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A. Tumor Suppressor Genes [2,13,26]

  1. TP53 (p53) [15]
    [Figure] "Cell Cycle Control Proteins"
    1. Chromosome 17p13.1
    2. Function: transcription factor and cell cycle regulation (checkpoint control)
    3. Mutations: loss of function or dominant negative, ~50% of human tumors
    4. Disruptive mutations associated with 1.7X increased risk for death in squamous cell carcinomas of the head and neck [11]
    5. Familial Syndrome: Li-Fraumeni Syndrome
  2. RB1 (retinoblastoma gene product) [1]
    1. Chromosome 13q14
    2. Function: Cell cycle (Go or G1 to S) and transcription regulation, E2F1 binding
    3. Prohibitin (chrom 17q21) interacts with RB1 and other RB family members
    4. Prohibitin-RB complex inhibits transcription by E2F1 transcription factor
    5. Mutations: retinoblastoma, osteosarcoma, small cell lung Ca, breast, prostate, bladder
    6. Familial Syndrome: Retinoblastoma Syndrome
  3. CDKN2A (p16; see also below) [12]
    1. Chromosome 9p21
    2. Function: Cdk 4 and 6 Inhibitor, G1 cell cycle arrest (associated with RB1)
    3. Mutations: melanoma, pancreatic, squamous, breast, lung [3,4]
    4. Familial Syndrome: Familial Melanomas (MLM), some pancreatic cancers
  4. APC (adenomatous polyposis syndrome) [15]
    1. Chromosome 5q21
    2. Function: ß-catenin regulation
    3. Mutations: colon, stomach, pancreas
    4. Familial Syndrome: Familial Polyposis Syndrome
  5. DCC (deleted in colon cancer) [14,15]
    1. Chromosome 18q21.2
    2. Function: Cell Adehesion, transmembrane receptor for netrin (?), cell guidance
    3. Mutations: colorectal; some gliomas, neuroblastomas, AML, germ cell tumors
    4. Familial Syndrome: unknown
    5. Loss of chromosome 18q in colorectal cancer correlates with poorer prognosis
  6. MSH2, MLH1, PMS1, PMS2 [15]
    1. Chromosome 2p16 MSH2 gene
    2. Function: DNA mismatch repair
    3. Mutations: colorectal, endometrial, gastric
    4. Familial Syndrome: familial non-hereditary polyposis
  7. DPC4 (deleted in pancreatic cancer)
    1. Chromosome 18q21.1
    2. Function: downstream signalling in TGFß pathway
    3. Mutations: pancreas, mutations are rare in gastric and colon cancers
    4. Familial Syndrome: unknown
  8. NF1
    1. Chromosome 17q11
    2. Function: GTP activating
    3. Mutations: Schwannoma, Myeloid Leukemias
    4. Familial Syndrome: Neurofibromatosis Type 1
  9. NF2
    1. Chromosome 22q
    2. Function: Cytoskeleton - juxtamembrane link
    3. Mutations: schwannoma, meningioma
    4. Familial Syndrome: Neurofibromatosis Type 2
  10. VHL [1,7]
    1. Chromosome 3p25
    2. Function: part of E3 ubiquitin ligase complex; blocks Elongin
    3. Mutations: hemangioma, renal cell carcinomas, pheochromocytoma
    4. Familial Syndrome: Von Hippel-Lindau Disease
  11. WT1
    1. Chromosome 11p13
    2. Function: Transcription factor (zinc finger)
    3. Mutations: Wilms' Tumor
    4. Familial Syndrome: WAGR and Denys-Drash Syndrome
  12. MEN-1
    1. Chromosome
    2. Function
    3. Mutations: parathyroid adenomas, pituitary adenomas, pancreatic endocrine tumors
    4. Familial Syndrome: Multiple Endocrine Neoplasia I
    5. Note: MEN II syndromes due to RET oncogene mutations (see below)
  13. PTCH basal
    1. Chromosome
    2. Function: transmembrane receptor for sonic hedgehog; inhibits smoothened protein
    3. Mutations: basal cell Ca of skin, medulloblastomas
    4. Familial Syndrome: Gorlin's Syndrome
  14. E-CAD
    1. Chromosome
    2. Function: transmembrane intercellular adhesion molecule
    3. Mutations: diffuse gastric and lobular breast; rare endometrial and ovarian
    4. Familial Syndrome: unknown
  15. Alpha-CAT
    1. Chromosome
    2. Function: links E-cadherin to the cytoskeleton
    3. Mutations: some prostate and lung
    4. Familial Syndrome: unknown
  16. TGF-ßII Receptor
    1. Chromosome
    2. Function: transmembrane receptor for TGFß
    3. Mutations: colorectal and gastric cancers
