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Pathology:____________________________________________________________________________________________________________INHERITED CANCER SYNDROMESMultiple Endocrine Neoplasia Type 2 (MEN2)Mode of Inheritance: Autosomal DominantMutation Type: Gain of FunctionMutation: RETConstitutive Activation of RTKSymptoms:Affects Endocrine GlandsHereditary Papillary Renal CarcinomaMode of Inheritance: Autosomal DominantMutation Type: Gain of FunctionMutation: METConstitutive Activation of METMET is a Hepatocyte Growth Factor Receptor (HGFR)Symptoms:Renal Tumor GrowthAngiogenesisMetastasis_______________________________________________________________________________________________________________TRANSLOCATIONS: ALL SPORADICBurkitt Lymphoma:Mode of Inheritance: SporadicMutation Type: Gain of FunctionMutation: Translocation between t(8:14)MYC (8) is placed under control of a strong promoter.Strong Promoter: Ig Heavy Chain Locus (14)MYC Up-regulates TelomeraseSymptoms:B Lymphocyte DamageEndemic: African BL: presents in mandible (EBV)Non-Endemic: Ileocecal or Peritoneal Mass t(8:14)Mar: Marker Chromosomes of Unidentifiable Origin.Follicular Lymphoma: (Malignant Lymphoma)Mode of Inheritance: SporadicMutation Type: Gain of FunctionMutation: Translocation between t(14:18)BCL-2 is placed under control of a strong promoter. (14)Strong Promoter: Ig Heavy Chain Locus (14)Symptoms:Lymphoma of Follicle Center (B-Cells)Chronic Myelogenous Leukemia (CML)Mode of Inheritance: SporadicMutation Type: Gain of FunctionMutation: BCR-ABL Fusion ProteinPhiladelphia Chromosome: der22Translocation between t(9:22)ABL: Chromosome 9, Proto-OncogeneBCR: Chromosome 22Constantly active Tyrosine Kinase Activity (intracellular)Symptoms:Often unresponsive to treatments, have characteristic Leukemia Symptoms, few months survival.Treatment: Imatinib/Gleevic (Tyrosine Kinase Inhibitor)Acute Lymphoblastic Leukemia (ALL)Same as CMLAcute Promyelocytic Leukemia (APL)Mode of Inheritance: SporadicMutation Type: Gain of FunctionMutation: PML-RARa Fusion ProteinTranslocation between t(15:17)Promotes proliferation and turns off genes needed for myeloid differentiation.RARa: transcription factor that allows for differentiation of WBCs.PML: transcription factor that blocks proliferation & induces apoptosis.Both of these genes are tumor suppressors, but the fusion makes them oncogenic.Ewing Sarcoma:Mode of Inheritance: SporadicMutation Type: Gain of FunctionMutation: EWS-FLI1 Fusion ProteinTranslocation between t(11:22)FLI1: transcription factorSymptoms:Tumors of bone and soft tissue (femur, tibia, humerus)Males are affected more._______________________________________________________________________________________________________________ONCOGENE ACTIVATION BY AMPLIFICATIONNeuroblastoma:Mutation Type: Gain of FunctionMutation: N-MYC AmplificationExtra Chromosomal Double MinutesThese are extra chromosome pieces amplification of N-MYC.N-MYC = AggressiveSymptoms:Causes tumors in adrenals, pelvis, etc. in young children.Sometimes they can spontaneously regress.Glioblastoma:Mutation Type: Loss of FunctionMutation: 100x Expression of an miRNACauses RNA-Mediated inhibition of Target GenesmiRNA causes degradation of mRNA.Called Oncomirs because they silence Tumor Suppressors.Symptoms:Most common and aggressive brain tumor.Progressive neurological decline.No treatment – PalliativeRetinoblastoma:Mode of Inheritance: Autosomal Dominant, SporadicMutation Type: Loss of FunctionMutation: RB1Tumor SuppressorSymptoms:Leucokoria , usually Bilateral tumors if it is inherited.Childhood cancerLi-Fraumeni Syndrome:Mode of Inheritance: Autosomal DominantMutation Type: