1798950
| Pregunta | Respuesta |
| Oncogene | Dominant. Activation of one allele drives cancer. Typically due to chromosomal rearrangement, amplification, or very specific (hot spot) sequence mutations. |
| Tumor Supressor Gene | Recessive. Inactivation of both alleles drives cancer. Typically due to deletion, or multiple different sequence mutations. |
| t(11;22)(q24;q11) EWSR1-FLI1 | Ewing Sarcoma |
| t(X;18)(p11;q11) SYT-SSX | Synovial Sarcoma |
| t(12;16)(q13;p11) TLS-DDIT3 | Myxoid Liposarcoma |
| t(9;22)(q34;q11) BCR-ABL | CML 90-95% cases ALL 10-15% cases Abelson proto-oncogene (ABL1) encodes a nonreceptor tyrosine kinase on 9q34, disrupted in intron 1. Breakpoint cluster region gene (BCR) encodes a phosphoprotein on 22q11, disrupted in 1 of 3 breakpoint clusters. BCR-ABLE1 fusion gene generates a fusion protein. |
| t(15;17)(q22;q21) PML-RARA | Acute promyelocytic leukemia ~95% cases (AML-M3) |
| t(11;14)(q13;q32) IGH-CCND1 | Mantle Cell Lymphoma Chronic lymphocytic leukemia, 10-30% cases |
| t(14;18)(q32;q21) IGH-BCL2 | Follicular Lymphoma ~100% cases |
| KRAS | Proto-oncogene. Lung and colon cancer. Part of RAS-MAPK pathway. |
| KIT | Oncogenes. Activated by point mutations. Hereditary Gastrointestinal stromal tumor syndrome (GIST), melanoma, AML. |
| BRAF | Oncogene. Modulates normal signaling transduction. Can result in sustained or increased transmission of growth-promoting signal. Colon, lung, and thyroid cancer, melanoma Rx Vandetanib for V600E mutated melanoma |
| IgH and T-cell receptor clonality testing | IgH PCR for semi-conserved sequences in V and J. TCR PCR for gamma receptor. General assumptions (not always true) If lymphoma, then monoclonal IgH/TCR. If clonal, then IgH/TCR sequences same. If sequences same, then sizes same. |
| t(4;11) AF4-MLL | AML ALL |
| t(8;21) AML1-ETO | AML M2 - myeloid blasts with maturation |
| t(12;21) TEL-AML1 | ALL |
| BCR-ABL testing | For diagnosis only if FISH or karyotype unavailable. Used for prognosis in ALL. Breakpoint determination in adults with ALL. Minimal disease detection in treated CML. |
| TP53 | Tumor suppressor gene. Most frequently mutated of all known cancer genes. Decreased cell death rate through apoptosis. Germline - Li Fraumeni syndrome. |
| NPM 4 bp insertion | Analysis in AML gives favorable prognosis |
| ABL Multiple point mutations | Testing used when there is poor initial response or secondary resistance in CML. |
| FLT3 Tandem duplications, D835 point mutations | Testing in AML gives an unfavorable prognosis |
| Wilms Tumor | 10-15% hereditary WT1 (chr11), BWS locus |
| Retinoblastoma | RB1, tumor suppressor, mutations in coding region or promoter Path: Gene product normally regulates entry of cell into S phase of cell cycle, loss of checkpoint allows uncontrolled proliferation 40% hereditary - usually bilateral, early onset, may affect pineal gland, LOH is most common second hit, secondary neoplasms (osteosarcomas, soft tissue sarcomas, melanomas), 15% unilateral cases have germline mutation 60% sporadic - unilateral, later onset Recurrence Risk: no family hx, bilateral 5-7% (germline mosaicism), unilateral 1% |
| Hepatoblastoma | 10-15% hereditary Germline APC mutation OR Somatic activating mutation beta catenin (CTNNB1 gene) |
| Neuroblastoma | 1-2% hereditary ALK, PHOX2B MYCN amplification is a poor clinical indicator. |
| Choroid Plexus Carcinoma | 50% hereditary P53 |
| Adrenocorticocarcinoma | 50-60% hereditary P53 |
| Optic Gliomas | 45% hereditary NF1 |
| Juvenile Myelomonocytic Leukemia | ~30-50% hereditary NF1 |
| Atypical Teratoid Rhabdoid Tumor | 20-30% SMARCB1/SNF5/INI1 |
| Cancer Risk in Beckwith-Wiedeman Syndrome | Hepatoblastoma ~1-3%, 95% cases by 4 yo (higher risk with IC2 hypomethylation) Wilms Tumor ~2-5%, 95% cases by 8 yo (higher risk with IC1 hypermethylation) |
| Dennys-Drash Syndrome | Germline missense mutation WT1 exon 8 or 9 Undermasculized external genitalia, diffuse mesangial sclerosis, early onset renal failure |
