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.
- 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.