-up
MLH1 & PMS2 Absent
15%
80% acquired
20% LS due to MLH1 mutationBRAF (V600E +) and/or MLH1 hypermethylation Genetics referral & MLH1 DNA analysis
MSH2 & MSH6 Absent3%Most LS due to MSH2 mutationGenetics referral & MSH2 DNA analysisMSH6 or PMS2 Absent
2%Most LS due to MSH6 or PMS2 mutation
Genetics referral & MSH6/PMS2 DNA analysisSlide37
Genetics Follow-upAccess to
CoPath – automatic search for all CRC specimensMonitor if IHC being done – interface with GI path fellowsReview IHC/BRAF resultsEnter into LSSN databaseAbnormal IHC resultsFollow-up letter to MD via EMRCoordination with RN staff to ensure genetics referralSubset of IHC positive screens to be seen at point of care (post-op or oncology appt)Enter follow-up/outcome data into LSSN dbSlide38Slide39
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.Slide40
Initial Genetic Counseling Visit
Review medical history and family historyAssess risk for hereditary cancerDiscuss 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 issuesSlide41
Informed Consent:
Potential Benefits of Genetic TestingImproved cancer risk managementPrevention
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 makingSlide42
Informed Consent:
Limitations of Genetic TestingNot all mutations are detectableUncertain 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 collectedSlide43
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, 38
d.45
Colon Ca, 45
Person seeking counseling (proband)
Test first, if possibleSlide44
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)Slide45
Impact of Genetic Testing
Family with known mutation
True
negative:
no increased risk beyond general population
Colon Ca, 52
Endometrial Ca, 47
Colon Ca, 45
MSH2
+
37
MSH2
-
d. 50
MSH2?
*
30
MSH2+
Mutation
Positive:
initiate
screeningSlide46
Informed Consent:
Potential Risks of Genetic TestingFalse sense of security if test negativePsychological distressChange in family dynamics
?? Insurance discrimination Slide47
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 protectedSlide48
Result Disclosure and Post-test
CounselingAssess cancer risk based on test resultsDiscuss 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 riskSlide49
Questions
CommentsThoughtsSuggestions?Thank You