CANCER GENETICS: IDENTIFICATION AND MANAGEMENT OF INDIVIDUALS WITH LYNCH SYNDROME HENRY T. LYNCH, MD Creighton University School of Medicine Omaha, Nebraska. Hereditary Cancer Syndromes: Nuts and Bolts. Family history; Hereditary cancer syndrome diagnosis; Genetic counseling;
CANCER GENETICS: IDENTIFICATION AND MANAGEMENT OF INDIVIDUALS WITH LYNCH SYNDROME
HENRY T. LYNCH, MD
School of Medicine
Hereditary Cancer Syndromes: INDIVIDUALS WITH LYNCH SYNDROMENuts and Bolts
Patient’s Modified Nuclear Pedigree INDIVIDUALS WITH LYNCH SYNDROME
• breast and ovary (HBOC syndrome);
• CRC, endometrium, ovary, others (Lynch syndrome);
• sarcomas, breast, brain, multiple others in SBLA (Li-
• medullary thyroid carcinoma and
pheochromocytoma (MEN-2a and MEN-2b);
• melanoma and pancreatic cancer with CDKN2A
(p16) mutation (FAMMM syndrome);
• diffuse gastric cancer and lobular breast cancer
with CDH1 mutation (HDGC syndrome);
...and the list goes on.
Familial/Hereditary CRC INDIVIDUALS WITH LYNCH SYNDROMEin US
Annual CRC incidence in US: 142,570
Lynch syndrome 3-5% of all CRC 4,277 - 7,129
FAP <1% of all CRC <1,426
Familial 20% of all CRC 28,514
Jemal et al. CA Cancer J Clin 60:277-300,2010.
Should we test all colorectal cancer for Lynch Syndrome? INDIVIDUALS WITH LYNCH SYNDROME
YES! Test everybody.
Search for LS Among CRC Affecteds* INDIVIDUALS WITH LYNCH SYNDROME
Among 500 CRC patients, 18 (3.6%) had LS.
Of these 18:
18 (100%) had MSI-H CRCs;
17 (94%) were correctly predicted by IHC;
only 8 (44%) were dx < 50 years;
only 13 (72%) met the revised Bethesda guidelines;
1/35 cases of CRC show LS.
*Hampel et al. J Clin Oncol 26:5783-5788, 2008.
Mismatch Repair (MMR) Mutations INDIVIDUALS WITH LYNCH SYNDROMEGenetic Heterogeneity in HNPCC
HNPCC is associated with germline mutations in any one of at least five genes
25-30% of patients who have surgery for a LS-associated CRC will
have a second primary CRC within 10 years, if surgery was < a
N Engl J Med 354: INDIVIDUALS WITH LYNCH SYNDROME 261-269, 2006.
Could this be INDIVIDUALS WITH LYNCH SYNDROME
Dis Colon Rectum 53: INDIVIDUALS WITH LYNCH SYNDROME77-82, 2010.
Meyer et al. INDIVIDUALS WITH LYNCH SYNDROMECancer Control 16:14-22,2009.
Familial INDIVIDUALS WITH LYNCH SYNDROME
AC-1 without MMR
(Familial CRC of syndrome “X”)
Mixed Polyposis Syndrome
= as yet undiscovered
hereditary cancer variants
Hereditary Polyposis Syndromes INDIVIDUALS WITH LYNCH SYNDROME
MORPHOLOGY INDIVIDUALS WITH LYNCH SYNDROME
Run PCR test
for MSI status
NO EVIDENCE OF
Is there loss
with any of
Run mutation analysis
for BRAF V600E
MMR GENES MUTATION
IHC for MLH1,
MSH2, MSH6, PMS2
a mutation in MMR
Gatalica Z, Torlakovic E. Fam Cancer 2008;7:15-26
Diagnosis INDIVIDUALS WITH LYNCH SYNDROME
Phenotype site specific CRC
ImpactsEpithelial Cell Adhesion Molecule (EPCAM) Gene and Its Lynch Syndrome Connection
5’ INDIVIDUALS WITH LYNCH SYNDROMEEPCAM deletion
Exons 8 and 9 and polyadenylationsequence
Transcriptional read through
Hypermethylation of the MSH2 promoter
Ligtenberg MJ, Nature Genetics 2009.
American and Dutch families have the same deletion in the INDIVIDUALS WITH LYNCH SYNDROMEEPCAM gene
(4.9 kb, starting in intron 7 and including exons 8 & 9)
Lightenberg, Nature Genetics 2009.
First patient identified with INDIVIDUALS WITH LYNCH SYNDROMEEPCAM mutation
American and Dutch INDIVIDUALS WITH LYNCH SYNDROMEEPCAM mutations originate from a common ancestor
Family R and the Dutch families share a 6.1 MB region surrounding
the same EPCAM deletion indicating a common ancestor. Based on the size of the shared region it is estimated the deletion occurred 10 generations ago.
Deletion and Region inherited from common ancestor
J Clin Oncol25: INDIVIDUALS WITH LYNCH SYNDROME3534-3542, 2007.
1. Pedigree consistent with hereditary colorectal
cancer (CRC) syndrome;
2. Known germline mutation predisposing to
3. Patients at acceptable high cancer risk status;
4. Presence of cancer syndrome stigmata
(phenotype): e.g., polyposis in FAP;
5. Genetic counseling, risks/benefits understood;
6. Consent given;
7. Results: full explanation of
Family Information Service (FIS) INDIVIDUALS WITH LYNCH SYNDROME
Cost-effective and highly efficient way of educating and counseling all available family members from a geographic catchment area during a single setting.
Makes best use of physician’s time and effort, has group therapy potential and patients welcome it.
Personalized Medicine INDIVIDUALS WITH LYNCH SYNDROME
Need Individual management
based upon Genetic diagnosis
(deleterious mutation helpful)
Need more clinical genetic education. Example: multiple
polyps = FAP; multiple primary cancer pattern = syndrome identification
What is advantage of extensive family history; genetic counseling; genetic testing (MMR, MSI, IHC, BRCA1/2); screening?