Loss of FunctionMutation: P53Tumor SuppressorSymptoms:Highly variable phenotypes (multiple cancer types can result)Depends on where the 2nd hit occurs.Neurofibromatosis Type 1Mode of Inheritance: Autosomal Dominant50% of the time, this is a NEW MUTATION in the Germ Line.No Family History, but all of their cells have the mutation.Tumor SuppressorMutation Type: Loss of FunctionMutation: NF1NF1 = RAS GapSymptoms:Complete PenetranceExtremely variable in presentation.Neurocutaneous Syndrome (Neurologic and Dermatologic Lesions)Freckles, Café Au Lait SpotsHereditary Breast Cancer:Mode of Inheritance: Autosomal Dominant (5%), Sporadic (95%)Mutation Type: Loss of FunctionMutation: BRCA1 and BRCA2Tumor SuppressorSymptoms:Bilateral Breast CancerCan also cause Ovarian and Prostate cancer.BRCA’s Function: usually response to dsDNA breaks during Homologous Recombination or DNA DamageBRCA GENES ARE NOT THE INTIATING EVENT IN SPORADIC BREAST CANCER.Her2/EGFR2 is amplified in 30% of breast cancers.Epidermal Growth FactorHerceptin (Trastuzumab) is monoclonal antibody against Her2Sporadic Breast Cancer: Estrogen Receptor: Transcription FactorBinds to Estrogen Response Element (ERE) Cyclin D TranscriptionTreatment: Tamoxifen (Estrogen Receptor Antagonist)Familial Polyposis Coli (FAP):Mode of Inheritance: Autosomal Dominant, SporadicMutation Type: Loss of FunctionMutation: APCTumor SuppressorUsually phosphorylates and inhibits B-Catenin (degraded)Symptoms: Numerous polyps develop in the colon and bleed.Hereditary Non-Polyposis Colon Carcinoma ():Also called Lynch SyndromeMode of Inheritance: Autosomal Dominant, SporadicMutation Type: Loss of FunctionMutation: MLH, PMSTumor SuppressorDNA Repair GenesMicrosatellite Instability Replication Error Positive (RER+)You see multiple bands or “alleles” on a blot. This is due to Replication Slippage.High percentage losing expression of P15INK.TGFBR2 is also mutated in 70% of cases10 Adenines, 3 LysinesUsually inhibits growthSlippage causes mutations in the 10 Adenine RepeatsThis is a secondary event.You also need a loss of function of BOTH alleles to lose this.Wilm’s Tumor:Pediatric Kidney Cancer – SporadicLoss of WT-1: involved in renal differentiation.CHROMOSOME INSTABILITY SYNDROMES: AUTOSOMAL RECESSIVEXeroderma Pigmentosum:Mutation Type: Loss of FunctionMutation: Defect in Nucleotide Excision Repair (NER)Most Common Mutation: Defective Excision Endonuclease DeficiencyMechanism:Absorption of UV Light Pyrimidine Dimers Normally repaired by NER.Without NER, higher risk of developing Skin Cancer when exposed to UV.Ataxia Telangiectasia:Mutation Type: Loss of FunctionMutation: Defect in ATMMechanism:Defects in DNA Damage SignalingDefects in dsDNA RepairATM cannot phosphorylate and signal P53 to stop the Cell CycleSymptoms:Ataxia: NeurodegenerationTelangiectasia: dilated vesselsPredisposition to LymphomaImmunodeficiencyBloom Syndrome:Mutation Type: Loss of FunctionMutation: BLMBLM = DNA HelicaseMechanism:Defective DNA Replication & RepairDefective Homologous RecombinationBLM usually prevents excess Sister Chromatid Exchanges (~10)Without BLM, you get hundreds of exchanges.Symptoms:High Risk for Various Cancer TypesImmunodeficiencyWerner Syndrome:Mutation Type: Loss of FunctionMutation: DNA Helicase and ExonucleaseMechanism:DNA Replication and Repair.Trims broken ends of damaged DNAImportant in the maintenance of telomeresDefective BASE EXCISION REPAIR (BER)Symptoms:Pre-Mature AgingFanconi Anemia:Mutation Type:Loss of FunctionMutation: Defective Cross-Link RepairMechanism:Multiple chromosomal breaksSymptoms:Pancytopenia, risk of AML, Skeletal Abnormalities_______________________________________________________________________________________________________________TUMOR