1. MLH 1 and Hereditary Nonpolyposis Colorectal Cancer
Nathan H. Calloway

2. HNPCC: what is it?
Most frequent autosomal dominant predisposition to the development of colon cancer.
A contributing factor in 2-4% of ALL colon cancer cases.
Characterized by an earlier onset of colorectal cancer and increased frequency of other cancers.
How do we identify those with HNPCC?...

3. Amsterdam Criteria Exclusion of familial polyposis.
Colorectal cancer in at least three relatives, one of them being a 1st-degree relative of the others.
Involvement of at least two generations of colorectal cancer.
At least one colon cancer diagnosed before age 50.

4. Enhanced susceptibility for cancers of the…
Colon Ovary
Also the endometrium (lining of uterus)

5. HNPCC and mismatch repair genes.
MMR genes are the genes responsible for HNPCC.
Major MMR genes and HNPCC
Major MMR Genes:
MLH1 (MutL Homolog)
MSH 2
Minor MMR Genes:
MSH6
PMS1
PMS2

6. MMR genes function to repair DNA damage.
DNA replication must occur without errors transmitted to the daughter cells.

7. MMR Genes Repair DNA damage or errors incurred during replication.
Damage can be slippage, misincorporation of bases, or other causes of changes in DNA.

8. MMR Genes And Growth
MMR genes have a more passive role in controlling growth, as opposed to tumor suppressor genes.
Tumor suppressor genes (RB1, p53…etc) have more active roles in controlling growth and apoptosis.
So, how do MMR gene alterations contribute to cancer?

9. Two MMR Hits
1 Normal MMR allele and 1 mutant: DNA repair is minimally impaired
2 Mutant alleles result in 100’s of errors each round of replication.
Can result in microsatellite instability (MI) phenotype.

10. Microsatellite Instability
1. Inactivate MMR genes.
2. Cells can’t correct errors in DNA (MI)
3. Errors pile up.
4. Errors occur in the wrong places (tumor-suppressor genes and oncogenes).
5. Increased/decreased activity of genes leads to CANCER.

11. MMR alterations can lead to risks for cancer in places other than the colon.
Tumors of the endometrium, stomach, small intestine, pancreas, hepatobiliary system, urinary tract, ovary, brain, and skin

12. Tying Together HNPCC, MMR gene alteration, MI, and Cancer.
How HNPCC may affect other genes important in cancer growth.

13. HNPCC and E2F-4

14. HNPCC and CCND1 (cyclin D gene)
CCND1 has an A/G polymorphism on exon 4.
2 transcripts (a and b)
Transcript b in blood/normal mucosa plus HNPCC resulted in earlier onset of colon cancer.

15. Other genes identified with HNPCC
TGF-B type II receptor.
tumor suppressor; activates SMAD pathway
IGF-receptor II
BAX
C-myc
Oncogene which acts at G1-S transition

16. Pulling it all together
HNPCC caused by MMR gene alterations (MLH1 and MSH2)
MMR gene defects can cause MI
MI can result in changes in other genes, when these genes are cancer-causing, problems arise.
Often these changes are specific to the colon, but can cause cancer elsewhere.