Comprehensive IHC Screening
for Lynch Syndrome:
What You Need to Know
Andrea Lewis, MS, CGC
January 14, 2010
Overview
Lynch syndrome review
Norton Comprehensive IHC Screening
Program
Interpreting IHC results
What is Lynch Syndrome?
 Hereditary cancer syndrome associated with an
increased risk for:
Colon cancer
2nd colon cancer
Uterine cancer
Gastric cancer
Ovarian cancer
Urinary tract
Hepatobiliary tract
Small bowel
CNS/Brain
80%
40-50%
60%
11-19%
9-12%
4-7%
2-7%
1-4%
1-3%
Immunohistochemistry Screening for
Lynch syndrome
IHC staining for the 4 mismatch repair
gene proteins is performed on tumor
tissue
MLH1, MSH2, MSH6, and PMS2 genes
Proteins are normally present
Absence of one or more of the proteins could
indicate Lynch syndrome
Can direct genetic testing
Can be done in house
Approximately 94% detection rate
Importance of IHC Screening
 Columbus area Lynch syndrome study
500 patients with CRC screened for Lynch
syndrome
18 had Lynch syndrome (3.6%)
Age range from 23-77
Only 44% were diagnosed under age 50
Only 72% met Amsterdam or Bethesda Criteria
An average of 3 family members tested per proband
 Average age of colon cancer diagnosed in
patients with Lynch syndrome is 61.2 years
Hampel, et al. JCO 2008, Hampel, et al. Gastroent 2005
Importance of IHC Screening
 Proper screening reduces cancer risks
 15 year colonoscopy screening
Colorectal cancer
Death from CRC
Overall deaths
Screened
Not Screened
n=133
8
0
10
n=119
19
p=0.014
9
p<0.001
26
P<0.001
 Colonoscopy screening decreases overall
mortality in Lynch syndrome families by 65%
Jarvinen, et al. Gastroent. 2000
Norton Comprehensive IHC Program
 Launched October 1, 2009
 IHC for Lynch sx performed on all colorectal
cancers resected at Norton Healthcare
 All results sent to Genetic Counseling Service
 Process for abnormal results
Surgeon is contacted to discuss follow-up plan
Patient is offered genetic counseling appointment
Gene specific testing for Lynch syndrome performed
Program Statistics
31 colorectal resections performed in the
Norton Healthcare system 10/1/09-present
7 abnormal IHC results (22.6%)
6 MLH1/PMS2
1 MSH2/MSH6
Surgeons of all 7 patients have been
contacted
1 patient underwent testing (neg)
2 patients have scheduled appointments
Interpreting IHC Results
Interpreting IHC Results
MLH1
Protein Expressed
MSH2
Protein Expressed
MSH6
Protein Expressed
PMS2
Protein Expressed
This test result indicates that ALL four genes are
likely functioning normally. Patients with this
test result are very unlikely to have Lynch
Syndrome.
***Patients with a significant family history or indication of a
different hereditary cancer syndrome should still be referred
to Genetic Counseling Services***
Interpreting IHC Results
MLH1
Protein Not Expressed
MLH1
Protein Expressed
MSH2
Protein Expressed
MSH2
Protein Not Expressed
MSH6
Protein Expressed
MSH6
Protein Not Expressed
PMS2
Protein Not Expressed
PMS2
Protein Expressed
This test result indicates that the MLH1 gene (or
rarely the PMS2 gene) is NOT functioning in the
colon tumor. Patients have a 20% chance to
have Lynch syndrome due to a deleterious
mutation in the MLH1 gene and an 80% chance
to have loss of expression due to somatic
hypermethylation of the MLH1 gene.
This test result indicates that the MSH2 gene (or
rarely the MSH6 gene) is NOT functioning in
the colon tumor. Patients with this test result
have nearly a 100% chance to have Lynch
syndrome due to a deleterious mutation in the
MSH2 gene.
Interpreting IHC Results
MLH1
Protein Expressed
MLH
1
Protein Expressed
MSH2
Protein Expressed
MSH
2
Protein Expressed
MSH6
Protein Not Expressed
MSH
6
Protein Expressed
PMS2
Protein Expressed
PMS
2
Protein Not Expressed
This test result indicates that the MSH6 gene is
NOT functioning in the colon tumor. Patients
with this test result have nearly a 100% chance to
have Lynch syndrome due to a deleterious
mutation in the MSH6 gene.
This test result indicates that PMS2 is NOT
functioning in the colon tumor. Patients with
this test result have nearly a 100% chance to
have Lynch syndrome due to a deleterious
mutation in the PMS2 gene.
Questions?