| Trisomy 21 and Leukemia | 1% risk of leukemia, ALL>AML ALL - ~4 yo, worse prognosis, unfavorable cytogenetics AML - ~2 yo, better prognosis, needs less intensive Rx |
| Transient Myeloproliferative Disorder | Circulating blasts in neonate 6-10% of DS infants 15-20% mortality Due to somatic truncating mutations of GATA1 13-33% progress to AMKL Treatment: supportive, low dose cytarabine for 5 days |
| Acute Megakaryocytic Leukemia (AMKL) | Develops in 16% of DS with hx of TMD Secondary mutations |
| Rhabdoid Tumor Predisposition Syndrome | Germline mutation in SMARCB1 (chr 22) AD, incomplete penetrance Rhabdoid tumors - kidney (poor prognosis), liver, skin, heart, CNS (cerebellum) Schwannomas (familial schwannomatosis) |
| Familial Pleuropulmonaryblastoma Tumor Predisposition | DICER1 syndrome, 60-70% germline Path: disrupts miRNA signalling Sx: Pleuropulmonary blastoma - rare embyronal cancer of lungs, Cystic nephroma (2/3 with DICER1 mut), Isolated ovarian Sertoli-Ledig cell tumor, Wilms tumor, Familial multinodular goiter, malignant cancers (rhabdomyosarcoma) |
| RET | chr 10q21.2 Three domains: extracellular (binds to glial cell-line derived neutrotrophil factor), transmembrane domain, intracellular tyrosine kinase domain (activates signal transduction) GOF - MEN 2A (extracellular domain mutation), MEN 2B (TK domain mutation), sporadic thyroid cancers LOF - familial Hirschsprung |
| MET | hereditary papillary renal cell cancer |
| HRAS | Costello syndrome Skeletal anomalies, DD, bladder cancer, neuroblastoma, rhabdomyosarcoma |
| ALK | Hereditary neuroblastoma |
| Familial and Hereditary Pancreatic Cancer | 10% with family history 10-15% identifiable genetic syndrome Fanconi pathway genes (BRCA1, BRCA2, PALB2) Lynch syndrome Peutz-Jeghers Syndrome (STK11/LKB1) Hereditary pancreatitis (PRSS1) Familial multiple mole and melanoma syndorme (CDKN2A/p16) |
| Cowden Syndrome | 1/200,000, AD, PTEN Phenotype: presents 2nd/3rd decade, macrocephaly, facial trichilemmomas, penile freckling, papillomas of face/lips/tongue, acral keratoses, Breast cancer 30% risk (<40yo), thyroid cancer 10% (follicular, <50 yo), goiter, hashimoto thyroiditis, dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease), intestinal hamartomas, esophageal glycogenic acanthosis Path: wild-type protein is a major lipid phosphatase that downregulates PI3K/Akt pathway to cause G1 arrest and apoptosis Rx: annual derm exam, annual breast exam, annual breast MRI/mammo age 30, annual thyroid US age 18, annual endometrial bx age 35 until menopause |
| Peutz-Jeghers Syndrome | Genetics: AD, STK11 (50% deletions, 45% truncating) Sx: pigmented spots on lips, buccal mucosa and GI tract; intussusception, Breast 25-50%, colorectal 39%, stomach 29%, pancreas 11-36%, ovary/sex cord 18-21% |
| Peutz-Jeghers Syndrome Management | Monitor for intussusception Breast MRI and mammogram - annual Colonscopy, EGD, & small bowel enterography q2-3 years starting late teens Annual testicular exam |
| Juvenile Polyposis Coli | Genetics: 1/16,000-1/100,00, BMPR1A, SMAD4 (can also cause HHT), AD, severe form w/ deletion of PTEN and BMPR1A, 1-2% PTEN mutations Dx: >5 juvenile polyps, throughout GI tract, or 1 JP + family history Risks: Colorectal 50% lifetime risk (average age 43 yo), gastric 20%, small intestine, pancreas Surveillance: monitor for rectal bleeding, anemia, CBC, colonoscopy, upper endoscopy starting at 15 yo, colectomy only required if very high polyp burden, dysplastic changes, or excess GI bleeding |
| Von Hippel Lindau Syndrome | Gene: AD, VHL (seq 72%, del 28%), 1/36,000 Sx: Hemangioblastoma (cerebellum 44-72%, brainstem 10-25%, spinal cord 13-50%, & retina 25-60%), Phenochromocytoma 10-20%, Tumors of inner ear (endolymphatic sac) 11-16%, Renal clear cell carcinoma or cysts 25-60% Surveillance: eye q1y, metanephrines, MRI, abdominal US, temporal bone MRI if hearing loss |
| Hereditary Leiomyomatosis and Renal Cell Cancer | Mutations in FH gene 16% risk for type 2 papillary RCC Management: q1-2 skin exam for leiomyosarcoma, annual gynecologic eval, annual renal imaging |
