Lynch Syndrome;
When the Molecular Cleaning Ladies Stop Working.
A few week ago my mom went to the SGNA
(Society of Gastrointestinal Nurses and Associates) conference in
Arizona. While there she attended lecture on hereditary colon cancer
by Dr. Larry J. Geier, the director of the Genetic Risk Evaluation
and Testing (GREAT) program. She told me about what a great lecture
it was and I was able to get ahold of his lecture slides and
contacted him about his sources. As his lecture focused on Lynch
Syndrome, I'll be using, Dr. Wendy Kohlmann's review on LynchSyndrome,
his primary source on the subject from his lecture.
Lynch syndrome is an autosomal dominant
genetic syndrome that effects approximately 1 in every 350 people.
There are numerous mutations that cause Lynch syndrome and
interestingly they can appear in any one of 5 recognized genes; MLH1,
MSH2, MSH6, PMS2, and EPCAM. The first four genes are involved in the
mismatch repair process. This is to say that they repair nucleotides
that have been incorrectly paired during DNA replication. The last
one, EPCAM, is special and I'll get to it soon. The MLH1, MSH2 and
PMS2 protein product all bind together to for the Mismatch Repair
Complex that actively binds to mismatched nucleotide bases and
matches them correctly. The MSH6 protein product has more of a
support function in the overall process. A detrimental mutation need
only exist in one of the genes in order to significantly reduce the
function of the overall complex. When this happens, the Mismatch
Repair Complex is incapable of adequately repairing the mismatches
between DNA replications. As a result, in the following DNA
replication when the DNA helix spits and replicates, one of the
daughter cells will have mutation where the unfixed mismatch
appeared. Over time and many DNA replications, mutations accumulate.
Each mutation occurs randomly, but follows the “bull's eye theory”
(ie. If I throw enough darts, eventually I'll hit a bull's eye).
Figure 1. Microsatellite instability
testing is used to identify tumors caused by defective mismatch
repair by comparing the number of nucleotide repeats in a
panel ofmicrosatellite markers in normal tissue with the number
from tumor tissue from the same individual. Microsatellite stability
(MSS) is present if the same number of repeats is present in
each marker in both the tumor and the normal tissue.
Microsatellite instability (MSI) is present if the number of repeats
in the tumor and the normal tissue differs
.
As I wrote about early, the WNT pathway
in the cell plays a major role in tumorigenesis in adenocarcinoma of
the colon. If a mutation occurs within any protein in the
Axin-TCF-APC complex protein genes (as is often the case in
adenocarcinoma of the colon resulting from Lynch syndrome), then
B-catenin goes under-regulated within the cell, complexes with TCF
and promotes the oncogene c-MYC, which leads to the synthesis of
Cyclin A and Cyclin E, the activation of CDK2 and CDK4, and the
suppression of P27. As we learned in class the actication of the
Cyclins A and E and CDK's 2 and 4 promote the movement of the cell
into and through S-phase of the cell cycle, essentially causing the
cell to proliferate. Since this mutation will remain in the cell in
the subsequent daughter cells, there will be a continuous
over-expression of c-myc leading to continuous over proliferation of
the cell as seen in Familial Adenomatous Polyposis (FAP).
Essentially, simply by providing a stream of unfixed de novo
mutations, Lynch Syndrome can create a novel incidence of Familial
Adenomatous Polyposis (FAP) within an epithelial mucous cell of the
colon. Naturally, the mutation could also take place in the promoter
or early exons of the c-MYC gene that would cause it to be expressed
more readily. As long as the mutation occurs somewhere within the WNT
pathway and leads to the over-expression of the c-myc gene, the end
result will be polyposis.
Next comes EPCAM, which I personally
find amusing. EPCAM isn't a Mismatch Repair protein. The reason it's
involved with the functioning of Mismatch Repair Genes is because it
sits just upstream of one on the chromosome. I find Dr. MatthiasKloor's study on EPCAM expression in Lynch Syndrome better explainsthe proposed mechanism. As it happens, deletions in the EPCAM gene in the 3' exon a and
coincidentally need the promoters of the MSH2 Mismatch Repair Gene,
can cause a problems with the functionality of the promoter, such
that MSH2 is simply read through without expression. The molecular
mechanism isn't very clear, but I believe that the deletion either
causes a histone binding site or stop/start codon top blend in with
the neighbor's nearby genetic code. Essentially, a deletion in it's
upstream neighbor's gene effectively silences MSH2. This opens a lot
of doors for possible gene interactions in adenocarcinoma of the
colon and more. As only one fifth of the adenocarcinoma of the colon
attributed to genetic risk factors have genetic risk factors that we
can identify, we can now see that germline mutations in some genes
can be caused by nearby genes in the genome that aren't normally
mechanistically associated with the genes that are being silenced
more mutated. I believe the saying, “there goes the neighborhood”
rather effectively summarizes EPCAM's effect on MSH2 and by extension
the Mismatch Repair pathway and resulting cancers.
A question I'm sure everyone has is,
why Lynch only causes adenocarcinoma of the colon when its mutations
are random? It doesn't. Lynch causes increased risk of a number of
differenct cancers. Adenocarcinoma of the colon simply happens to be
the premiere example of cancers it causes as it raises the
probability of formation of 5% to ~80% and it happens to be my
subject matter.
The question I have is; how was an
oncogene as powerful as c-CYM be moderated by medice. The gene is
essentially an on/off switch for cancer. It cascades into such a wide
variety of proto-oncogenes and oncogenes that over-activation of it
practically guarantees you'll develop cancer. It's like the Lynch pin
(pun intended) and pressure point of cell proliferation. All
molecular roads in adenocarcinom lead to and through the c-MYC gene.
If we could learn to properly moderate it expression, then we could
prevent the grand majority of colon cancer.
Sources
- Kohlmann, Wendy; Gruber, MS; Gruber, Stephen B (2011). Lynch Syndrome. 2004 Feb 5 [Updated 2011 Aug 11]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-.
- Kloor, Matthias; Voigt, Anita Y; et. All (2011). Analysis of EPCAM Protein Expression in Diagnostics of Lynch Syndrome. Journal of Clinical Oncology, 29(2):223-7.
