MLH 1 and Hereditary MLH 1 and Hereditary Nonpolyposis Colorectal Nonpolyposis Colorectal

CancerCancer

Nathan H. CallowayNathan H. Calloway

HNPCC: what is it?HNPCC: what is it?

Most frequent Most frequent autosomal dominant autosomal dominant predisposition to the predisposition to the development of colon development of colon cancer. cancer.

A contributing factor A contributing factor in 2-4% of ALL colon in 2-4% of ALL colon cancer cases. cancer cases.

Characterized by an Characterized by an earlier onset of earlier onset of colorectal cancer and colorectal cancer and increased frequency increased frequency of other cancers.of other cancers.

How do we identify How do we identify those with HNPCC?...those with HNPCC?...

Amsterdam CriteriaAmsterdam Criteria

1.1. Exclusion of familial polyposis.Exclusion of familial polyposis.

2.2. Colorectal cancer in at least three Colorectal cancer in at least three relatives, one of them being a 1relatives, one of them being a 1stst-degree -degree relative of the others.relative of the others.

3.3. Involvement of at least two generations Involvement of at least two generations of colorectal cancer.of colorectal cancer.

4.4. At least one colon cancer diagnosed At least one colon cancer diagnosed before age 50.before age 50.

Enhanced susceptibility for cancers Enhanced susceptibility for cancers of the…of the…

Colon OvaryColon Ovary

Also the endometrium (lining of uterus)Also the endometrium (lining of uterus)

HNPCC and mismatch repair HNPCC and mismatch repair genes.genes.

MMR genes are the MMR genes are the genes responsible for genes responsible for HNPCC. HNPCC.

Major MMR genes Major MMR genes and HNPCCand HNPCC

Major MMR Genes:Major MMR Genes: MLH1 (MutL MLH1 (MutL

Homolog)Homolog) MSH 2MSH 2

Minor MMR Genes:Minor MMR Genes: MSH6MSH6 PMS1PMS1 PMS2PMS2

MMR genes function to repair DNA MMR genes function to repair DNA damage.damage.

DNA replication must DNA replication must occur without errors occur without errors transmitted to the transmitted to the daughter cells. daughter cells.

MMR GenesMMR Genes

Repair DNA Repair DNA damage or errors damage or errors incurred during incurred during replication. replication.

Damage can be Damage can be slippage, slippage, misincorporation misincorporation of bases, or other of bases, or other causes of changes causes of changes in DNA. in DNA.

MMR Genes And GrowthMMR Genes And Growth

MMR genes have a more passive role in MMR genes have a more passive role in controlling growth, as opposed to tumor controlling growth, as opposed to tumor suppressor genes.suppressor genes.

Tumor suppressor genes (RB1, p53…etc) Tumor suppressor genes (RB1, p53…etc) have more active roles in controlling have more active roles in controlling growth and apoptosis. growth and apoptosis.

So, how do MMR gene alterations So, how do MMR gene alterations contribute to cancer? contribute to cancer?

Two MMR Hits Two MMR Hits

1 Normal MMR allele and 1 Normal MMR allele and 1 mutant: DNA repair is 1 mutant: DNA repair is minimally impairedminimally impaired

22 Mutant alleles result in Mutant alleles result in 100’s of errors each 100’s of errors each round of replication.round of replication.

Can result in Can result in microsatellite instability microsatellite instability ((MIMI) phenotype. ) phenotype.

Microsatellite InstabilityMicrosatellite Instability

1. Inactivate MMR genes.1. Inactivate MMR genes.

2. Cells can’t correct errors in DNA (MI)2. Cells can’t correct errors in DNA (MI)

3. Errors pile up.3. Errors pile up.

4. Errors occur in the wrong places 4. Errors occur in the wrong places (tumor-suppressor genes and oncogenes).(tumor-suppressor genes and oncogenes).

5. Increased/decreased activity of genes 5. Increased/decreased activity of genes leads to CANCER.leads to CANCER.

MMR alterations can lead to risks MMR alterations can lead to risks for cancer in places other than the for cancer in places other than the

colon.colon.Tumors of the Tumors of the endometrium, endometrium, stomach, small stomach, small intestine, pancreas, intestine, pancreas, hepatobiliary system, hepatobiliary system, urinary tract, ovary, urinary tract, ovary, brain, and skin brain, and skin

Tying Together HNPCC, MMR gene Tying Together HNPCC, MMR gene alteration, MI, and Cancer.alteration, MI, and Cancer.

How HNPCC may affect other genes How HNPCC may affect other genes important in cancer growth.important in cancer growth.

HNPCC and E2F-4 HNPCC and E2F-4

HNPCC and CCND1 (cyclin D HNPCC and CCND1 (cyclin D gene)gene)

CCND1 has an A/G CCND1 has an A/G polymorphism on polymorphism on exon 4.exon 4.

2 transcripts (a and b)2 transcripts (a and b)

Transcript b in Transcript b in blood/normal mucosa blood/normal mucosa plus HNPCC resulted plus HNPCC resulted in earlier onset of in earlier onset of colon cancer. colon cancer.

Other genes identified with HNPCCOther genes identified with HNPCC

TGF-B type II receptor.TGF-B type II receptor. tumor suppressor; activates SMAD pathwaytumor suppressor; activates SMAD pathway

IGF-receptor IIIGF-receptor II

BAXBAX

C-mycC-myc Oncogene which acts at G1-S transitionOncogene which acts at G1-S transition

Pulling it all togetherPulling it all together

HNPCC caused by MMR gene alterations HNPCC caused by MMR gene alterations (MLH1 and MSH2)(MLH1 and MSH2)

MMR gene defects can cause MIMMR gene defects can cause MI

MI can result in changes in other genes, MI can result in changes in other genes, when these genes are cancer-causing, when these genes are cancer-causing, problems arise.problems arise.

Often these changes are specific to the Often these changes are specific to the colon, but can cause cancer elsewhere.colon, but can cause cancer elsewhere.