VIRUSES:Virus: EBVCancers:Burkitt’s LymphomaB-Cell LymphomaNon-Hodgkin LymphomaVirus: Hepatitis B & C VirusesCancer: Hepatic CancerVirus: HTLV-I RetrovirusCancer: T-Cell LeukemiaVirus: HPVCancer: Cervical CancerOncogene E6: Inhibits P53Oncogene E7: Inhibits RBVirus: HIV RetrovirusCancer: Kaposis Sarcoma – HHV-8_______________________________________________________________________________________________________________Dyskeratosis Congenita:1 Mutated Telomerase Allele Prematurely shortened telomeresEpidermal Structure Abnormalities (skin, hair, nails)Malignancy (chromosome instability fusion events)Triggers p53 to repair damageProstate Cancer:Occurs Primarily in the Peripheral ZoneBPH occurs in the Transition ZoneOveractive Signaling produces PSA used as a marker.Androgen Receptor Antagonists are used to treat.PTEN is mutated in 60% of cases.P53 is mutated.Having a BRCA1/BRCA2 Mutation increases the risk.Warburg Effect: Despite abundant O2, the cancer cells still use glucose fermentation and have an increased level of glucose uptake. This increases the amount of Lactic Acid surrounding tissues, causing toxic effects and damage.Anaerobic Glycolysis provides energy for Wound Healing, Skin Grafting, Angiogenesis.CLINCAL CASE STUDIES:Case 8: CMLPrincipal Findings and History:45-year old womanNo specific complaintsPalpable spleen tipBlood work showed elevated WBC and Platelet counts.Smear revealed basophilia and immature granulocytesBone Marrow HypercellularIncreased number of Myeloid and Megakaryocytic Cells.Cytogenic analysis identified multiple cells with a Philadelphia Chromosome t(9:22)Given therapy, potential bone marrow transplantation.Hopeful that treatments can induce long-lasting remission.Disease Etiology and Incidence:CML is caused by a clonal expansion of transformed hematopoietic progenitor cells that increases circulating myeloid cells.Transformed cells express the BCR-ABL OncogenePhiladelphia ChromosomeT(9:22)More common in men than in women.Accounts for 15% of Adult LeukemiaPathogenesis:95% of CML Patients have the Philadelphia Chromosome.The derivative chromosome is 22.ABL:Proto-OncogeneEncodes for Tyrosine Kinase (non-receptor)Function not clearly definedBCR: Function not clearly definedBCR-ABLConstitutive Tyrosine Kinase ActivityINTRACELLULARConfined to the CytoplasmActivates signaling cascades that control growth and differentiation Unregulated GrowthSymptoms:As CML progresses, it becomes increasingly aggressive.Additional Chromosomal Changes AccumulateBlast Crisis: acute leukemia in which blasts can be myeloid, lymphoid, erythroid, or undifferentiated, rapidly fatal.Accelerated Phase: intermediate between the Chronic Phase and Blast Crisis.Chronic Phase: can lead to Blast Crisis fatality very quickly. 85% of patients are diagnosed in this stage. Management:Imatinib (Gleevic)BCR-ABL Tyrosine Kinase Inhibitor85% of patients have a clear cytogenic response after therapy.Resistance is frequest and symptoms return.Allogenic Bone Marrow Transplantation is curative.A limited population has access to this.The success depends on the stage of CML, the match, the age of the patient.Graft-Versus-Host Response: directed against leukemic cells, can lead to long-term success.Inheritance Risk:ZERO.Occurs from a Somatic Mutation, not a Germ Line Mutatation.Case 13: Familial Adenomatous Polyposis (FAP):Physical Findings and History:35-year old man.Underwent total ColectomyMucosa had over 2000 polyps.Hypertrophy of Retinal Pigment EpitheliumSeveral relatives died of cancer.Suggested molecular testing to check his children.Screening showed a nonsense mutation in APC.Disease Etiology and