Development of Carcinoma Pathways
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1 The Construction of Genetic Pathway to Colorectal Cancer Moriah Wright, MD Clinical Fellow in Colorectal Surgery Creighton University School of Medicine Management of Colon and Diseases February 23, 2019 Disclosures None 1
2 History Sentinel account of hereditary colorectal family by Dr. Alfred Warthin He began studying the family of a woman who subsequently died of endometrial cancer in 1895 Family G Published his report in 1913 documenting a pattern of gynecologic cancer (endometrial), and gastrointestinal cancers (gastric and colon) Autosomal dominant familial severe polyposis recognized in the 1930s Now known as familial adenomatous polyposis Updated studies of Family G performed in 1971 Henry Lynch Lynch syndrome 70 80% excess of proximal colon cancer Two hit hypothesis Knudson Both copies of a tumor suppressor gene must be mutated in order for cancer to develop As genes associated with colorectal cancer were discovered, the importance of a thorough family history became more obvious Allowed for identification of extracolonic cancers of Lynch Syndrome Development of Carcinoma Pathways The most well known pathway is the chromosomal instability pathway (CIN) First described by Fearon and Vogelstein in 1990 Details the multiple mutations required to progress from normal colonic mucosa to carcinoma It was understood that the accumulation of genetic mutations is what leads to carcinogenesis, rather than the specific order 2
3 Chromosomal Instability APC mutation Adenomatous Polyposis Coli gene Tumor suppressor gene regulates neoplasia prevention Most common mutation in the CIN pathway Affects up to 85% of patients with sporadic colorectal cancer Biochemistry Break APC regulates Cell division Cell attachment Cell migration Cell polarization Chromosome segregation during division Levels of β catenin WNT pathway Without WNT ligand APC forms a complex that destroys β catenin With WNT ligand the APC complex dissociates and allows β catenin to move to the nucleus and bind to DNA to activate transcription of genes that promote cell growth Mutation in APC prevents formation of the destructor complex resulting in unregulated cell growth 3
4 Chromosomal Instability K ras mutation Next most common mutation Part of the MAPK pathway Major cell proliferation signalling pathways from the cell surface to the nucleus ERK MAPK pathway is most connected with pathogenesis, progression, and oncogenic behavior of CRC Mutations found in both tumor and metastasis indicating these mutations occur early on Oncogenic activation of K ras appears to consistently follow APC inactivation during tumor progression Biochemistry Break Mutation in K ras confers elevated Ras activity Accompanied by raised ERK activity Uncoupled from EGFR stimulation Mutations in codons 12 and 13 of the K ras gene have been found to confer resistance to anti EGFR chemotherapy In cases with mutated K ras an anti VEGF agent is used as part of metastatic chemotherapy Wild type K ras can be treated with an anti EGFR agent 4
5 Biochemistry Break BRAF is another member of the same pathway Mutations are presenting in 5 15% of CRC Associated with increased kinase activity Mutations have a less clear effect on responsiveness to anti EGFR chemotherapy BRAF is important in determining prognosis since mutations of this gene are associated with worsened survival Chromosomal Instability p53 is the final step in the adenoma to carcinoma sequence Preserves the cell cycle and genomic stability Tumor suppressor gene which stops the cell cycel in G1/S phase to allow repair of mutations or replications If the errors cannot be repaired then wild type p53 will induce apoptosis Key event in the pathogenesis of CRC Results in genomic chaos and conversion for benign to malignant 5% mutation in adenoma 50% in malignant polyps 75% in invasive cancer 5
6 Mismatch Repair DNA mismatch repair (MMR) pathway is another well known carcinogenesis pathway MMR genes code for proteins that band together to repair DNA mutations This is the pathway associated with Lynch Syndrome and microsatellite instability (MSI) Microsatellites are noncoding segments of DNA that contain repetitive sequences of 1 4 nucleotides Occur throughout the genome About 15% of CRC arise from this pathway 12% are sporadic from somatic mutations or epigenetic mechanisms 3% are from germ line mutations associated with Lynch Syndrome Mismatch Repair Four genes most associated with MMR MLH1, MSH2, MSH6, and PMS2 MLH1 is the most common source of sporadic MMR deficiency MMR deficiency leads to an elevated mutator phenotype with a very specific mutation spectrum Frameshift mutations in repeated sequences present in target tumor suppressor genes which have multiple repetitive sequences prone to DNA mismatch When MMR mechanism fails, spontaneous errors of replication due to slippage by strand misalignment are fixed as mutations Can be seen in microsatellites demonstrating high instability and variable size of the genetic material that can be detected by PCR 6
7 Mismatch Repair MSI is useful as a screening marker to identify patients with Lynch Syndrome Also a marker of better prognosis and potentially a marker of chemotherapy efficacy in sporadic and inherited CRC Sporadic CRC with MSI high and Lynch Syndrome associated CRCs have similar morphologic features BRAF is an important factor Mutations have a substantially worse prognosis CpG Island Methylator Phenotype Final major pathway to carcinoma CIMP CpG islands are CG rish stretched of DNA that occur in half of all gene promoters These islands are usually unmethylated in non neoplastic cells Methylation silences the activity of these genes Methylation is essential for normal development Pathologic methylation focally silences the affected genes CIMP is known to be present in multiple kinds of cancers Considerable overlap between CIMP and MSI H pathways CIMP has been proposed to explain the silencing of MLH1 in sporadic cancers with MSI H Strong correlation between CIMP and V600E mutation in BRAF Serves as a marker for MLH1 promoter methylation testing Mutation in BRAF indicated a sporadic MSI H cancer 7
8 Clinical Applications Chemotherapy and Chemoradiotherapy MSI H is generally a good prognostic indicator Stage adjusted prognosis is better for MSI H than for MSS CRC Stage II MSI H patients might be spared adjuvant therapy K ras mutation has prognostic effects and can help determine which chemotherapy agents will provide benefit K ras mutation usually does not benefit from anti EGFR monoclonal antibody treatment Clinical Applications Current therapies targeting molecular markers of CRC Bevacizumab (Avastin) antibody targeting vascular endothelial growth factor (VEGF) Inactivates all forms to inhibit angiogenesis and tumor growth and proliferation Cetuximab (Erbitux) and Panitumumab antibodies against epidermal growth factor receptor (EGFR) Stops the binding and activation of signalling pathways and prevents cell proliferation, invasion, metastasis, and neovascularization K ras mutation is a negative predictor of response to these agents 8
9 Thank you 9
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