Replication error results in a frameshift mutation inactivating TSGs in HNPCC: defective DNA mismatch repair: Mismatch repair genes (Repair of base pair errors in DNA replication) are Defective in HNPCC Such mismatches arising from the above scenario are therefore not repaired hMSH2, hPMS1, hPMS2, hMSH6, hMLH3, MLH1 Methylation CpG Island hyperMethylation Phenotype (CIMP): Aberrant methylation of cytosine results in gene silencing Normally occurs in repetitive sequences outside of exons CRC phenotype less methylation but increased in CpG promoter islands Observed in 15% of sporadic CRC May occur in alleles prior to conception (Loss Of Imprinting) Hereditary Non-Polyposis Coli (= HNPCC = Lynch Syndrome) Inherited mutation in mismatch repair gene 3-5% CRC 30-90% risk of CRC Associated malignancies (Ovary, Endometrial, Small bowel, Stomach, Hepatobiliary, Ureteric) Biennial colonoscopy [every two years] Associated screening Vs sporadic colorectal cancer (CRC), HNPCC has: More right sided lesions Increased mucinous component Lymphocytic Poorly differentiated Better prognosis MYH-Associated Polyposis Germline mutation in MYH gene Protein repairs oxidative damage to guanine associated with sporadic APC mutation Recessive inherited CRC Phenotype identical to FAP Carriers may be predisposed to CRC
Replication error results in a frameshift mutation inactivating TSGs in HNPCC: defective DNA mismatch repair: Mismatch repair genes (Repair of base pair errors in DNA replication) are Defective in HNPCC Such mismatches arising from the above scenario are therefore not repaired hMSH2, hPMS1, hPMS2, hMSH6, hMLH3, MLH1 Methylation CpG Island hyperMethylation Phenotype (CIMP): Aberrant methylation of cytosine results in gene silencing Normally occurs in repetitive sequences outside of exons CRC phenotype less methylation but increased in CpG promoter islands Observed in 15% of sporadic CRC May occur in alleles prior to conception (Loss Of Imprinting) Hereditary Non-Polyposis Coli (= HNPCC = Lynch Syndrome) Inherited mutation in mismatch repair gene 3-5% CRC 30-90% risk of CRC Associated malignancies (Ovary, Endometrial, Small bowel, Stomach, Hepatobiliary, Ureteric) Biennial colonoscopy [every two years] Associated screening Vs sporadic colorectal cancer (CRC), HNPCC has: More right sided lesions Increased mucinous component Lymphocytic Poorly differentiated Better prognosis MYH-Associated Polyposis Germline mutation in MYH gene Protein repairs oxidative damage to guanine associated with sporadic APC mutation Recessive inherited CRC Phenotype identical to FAP Carriers may be predisposed to CRC
Alimentary-notes-BETA.docx