Incidence:Autosomal DominantAPC MutationCan also occur in 80% of Sporadic CasesAccounts for less than 1% of Colon CancerPathogenesis:APC Protein:Tumor Suppressor GeneBoth alleles must be inactiveRegulates transcription, cell adhesion, the microtubular cytoskeleton, cell migration, apoptosis, and proliferation.Forms complex with B-Catenin to inhibit the Cell Cycle.Second Hit:Having FAP means that you already have one bad APC allele. All you need is a mutation in the other one to start getting adenoma (not carcinoma):Loss of HeterozygosityIntragenic MutationTranscriptional InactivationDominant-Negative Effects (rare)The Second Hit causes Dysplastic Foci within intestinal crypts, but these cells are not cancerous and must acquire other mutations to progress to cancer.Phenotype and Natural History:Hundreds to thousands of colonic adenomatous polyps.More than 100 are sufficient for diagnosis.10-100 is sufficient if patient has an FAP+ relative.If untreated, 93% develop colon cancer by Age 50.Non-Penetrance is very rare, but does happen. 2 APC hits does not guarantee cancer. They are likely to become cancerious because:Patients develop adenomas earlier in lie, meaning they are less likely to die of other causes before getting cancer.Although only 1% of adenomas turn into carcinomas, patients have hundreds-thousands of adenomas. Other Closely-Related Syndroms:Gardner Syndrome: colonic adenomatous polyposis, osteomas, soft tissue tumors, congenital hypertrophy of the retinal pigment epithelium.Turcot Syndrome: colon cancer and central nervous system tumors, usually medulloblastoma.Management:Early recognition.Total colectomy, colonoscopy every 1 or 2 years at age 10-12.Identify at-risk family members.Inheritance Risk:Usually, the risk of developing colon cancer is about 5-6%.This number can go up depending on the family history: the more family members with colon cancer + the younger they developed it = a higher risk for you.A patient with FAP has a 50% chance of having a child with FAP.Case 29: Neurofibromatosis 1History and Physical Findings:2-year old maleCafé au lait spots, Lisch Nodules in both eyes, axillary freckling.De novo mutation in NF1.Recurrence risk was low, but genetic mosaicism is a possibility.Disease Etiology and Incidence:Autosomal Dominant1-3500, one of the most common genetic conditions.Approximately ? have de novo mutations.Mutation rate of NF1 is the highest for any known gene.Pathogenesis:NF1: Large gene, encodes for NeurofibrominWidely expressed in all tissuesIs a RAS GAP (inactivates RAS)Tumor Suppressor GeneMultiple genes have been identified to result in the loss of function of NF-1, usually unique to a family. 80% of the mutations cause protein truncation.Extreme clinical variability. No clear genotype-phenotype correlation has been identified.Phenotype and Natural History:Criteria for Diagnosis: (must meet 2)6 or more Café au lait spotsPrepubertal: measuring 5 mm diameterPostpubertal: measuring 15 mm diameter2 or more neurofibromas of any type1 plexiform neurofibromaAxillary or inguinal frecklingOptic glioma2 or more Lysch NodulesA distinctive osseous phenotype (sphenoid dysplasia)First-degree relative with NF1Complete PenetranceSegmental/Regional NF1: patients having NF1 in only one region of the body.Management:No curative treatmentsRegular assessments, including eyesRegulator Developmental/Mental checksSurgical removal of spots/nodules.Inheritance Risk:Individuals with NF1 have a 50% risk of a having a child with NF1.Features of the disease may be different in the child.Prenatal diagnosis is accurate, but you do not know how the disease will present. ................
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