Emerging Concepts in Colorectal
Cancer:
Hereditary Non-Polyposis Cancer
(Lynch Syndrome)
Short Presentations in Emerging
Concepts (SPEC)
Colorectal Cancer:
Molecular Pathways
Hypermutability
Pathway
Chromosomal
Instability Pathway
Molecular pathways in colon cancer
What value is there in recognizing MSI-H
colorectal tumors?
1. Prognosis
2. Response to chemotherapy
3. Screen for Lynch Syndrome (HNPCC)
Prognostic significance of MSI-H in sporadic
CRC
Gryfe,R et al, NEJM 2000; 342:69-77
Tumor Microsatellite-Instability Status as a Predictor of Benefit
from Fluorouracil-Based Adjuvant Chemotherapy for Colon
Cancer
Ribic, C.R., et al. New Engl J Med 349:247-57 (2003)
Colorectal Cancer:
Molecular Pathways
Hypermutability
Pathway
Chromosomal
Instability Pathway
APC
Lynch
Lynch Syndrome (HNPCC)
• HNPCC – Hereditary Non-Polyposis Colon Cancer
– Historically:
• Lynch Syndrome I – restricted to colon
• Lynch Syndrome II – colon and extracolonic sites
• Accounts for 3-4% of all colon cancers
• Accounts for 15-20% of MSI tumors
• Inherited predisposition to many different cancers,
including colon cancer
Lynch Syndrome: Cardinal Features
• Autosomal dominant inheritance
• Gene penetrance for CRC of 85-90%
– Develop CRC at an early age - 45 yrs
– Most CRC (70%) proximal to splenic flexure
– Multiple CRC’s common - synchronous and
metachronous
– Prognosis better than sporadic CRC
– Associated pathologic features
• Increased risk for other malignancies
Lynch Syndrome:
Extracolonic Tumors
Site
Features
Endometrium
Second most common
Stomach
Older generations
Small bowel
Risk 25X in HNPCC
Hepatobiliary tract
5% risk
Ureter and pelvis
14-20% risk
Skin
Muir-Torre Syndrome
Pancreas
Trend for increase
Brain
GBM in some HNPCC (Turcot’s)
Hematologic
Case reports
Soft tissue
Case reports
Larynx
Case report
Lynch Syndrome:
Cumulative cancer risk in LS carriers by age
70
Site of tumor
Finnish population (%)
HNPCC families (%)
Colon/rectum
1.6
82
Endometrium
1.3
60
Stomach
0.8
13
Ovary
1.3
12
Bladder, ureter, urethra
0.7
4.0
Brain
0.9
3.7
Kidney
0.8
3.3
Biliary tract, gallbladder
0.2
2.0
Aarnio M, et al, Int J Cancer 1999; 81:214-218.
Lynch Syndrome:
Cumulative cancer risk by age 70
By age 70, the risk for endometrial cancer
exceeds that of colon cancer:
Site
Incidence by age 70 in
women
Endometrium
Colon
60%
54%
Aarnio, M et al, Int J Cancer 1999; 81:214-18
Lynch Syndrome:
Pathological features of colorectal cancer
•
•
•
•
•
•
Poor differentiation
Increased signet cells
Medullary features
Peritumoral lymphocyte infiltration
Crohn’s like reaction
Tumor infiltrating lymphocytes (TIL’s)
How to recognize Lynch Syndrome
• Amsterdam Criteria
– Clinical guidelines for when to suspect Lynch
Syndrome
• Bethesda Guidelines
– Guidelines for when to do MSI testing
• Screen all new colon cancers?
Lynch Syndrome - Amsterdam
Criteria II (1999)
• At least three family members with a Lynch Syndromeassociated cancer, two of whom are first-degree
relatives.
• At least two generations represented.
• At least 1 individual younger than 50 years at diagnosis.
• FAP should be excluded.
• Tumors should be verified by pathologic examination.
Vasen et al, Gastroenterology 1999;116:1453-56
Revised Bethesda Guidelines for testing
colorectal tumors for MSI - 2004
Tumors from individuals should be tested for MSI in the following
situations:
1. Colorectal cancer in a patient less than 50 years of age.
2. Presence of synchronous, metachronous colorectal, or other HNPCC
associated tumors, regardless of age.
3. Colorectal cancer with the MSI-H histology diagnosed in a patient less
than 60 yr.
4. Colorectal cancer diagnosed in one or more first-degree relatives with
an HNPCC-related tumor, with one of the cancers being diagnosed
under age 50 yr.
5. Colorectal cancer diagnosed in two or more first- or second-degree
relatives with HNPCC-related tumors, regardless of age.
Umar, et al., J Natl Cancer Inst 2004; 96:261-8
Lynch Syndrome:
Mismatch repair gene mutations
Gene
Frequency in HNPCC
MSH2
~39%
MLH1
~32%
PMS1
Rare
PMS2
~14%
GTBP/MSH6
~14%
Other
?
Immunohistochemistry
for MMR Protein Expression
MLH1
MSH6
Loss of expression
Due to mutation
Due to methylation
MSH2
PMS2
Lynch Syndrome
Sporadic MSI CRC
Universal screening
Recommendations from the EGAPP Working Group:
genetic testing strategies in newly diagnosed individuals
with colorectal cancer aimed at reducing morbidity and
mortality from Lynch syndrome in relatives
Evaluation of Genomic Applications in Practice and Prevention Working Group
Genetics in Medicine 11:35-41 (2009)
Significance of Lynch Syndrome
1. The patient is at risk for other cancers
and needs appropriate surveillance.
2. The patient’s relatives will also be at
increased risk if they carry the same
mutation, and will need appropriate
surveillance.
3. Relatives can be tested to determine their
risk, and level of surveillance.
Summary
• MSI-H tumors account for about 20% of all colon
cancers.
• Lynch Syndrome tumors account for 15 - 20% of MSI-H
colon cancers, and about 4% of all colon cancers.
• MSI-H colon cancers are biologically distinctive in their
behavior.
• MSI testing should be performed if indicated by
Bethesda Guidelines.
• MSI testing can be performed on fixed tissue.
• Patients with MSI-H tumors are candidates for genetic
counseling and further genetic testing.
Selected Resources
Lynch HT, et al. Hereditary nonpolyposis colorectal carcinoma and
HNPCC-like families: problems in diagnosis,m surveillance, and
management. Cancer .2004 ;100:53-64.
EGAPP Working Group. Recommendations from the EGAPP Working
Group: genetic testing strategies in newly diagnosed individuals with
colorectal cancer aimed at reducing morbidity and mortality from Lynch
syndrome in relatives. Genet Med. 2009 ;11(1):35-41.
Vasen HF, Blanco I, Aktan-Collan K, et al. Revised guidelines for the clinical
management of Lynch Syndrome (HNPCC): recommendations by a group
of European experts. Gut. 2013;62(6):812-823.
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