Transcript MLH 1 and Hereditary Nonpolyposis Colorectal Cancer

MLH 1 and Hereditary
Nonpolyposis Colorectal
Cancer
Nathan H. Calloway
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?...
Amsterdam Criteria
1.
2.
Exclusion of familial polyposis.
Colorectal cancer in at least three
relatives, one of them being a 1st-degree
relative of the others.
3. Involvement of at least two generations
of colorectal cancer.
4. At least one colon cancer diagnosed
before age 50.
Enhanced susceptibility for cancers
of the…
Colon
Ovary
Also the endometrium (lining of uterus)
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

MMR genes function to repair DNA
damage.
DNA replication must
occur without errors
transmitted to the
daughter cells.
MMR Genes
Repair DNA
damage or errors
incurred during
replication.
Damage can be
slippage,
misincorporation
of bases, or other
causes of changes
in DNA.
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?
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.
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.
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
Tying Together HNPCC, MMR gene
alteration, MI, and Cancer.
How HNPCC may affect other genes
important in cancer growth.
HNPCC and E2F-4
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.
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
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.