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TRANSCRIPT
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COLON CANCER &
GENETICSVERMONT COLORECTAL CANCER
SUMMIT
NOVEMBER 15, 2014
WENDY MCKINNON, MS, CGC
CERTIFIED GENETIC COUNSELOR
FAMILIAL CANCER PROGRAM
UNIVERSITY OF VERMONT MEDICAL CENTER
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� Multiple relatives with colorectal cancer on same side of the family (maternal or paternal lineage)
� Early age at diagnosis of colon cancer (<50)
� Multiple primary tumors in same individual
� Multiple colon polyps
� Other benign and/or malignant tumors in the family known to be associated with inherited CRC
CHARACTERISTICS OF HEREDITARY
COLORECTAL CANCER
�Lynch syndrome / HNPCC� Autosomal dominant
� Variants: Turcot, Muir-Torre
� Genes: MLH1, MSH2 (EPCAM), MSH6, PMS2
�Familial adenomatous polyposis (FAP)� Autosomal dominant
� Variants: AFAP, Gardner, Turcot
� Gene: APC
�Multiple adenomatous polyposis (MAP)� Autosomal recessive
� Gene: MUTYH
INHERITED CRC: ADENOMATOUS
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� Peutz-Jegher syndrome (PJS)
�Gene: STK11
� Juvenile Polyposis (JP)
�Genes: SMAD4, BMPR1A
�Mutations in SMAD4 also associated with HHT
� Cowden syndrome (CS)
�Variant: Bannayan-Ruvalcaba-Riley (BRR)
�Gene: PTEN
INHERITED CRC: HAMARTOMATOUS
* All are autosomal dominant
�Accounts for at least 3% all colon
cancers
�Characteristics:
�Early age onset
�Proximal tumors
�Pathologic characteristics
�Extra-colonic cancers
� LS accounts for at least 3% all endometrial cancers
� Gastric, small intestine, urinary tract, ovarian, hepatobiliary,
sebaceous skin tumors, and glioblastomas
LYNCH SYNDROME
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LIFETIME CANCER RISKS FOR LS
Cancer siteCancer siteCancer siteCancer site MLH1MLH1MLH1MLH1 MSH2MSH2MSH2MSH2 MSH6MSH6MSH6MSH6 PMS2PMS2PMS2PMS2
Any Lynch
cancer
44-79% 38-78% 25-65% 16-53%
ColorectalColorectalColorectalColorectalMenMenMenMen
WomenWomenWomenWomen
58585858----65%65%65%65%
50505050----53%53%53%53%
54545454----63%63%63%63%
39393939----68%68%68%68%
36363636----69%69%69%69%
18181818----30%30%30%30%
20%20%20%20%
15%15%15%15%
Endometrial 57-66% 21% 17-44%
15%
Lynch syndrome Surveillance Options
Lindor et al, 2006; Vasen et al, 2007; Lu 2007
Intervention Recommendation
Colonoscopy Every 1-2 y beginning at age 20-25 (MLH1
& MSH2), or age 30 (MSH6 & PMS2).
Annual after age 40.
