Cancer Syndromes

A cell can only become mutagenic if it has two mutant alleles So those who have a germline mutation in one of their alleles only require one hit to get cancer  Those with germline mutation can get cancer in more than one place e.g. bilateral breast cancer and BRCA1/2

Tumour suppressor genes = encode a gene product that inhibits cell proliferationLoss of function can lead to cancer (both alleles must be inactivated to change the activity of the cell)First mutation usually inheritedSecond mutation usually caused by loss of part of the chromosomeTypes:GatekeeperAffect cell growth e.g. BRCA1/2, APCCaretakerControl DNA proofreading and repair - mismatch repair e.g. MLH1, PMS1Loss of heterozygosity LOHLoss of function of one allele in a cell where the other allele was already inactivatedie. the 'second hit' when someone already has a germline mutation Observation that tumour DNA is homozygous for a DNA polymorphism for which their normal tissue is heterozygousIf seen repeatedly, implies that the chromosome carrier a tumour suppressor gene Mechanisms: Mitotic recombination Deletion of chromosomal region Gene conversion 

Lynch Syndrome Genes involved in MMR MSH2 - MSH6 MLH1 - PMS2  All Tumour Suppressor Genes (Caretakers)  Clear family history of dominantly inherited early-onset colon cancer but generally do not have polyps  Why does this defect lead to bowel cancer in particular? Transforming Growth Factor B (TGFB) is a strong inhibitor of cell proliferation in the colorectumIt acts on a cell-surface receptor of which the TGFB receptor 2 (TGFBR2) protein is part The TGFBR2 gene contains a run of 10 consecutive A nucleotides MMR-deficient cells are liable to slippage in this region, rendering the TGFR2 protein non-functional EpigeneticsLynch syndrome can also be caused by a deletion of the 3' end of the EPCAM gene, which leads to methylation of the promoter of MSH2 so the gene is silenced in EPCAM-expressing tissues. OR spontaneous methylation of CpG islands in 5'-UTR of MLH1 leads to transcriptional silencing. This can be mosaic throughout cells leading to a milder phenotype, also reversible on transmission to offspring so can show non-mendelian pattern of inheritance.  FAPAutosomal dominant disorderDue to mutations in APC 2nd decade of life start developing 1000s of colonic polypsThese can become enlarged and bleedCan become cancerousMutations in APC - lead to a truncated protein - loss of functionNormally protein product regulates the b-catenin pathway (modulates cell growth, apoptosis etc)  

Genetic Predisposition Genes: BRCA1/2 TP53 BRCA1Normal function: Forms part of complex that activates repair of double stranded breaks and induces homologous recombination Forms part of surveillance complex that recognises errors in DNA replication or DNA damage Works as a checkpoint control - essential for cell survival, prevents propagation of DNA damage through cell cycle Germline mutation - 80% lifetime risk breast cancer, 60% lifetime risk ovarian cancer BRCA2 Forms part of complex that activates repair of double stranded breaks and induces homologous recombination Germline mutation - 80% breast cancer, 30% ovarian, men - risk of breast and prostate cancer elevated Mutation in BRCA1/2Leads to truncated protein - non functionalCan occur through LOH (never through epigenetic silencing)Genotype targeted cancer therapy - PARP PARP normally repairs single stranded breaks If it is inhibited single stranded breaks progress into double stranded breaks In cells lacking functional BRCA protein these double stranded breaks will not be repaired through homologous recombination The cell will die Li Fraumeni SyndromeBreast cancer, soft tissue sarcomas, brain tumours - 80% have cancer by age 50Germline TP53 (tumour suppressor gene, regulates cell cycle) mutations cause the majority of cases (most mutations in the DNA binding domain)

Knudson's 2-Hit Hypothesis

Tumour Suppressor Genes

Bowel Cancer

Breast Cancer