Commentary by Sabina Berezovskaya MD PGY-3
Please also see the clinical vignette presented during last week’s grand rounds
On Wednesday, October 8, 2004, the NYU Department of Medicine Grand Rounds featured guest lecturer Vincent Yang, M.D. Ph.D., Professor of Medicine and Director of Division of Digestive Diseases at Emory University School Medicine with a presentation entitled “Molecular Genetics of Colorectal Cancer”.
Dr. Yang first oriented the audience to the outline of the talk and began his presentation with a case discussion of a 21 year old female with complaints of occasional bright red blood per rectum and family history of colorectal carcinoma (CRC). The patient proceeded to have an upper endoscopy notable for fundic gland polyps and a colonoscopy notable for numerous adenomatous polyps. The patient subsequently was diagnosed with familial adenomatous polyposis (FAP). It was discussed that FAP syndrome was pivotal to our current understanding of the pathogenesis of colorectal carcinoma from adenomatous polyps.
The lecturer gave an overview of epidemiologic data on colorectal carcinoma. It was estimated that US has the highest incidence of CRC followed by Western Europe and Australia. Recent data show that there are approximately 153,000 new cases and 53,000 deaths attributed to CRC annually in the US. At this time CRC has the 2nd highest incidence and mortality of all gastrointestinal malignancies. It is the 3rd most common cause of cancer and 2nd most common cause of cancer deaths. This is likely to be related to environmental factors, most prominently the Western diet.
Next, an overview of the genetic “road to cancer” was presented. Here Dr. Yang discussed components necessary for cancer development. Typically, the genes involved are classified as tumor suppressor genes (the “brakes”) vs. oncogenes (the “gas pedal”). The mutations subtypes described were germline vs. somatic and genetic (directly involving the DNA) vs. epigenetic (DNA silencing by hypermethylation) mutations. A brief review of Dr. Alfred Knudson’s two hit hypothesis followed. Outlining the importance of multiple genetic mutations involved in carcinogenesis. To further highlight the intricacies of carcinogenesis, one study presented estimated a mean of 23 genetic pathways and 63 mutations involved in an average cancer!
Furthermore, the audience received an overview of hereditary CRC syndromes, such as APC I1307K mutation syndrome, FAP, HNPCC, MAP (MYH associated polyposis), and hamartomatous polyposis syndromes. Special attention was paid to FAP and HNPCC. An autosomal dominant condition with 100% penetrance, FAP occurs in 1/8,000 live births and typically involves germline mutation in the APC gene. Patients with FAP usually develop multiple adenomas (100-1000) by the age 15 and CRC, if untreated, by the age of 34. Similarly, HNPCC has autosomal dominant inheritance with estimated 80% penetrance, but is 5 times as common as FAP, with median age of CRC development estimated to be 42 years. It involves germline mutation in the DNA mismatch repair (MMR) genes that result in microsatellite instability (MSI) phenotype. Both genetic syndromes have associated extra colonic manifestations.
Dr. Yang went on to discuss genetic paradigms of colorectal carcinoma. He presented a detailed outline of the Chromosomal Instability (CIN) pathway, which is responsible for 85% of CRC we encounter and typically involves loss of heterozygosity and anueploidy with more left sided tumors that are difficult to treat. This was contrasted with the Microsatellite Instability (MSI) pathway, which is implicated in 15% of CRC cases. In summary, the CIN model delineates a progression of normal colonic epithelium to adenoma and, finally, to carcinoma via multi-step sequence involving beta-catenin, COXx-2, K-RAS, and p53 mutations. Histologically, this can be observed as progression of normal epithelium, where undifferentiated proliferative (stem) cells reside solely in the crypts and the differentiated cells reside in the villi, to abnormal epithelium where the stem cells become abundant in the villi. Dr. Yang stressed the importance of the Wnt pathway in this progression. The wnt pathway is activated in proliferative cells, like the stem cells in the crypts. In contrast, the APC genes suppress cell proliferation and are expressed in mature cells of the villous epithelium. It has been noted that a mutation of the APC gene is equivalent to wnt activation, as both modulate cell activity via beta-catenin expression.
Dr. Yang proceeded to present the findings of his own research on pathobiology of Kruppel-like factors (KLF) in colorectal cancer. KLF genes were initially identified as members of the “gap” class of segmentation genes of Drosophila melanogaster and are characterized by a common zinc finger motif. (See Ghaleb and Yang V, Current Colorectal Cancer Reports 2008, 4:59-64). The lecturer focused on 2 members of the KLF family: KLF 4 and KLF 5. Normally, KLF4 is under the control of APC and p53. It modulates growth arrest in villous cells, whereas KLF5 is activated by the Wnt system and is involved in cell proliferation. These diametrically opposite modulators of the cell cycle have a critical role in CRC development. Furthermore, supporting evidence of KLF5 involvement in CRC pathogenesis from several animal studies were presented. For example, in mice with colon cancer, all cells of the colonic epithelium, crypts and villous cells, stained positive for KLF5. Another study presented supported KLF5 involvement in the Wnt pathway, where activation of KLF5 resulted in increase B-catenin activity.
The presentation was concluded with a discussion of therapeutic applications of these research findings. At this time a search for KLF5 inhibitors is underway. In fact 4 inhibitors have already been identified with the help of High Throughput Screening (HTS). Two of which are tyrosine kinase inhibitors. Dr. Yang ended on an enthusiastic note with great hope for development of novel therapeutic compounds based on KLF5 inhibitors.
Ghaleb AM, Yang VW. The Pathobiology of Kruppel-Like Factors in Colorectal Caner. Current Colorectal Cancer Reports. 2008, 4:59-64.