| Hereditary Diffuse Gastric Cancer | CDH1 (E-Cadherin) Dx criteria: Family history of diffuse gastric cancer with 2 or more cases of gastric cancer, with at least one diffuse gastric cancer dx before 50 yo. Lifetime gastric cancer risk: 67% men, 83% women Breast cancer: 39% (lobular) |
| Multiple Endocrine Neoplasia 1 | Genetics: MEN1; AD; Classic tumor suppressor genes with LOF and 2nd hits Sx: Parathyroid, Pancreatic islet cell tumors, anterior Pituitary hyperplasia, Zollinger-Ellison syndrome. Facial angiofibroma, collagenoma, cafe au lait, lipoma. Management: yearly prolactin (start at 5 yo), total calcium (at 8 yo), gastrin (at 20 yo); imaging q3-5 y head MRI (age 5), abdominal CT or MRI (age 20) |
| Multiple Endocrine Neoplasia 2 | Gene: RET protooncogene; 10q11.2; AD Path: GOF, increased kinase activity in absence of ligand Medullary thyroid carcinoma (100%) MEN2A - pheochromocytoma, parathyroid hyperplasia; Exon 10 and 11 (95%) MEN2B - rarer type, tumors of 2A + neuromas on mucosa & GI tract, medullated corneal nerve fibers, developmental abnormalities, marfanoid phenotype; Exon 16 (95%) Eval: calcitonin, catecholamines, PTH, Ca Management: prophylactic thyroidectomy (by age 1 in 2B b/c lower age onset), screen for pheochromocytoma annually and prior to any surgery, annual calcitonin stim test, annual PTH |
| Pheochromocytoma and Paraganglioma Genes | Succinate dehydrogenase subunits encode mitochondrial proteins - SDHD (imprinted, affected when inherited from father), SDHB more malignant forms of tumors. VHL type 2 missense mutations. RET - MEN2 syndrome. Rarely NF1. |
| Li-Fraumeni Syndrome | Gene: TP53, CHEK2; AD Sx: soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, lung broncheoalveolar cancer. Chompret Criteria: proband with tumor in LFS spectrum before 46 yo AND at least one 1st or 2nd degree relative with LFS tumor (except breast ca if proband has breast ca) before 56 yo; OR proband with multiple tumors, 2 of which LFS and 1st before 46 yo; OR adrenocortical carcinoma or choroid plexus tumor, irrespective of family hx |
| Li Fraumeni Syndrome Management | Age 18-21 - breast cancer screening with MRI Age 25 - Colonoscopy Recently reported: whole body MRI, brain MRI, abdominal US, serum study for ACC, CBC |
| Gorlin Syndrome | Multiple nevoid basal cell carcinomas (in teens) Massive increase in BCC in radiation Odontogenic jaw cysts, bifid ribs, prominent forehead, calcification of falx cerebri, planta and palmar pits 4-5% risk of medulloblastoma PTCH gene (chr 9q22) mutation |
| Hereditary Paraganglioma Syndromes | Genes: SDHA, SDHB, SDHC, SDHD <- (only when paternally inherited) -> SDHAF2, TMEM127, VHL, RET, NF1 Autosomal dominant transmission |
| Base excision repair | Removal of abnormal bases MYH gene Disorders: Colorectal cancer |
| Nucleotide excision repair | Removal of thymine dimers and large chemical adducts. Complex process involves more than 30 proteins removing fragments ~30 nucleotides. Gene: XP + others Disorder: Xeroderma pigmentosa |
| Post-replication repair | Removal of double-stranded breaks by homologous recombination or non-homologous end-joining. |
| Nijmegen breakage syndrome | Gene: NBS Post-replicaiton repair gene |
| Bloom syndrome | Gene: BLM (15q26.1), AR (1/100 carrier freq Ashkenazi) Sx: IUGR, photosensitive rash, telangiectasia, microcephaly, high pitched voice, normal IQ, immunodeficiency, azoospermia, POF, cancer risk (wide types and sites, colon most common) Dx: chromatid/chromosome breaks (sister chromatid exchange), triradial and quadriradial figures, BLM sequencing (2881 del6ins7 in AJ) Path: abnl DNA replication and repair leading to genomic instability |
| BRCA1/2 | Tumor-suppressor gene. Post-replication repair gene. BRCA1 interacts with Rad51 DNA repair protein in homologous recombination. BRCA2 interacts with Rad52 and PALB2 (partner and localizer of BRCA2). Ovarian tumors have increased sensitivity to PARP inhibitors (Olaparib). |
