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HNPCC and FAP are both associated with familial colon cancer but differ in many aspects. Describe the similarities and differences between these conditions. How does MYH polyposis differ from both?. How to answer?. Introduction Genetic basis for the conditions Similarities and differences

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How to answer?

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  1. HNPCC and FAP are both associated with familial colon cancer but differ in many aspects. Describe the similarities and differences between these conditions. How does MYH polyposis differ from both?

  2. How to answer? • Introduction • Genetic basis for the conditions • Similarities and differences • Differences between clinical phenotypes • Polyposis vs non-polyposis • Methods of diagnosis • Management • MYH • Clinical similarity to FAP • Mode of inheritance and genetics

  3. HNPCC Genetics • Hereditary non-polyposis colorectal cancer or Lynch syndrome • Dominant mutations in the mismatch repair (MMR) genes: • MLH1, MSH2, MSH6 (PMS2) • Others, but no proven involvement in HNPCC, possibly due to functional redundancy • Act to resolve 1-4 base mismatches generated during replication • 1st hit is inherited mutation (typically truncating) • 2nd somatic hit is first step towards cancer development • i.e. classic dominant gate-keeper

  4. FAP Genetics • Familial adenomatous polyposis • Caused by dominant mutations in the APC gene • Normal APC function: • Also dominant-acting gate-keeper • Transcriptional repressor of proto-oncogenes • APC phosophorylates β-catenin causing its degradation • β-catenin upregulates trancription of proto-oncogenes • E.g. c-myc, cyclin D1... • Therefore without APC there is upregulation of these genes • Leads to polyposis phenotype in heterozygous state, cancer when both copies missing

  5. Clinical differences • HNPCC • No polyps • Sporadic cancers, early age, sometimes multiple primaries (80% lifetime risk) • Spectrum of other cancers: • Endometrial, ovary, stomach, bile duct, kidney… • FAP • Variable numbers of polyps: • Attenuated FAP – 10-100 (+delayed onset and diminished phenotypic range) • Mutations in 5’ and 3’ domains • Sparse – 100-500 • Classic – 100-1000s (APC codons 168-1580) • Profuse - >2000 (APC codons 1290-1400) • One or more polyps will develop into cancer without treatment • Other clinical features: • Gastric+small bowel polyps • Supernumerary teeth • Other cancers (thyroid, desmoid, adrenal gland) • CHRPE: congenital hypertrophy of retinal pigment epithelium • Mutations distal to exon9

  6. Diagnosis • FAP • By polyposis • CHRPE (90%) retinal lesions • Desmoid disease • HNPCC • Amsterdam criteria: • Various parameters involving numbers and relatedness of affected family members, age of onset and exclusion of FAP • Updated to Amsterdam II and then Bethesda • Takes MSI into consideration… • Microsatellite instability (MSI): • DNA replication errors commonly occur at repeat loci • Lack of MMR activity = errors not corrected • MSI testing: • Panel of markers • >2 markers showing instability = MSI-high • 1 or 0 markers = MSI-low • Tumour expression analysis: • Immunohistochemical analysis of tumour tissue • Loss or reduction of expression of one of MMR genes indicates likely HNPCC and directs testing to that gene

  7. Management • HNPCC • Colonoscopy every 2yr from 25yrs, every year from 40yrs • Women: endometrial+ovarian assays and ultrasound • With confirmed mutation: • Counselling regarding colonectomy/hysterectomy/oophorectomy • FAP • Clinical monitoring from 10-12yrs • Colonoscopy every year • Upper endoscopy every 1-2yrs from 20yrs + thyroid exam • Prophylactic surgery recommended late teens/early 20s

  8. MYH Polyposis • Phenocopy of FAP • No. polyps: 10-1000 but typically not in the thousands • Differences: • Recessive: inheritance of two mutations • Typically later onset • Common mutations • 2 missense changes account for 80% cases • FAP/HNPCC typically private (1 FAP Ashk. Mut.) • Involved in base excision repair (BER) • Correction of oxidation of Guanine residues • No MYH function = transversion (G:C to T:A) missense changes • Absence causes build-up of mutations in other genes, e.g. FAP • ? Is MYH ‘upstream’ of APC in the MYH-polyposis • Are other cancers common in individuals with MYH mutations, esp. breast cancer • Disputed between different papers • ? Are there secondary mutations in other gate-keeper genes

  9. Other reference: • The genetics of hereditary colon cancer • Anil K. Rustgi, Genes and Development 21:2525-2538

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