Endometrial sampling
Transvaginal US
Upper endoscopy
Annual beginning at age 30-35
Consideration of TAH/BSO
Urinalysis Every 1-2 y beginning at age 25-35
History & Exam w/
review of systems
Annual beginning at age 21
Periodic
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�Family history / clinical criteria
�Tumor based testing
�Molecular / DNA based testing
�Multi-gene panels
�Tumor genomics
APPROACHES TO DIAGNOSING LYNCH
SYNDROME
THE FAMILY HISTORY AND
DIAGNOSING LYNCH SYNDROME
CRCdx 50s
CRCdx 45
CRCdx 61
CRCdx 75
OvarianCa, dx
64
CRCdx 48
CRCdx 52
EndometrialCa, dx 59
CRCdx 42
45
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�Many families do not meet current clinical criteria for Lynch syndrome
�Amsterdam Criteria I and II
�Bethesda Criteria, original and revised
�Hampel, et al NEJM, 2005
�Screened 1500 CRC; 44 LS mutation carriers
�50% CRC diagnosed after age 50
�25% did not meet AC or BC
CLINICAL CRITERIA
� Genes belong to DNA mismatch repair (MMR)
family
� Mutations in MMR genes lead to microsatellite
instability (repetitive sequences of DNA)
� MMR proteins are missing in the tumor tissue
GENETIC FEATURES OF LYNCH
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� Identify MMR proteins normally present
� If protein is absent, gene is not being expressed (mutation or methylation)
� Helps direct gene testing by predicting likely involved gene
IMMUNOHISTOCHEMISTRY
MSH2MLH1
MSH6PMS2
ABNORMAL – MLH1 & PMS2 ABSENT
�15% of the
time
�80% acquired
methylation of
MLH1
�20% will be LS
MLH1 MSH2
MSH6PMS2
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ABNORMAL – MSH2 & MSH6 ABSENT
�3% of the time
�Most likely LS due to either MSH2 or MSH6gene mutation
�Refer to Genetics for GC and GT
MLH1 MSH2
PMS2MSH6
ABNORMAL – MSH6 OR PMS2 ABSENT
�2% of the time
�Most likely LS due to an MSH6 or PMS2 gene mutation
�Refer to Genetics for GC and GT
MLH1MSH2
MSH6 PMS2
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� Columbus-area HNPCC studies◦ NEJM 2005;352:1851-60; J Clin Oncol 2008;26:5783-88
� EGAPP Recommendations◦ All CRC be screened for LS; Genet Med, 2009,11:35-41
� Cost-effectiveness evaluations◦ Genet Med, 2010, 12:93-104; Ann Int Med, 2011, 155:69-79
� Healthy People 2020; www.healthypeople.gov
� Institutions adopting universal screening◦ 71% NCI Cancer Centers
◦ 28% COC Accredited Cancer Centers
◦ 15% Community Cancer Centers
EVIDENCE FOR UNIVERSAL SCREENING
POTENTIAL IMPACT
�146,970 new cases of CRC in the US
�4,115 have Lynch syndrome (2.8%)
�12,345 of their relatives have LS (~3 per
proband)
�Total of 16,460 individuals who could be
diagnosed with LS by universal screening on
colon cancers
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�For cancer patient with LS diagnosis:
� Increased risk of second primary cancer
� 50% after 20 years
�Guidelines differ for cancer patients with/without LS
�For relatives:
� Individualize screening for relatives with/without LS
�Early diagnosis / prevention
IMPLICATIONS OF DIAGNOSIS OF LYNCH
SYNDROME
�2010-11, a targeted approach was used
�Jan 2012, all colon cancers tested for Lynch
syndrome
�colon resections
�biopsies under age 50
�September 2014, switched to testing all
biopsies containing cancer regardless of age
� IHC is screening tool used
UNIVERSAL SCREENING FOR LYNCH
SYNDROME AT FAHC/UVMC
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IHC LETTER
�Genetic Counselor notified by pathology of all
results
�For abnormal results, GC asks permission of
ordering physician to contact patient
�Patient contacted and GC appointment
scheduled
�All results entered into database housed in
the EMR
�All patients with normal results sent letter
COMMUNICATION OF RESULTS
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PRISM (EPIC) Document Flowsheet
NORMAL IHC RESULT LETTER
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Established Guidelines
� MLH1
� MSH2
� MSH6
� EPCAM
� PMS2
� APC
� MUTYH
� SMAD4
� BMPR1A
� TP53
� STK11
Newer genes; no
established guidelines
� CHEK2
� GREM1
� GALNT12
� POLE
� POLD1
GENES ASSOCIATED WITH INCREASED COLON
CANCER RISK
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� Family history is key component
� Thanksgiving is National Family History Day
� Access the My Family Health Portrait Web
tool at https://familyhistory.hhs.gov/
FAMILY HISTORY
Contact Information:
Familial Cancer Program
(802) 847-4495
THANK YOU!