| Mismatch repair | Corrects mismatched bases caused by mistakes in DNA replication. Gene: MSH, MLH Disorders: colorectal cancer (HNPCC, aka Lynch) |
| Ataxia Telangiectasia | Gene: ATM (11q22.3), AR Carrier mothers have increased risk of breast cancer (30% risk by age 60) Sx: progressive cerebellar ataxia (~age 1-4 yo), oculomotor apraxia, conjunctival telangiectasia, immunodeficiency, choreoathetosis, ionizing radiation sensitivity, risk cancer (lymphoma and leukemia). Dx: ATM sequencing (>95%). Amish founder mutation. decreased ATM kinase activity, 7;14 translocation (5-15% lymphocytes after PHA stimulation). Path: Most mutations are null leading to no protein product. Normal protein finds dsDNA breaks and coordinates cell cycle checkpoints prior to repair. |
| Alveolar rhabdomyosarcoma | translocation between 2 and 13 chimeric transcript involves PAX3 at 2q35 rare lung tumor in children |
| Irinotecan | Drug used to treat colorectal cancer. 10% North American, African, and Europeans are homozygous for UCT1A1*28 variant that results in reduced glucuronidation of drug with increased risk of severe neutropenia with standard dose. |
| Herceptin (trastuzumab) | Antibody that targets overexpression of HER2/neu protein observed in 1/3rd of patients with breast cancer. ERBB2/HER2/neu |
| Imatinib mesylate (Gleevec) | Protein tyrosine kinase inhibtor used to treat CML by binding BCR-ABL fusion protein from t(9;22). Also effective in gastrointestingal stromal tumors that harbor KIT mutations. |
| EGFR Non-Small Cell Lung Cancer | 13% pt with non-small-cell lung cancer have activating EGFR mutation. Drugs like gefitinib and erlotinib can block EGFR tyrosine kinase domain and inhibit effects |
| Multiple Myeloma | Make a single or monoclonal Ab species in large abundance, which in proportion of patients can be detected in urine as Bence Jones protein (Ab L chains). |
| Variable region | The amino terminal region of Ab. 60 DNA segments coding for V region on Heavy chain, 40 for V region on kappa light chain, 30 for V region on gamma light chain. |
| Joining region | Between the constant and diversity region on Ab. Six DNA segments code for J region H-chain, 5 for kappa L-chain, 4 for gamma L-chain. |
| Constant region | Constant region of Ab. 11 DNA segment codes for H-chain,1 for kappa L-chain, 7 for gamma L-chain. Class switching involves maintaining V region but switching the C-region of H-chain of the IgM molecule to new class of H-chain. |
| Diversity Region | Region between V and J region. 27 DNA segments coding for the D region of H-chain. |
| Philadelphia Chromosome | t(9;22)(q34;q11) 90% individuals with CML Transferes ABL from chr 9 into a region of chr 22 BCR region on chr 22 resulting in chimeric transcript from c-ABL and BCR genes. |
| Burkitt Lymphoma | 80% cases have translocation of c-MYC on chr 8 to heavy chain immunoglobulin locus on chr 14 t(8;14)(q24;q32). 15% t(8;22)(q24;q11). 5% t(2;8)(q11;q24) MYC comes under the influence of regulatory sequences of Ig Gene and is overexpressed 10x more. |
| Two hit theory | Can lead to development of tumor. Loss of heterozygosity. Mechanisms: non-disjunction, non-disjunction and replication, mitotic recombination, gene conversion, gene deletion, point mutation |
| Familial Adenomatous Polyposis | Tumor-suppressor gene. Gene: APC gene, AD, high penetrance, 15-30% de novo, 80% truncating mutations, 5-10% deletions, attenuated with mutations at far 5' and 3'; MUTYH AR form Sx: Numerous polyps large intestine, 100% risk of colon cancer, 50% by age 33 years, absent/supernumerary/malformed teeth, hepatoblastoma, thyroid cancer, epidermoid cysts. Attenuated - fewer polyps in proximal colon. Gardner Syndrome (exon 15) - osteomas, CHRPE, soft tissue tumors Turcot syndrome - colon cancer and medulloblastoma Path: loss of APC results in high free cytosolic beta-catenin that migrates to nucleus, binds to T-cell factor 4, and inappropriately activates gene expression Surveillance: colonoscopy starting age 10-12, q1-2y, colectomy by late teens, upper GI endoscopy starting late teens, annual thyroid exam |
| Lynch Syndrome (Hereditary non-polyposis colorectal cancer) | Genetics: AD; mismatch repair genes MLH1 and MLH2 most common. MSH6 and PMS2 lower penetrance. Upstream deletion of EPCAM/TACSTD1 which methylates and turns off MSH2. Path: repair incorrect DNA base pairing, microsatellites particularly vulnerable because of slippage leading to microsatellite instability Pheno: 80% risk CRC (right sided), 40% risk endometrial cancer, biliary tract, urinary tract, ovary, sebaceous gland tumors of skin (Muir-Torre syndrome) Tumor histology: microsatellite instability (only 5% have germline mutation), immunohistochemistry fails to stain for protein that lost expression Surveillance: Colonoscopy q1-2y at 25 yo, prompt evaluation of endometrial bleeding |
| MYH Polyposis | MYH gene, AR, 1p33 Knock out gene leads to defects in base excision-repair pathway Attenuated polyposis <100 adenomas |
| BRCA1 | Gene: LOF mutations, most truncating, rare somatic, Ashkenazi (185delAG, 5382insC) Sx: 50-80% lifetime risk breast cancer (more likely triple negative), 24-40% risk of ovarian cancer (higher than BRCA2), 1-2% male breast cancer, 1-3% pancreatic, <30% prostate |
| BRCA2 | Gene: rare somatic, Ashkenazi (6174delT) Sx: 40-70% lifetime risk breast cancer, 11-18% risk ovarian cancer, 5-10% male breast cancer, 2-7% pancreatic cancer, <39% prostate cancer |
| Dysplastic Nevus Syndrome | CMM1 Increased risk melanoma |
| Birt-Hogg-Dube Syndrome | AD, FLCN gene Pheno: facial trichodiscomas, renal cell carcinoma (chromophobe/oncocytic histology of RCC) |
| Manchester Scoring System | Predicts likelihood of BRCA1 or BRCA2 mutation will be identified in family. Based on age of cancer dx (breast or ovarian) and if pancreatic cancer present (for BRCA2) |
| Amsterdam Criteria | Used to select high-risk individuals with colorectal cancer for genetic screening. 1. At least 3 affected relatives (related to one by first-degree relationships, FAP excluded) 2. At least two successive generations affected. 3. Cancer diagnosed before age 50 years in at least one relative. |
| MUTYH Associated Polyposis | Genetic: MUTYH, AR Sx: polyposis >100 polyps, two common mutations Y165C (homozygous onset 46 yo) and G382D (homozygous onset 58 yo), onset 40-50s, conflicting data of increased risk in heterozygotes Path: base excision repair protein |
| Bethesda Criteria | For assessing proband for Lynch syndrome CRC <50 yo CRC + Lynch associated Cancer First degree relative with 2 Lynch cancers (one before age 50) Two second degree relatives one with CRC and one with lynch cancer |
| Mismatch Repair Deficiency Syndrome Turcot Syndrome | Genetics: AR, biallelic inactivation of MMR genes Sx: brain tumors and colon polyps in childhood, atypical cafe au lait spots and axillary freckling |
| Dyskeratosis Congenita | Genetic: dysfunctional telomeres, telomeres less than 1st percentile, locus hetoerogenity, common form X-linked Sx: nail dystrophy, oral leukoplakia, abnormal skin pigmentation, hypoplastic bone marrow failure, immunodeficiency, pulmonary complications, malignancy 20% (AML, head and neck cancer), mean age of death 3rd decade. Dx: Telomere length measurement |
| Nature of Second Hit | Somatic Mutation. Epigenetic silencing. Somatic recombination. Loss and duplication. Chromosome loss. |
| Imatanib | EGFR inhibitor. Need to test patient for KRAS mutations prior to prescribing since KRAS is downstream of EGFR and auto-activating mutations in KRAS result in growth that bypasses EGFR. |
| Gail Model | Health women (over age 35) Used to predict risk of breast cancer Can't be used if already dx with breast cancer. |
| Crizotinib | EML4-ALK ALK missense mutation |
| Everolimus | TSC1/TSC mutant Subependymal giant cell astrocytoma |
| Familial Isolated Pituitary Adenomas | AD, reduced penetrance, AIP gene (aryl hydrocarbon receptor interacting protein); 90% sequence, 10% del/dup Sx: pituitary adenomas expressing GH, prolactin, TSH, ACTH, or nonfunctioning; age of onset 20-24 yo |
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