    4. Familial Syndrome: unknown
  17. PTEN
    1. Chromosome
    2. Function: tyrosine phosphatase
    3. Mutations: glioma, breast, prostate, head and neck, follicular thyroid, squamous skin, uterine
    4. Familial Syndrome: Cowden's Disease
  18. BRCA1 [6]
    1. Large gene, protein 1863 residues, probable binds DNA, normally found in nucleus
    2. Mutations increase risk for breast and ovarian cancer (especially familial syndromes)
    3. Protein terminating mutations appear to code for increased cancer risk
    4. Mutant protein leads to abnormal localization to cytoplasm in majority of breast tumors
    5. Large number of different mutations found, ~50% are deleterious [8]
    6. In general population, <2% of breast Ca and ~10% of ovarian Ca have BRCA1 mutations
    7. Overall 60-87% risk of breast and 60% risk of ovarian cancers with BRCA1 mutations
    8. In Jewish women, mutation 185delAG is strongly associated with breast Ca <40 years
    9. Genomic profiling has aided in understanding gene expression changes in spontaneous and familial breast cancer [17]
    10. Bilateral oophorectomy is associated with 80% reduced ovarian/Fallopian tube cancers [25]
  19. BRCA2
    1. Gene localized to 13q12-q13 and recently cloned (2329 amino acids)
    2. Involved in DNA repair, binds to Rad51 gene product
    3. Mutations in affected persons are deletions (likely tumor suppressor)
    4. Genetics in affected families suggest autosomal dominant inheritance
    5. In general population, mutations present in familial breast and pancreatic cancers
    6. Mutations found in ~30% patients with young onset, familial breast cancer
    7. Presence of BRCA2 mutations has risk of 85% for breast and 15% for ovarian cancers
    8. Bilateral oophorectomy is associated with 80% reduced ovarian/Fallopian tube cancers [25]
  20. CDKN2A (p16) [12]
    [Figure] "Cell Cycle Control Proteins"
    1. CDKN2A on chromosome 9p21 encodes two proteins (distinct overlapping reading frames)
    2. These proteins include p16 and p19
    3. p16 is a negative regulator of the cell cycle which bind protein kinases and inhibit them
    4. This leads to inhibition of Rb phosphorylation, and inhibition of cell cycle
    5. p19 functions upstream of p53
    6. Mutations of CDKN2A found in famillial melanoma and in some pancreatic cancers
  21. Prohibitin [19]
    1. Chromosome 17q21
    2. Function: binding RB family (RB1, p107, p130) and blocking E2F transcription
    3. Function: 3'UTR of prohibitin arrest G1/S transition in cell cycle
    4. Deletions: bamilial and sporadic breat cancer
    5. Mutations: T allele of prohibitin lacks G1/S blocking effects
    6. Familial Syndrome: increased risk of familial breast cancer independent of BRCA genes
  22. Fragile Histidine Triad Gene (FHIT) [20]
    1. Encompasses human common fragile site FRA3B on chrom 3p14.2
    2. Fragile sites are chromosomal regions sensitive to breakage from carcinogens
    3. 60% of primary tumors show absent or markedly reduced FHIT protein expression
    4. Preneoplastic lesions also show alterations of FHIT expression (~30%)
    5. FHIT introduction to cell lines led to inhibition of tumor cell growth in >50% of lines
    6. Restoring FHIT expression in tumors may reduce cancer progression
  23. DNA methylation reduces gene expression and may down regulate tumor suppressor genes [18]

B. Oncogenes [2,13]

  1. K-RAS
    1. Chromosome
    2. Function: p21 GTPase
    3. Mutations found in pancreatic, colorectal, lung adenoCa, endometrial, pacnreatic, others
    4. Mechanism of activation: point mutations
    5. K-ras mutations are also associated with exposure to organophosphates (DDT, DDE) [16]
  2. H-RAS
    1. Chromosome
    2. Function: p21 GTPase
    3. Mutations found in urinary bladder cancer
    4. Mechanism of activation: point mutations
  3. N-RAS
    1. Chromosome 1
    2. Function: p21 GTPase
    3. Mutations found in myeloid leukemias, some neuroblastomas
    4. Mechanism of activation: point mutations
    5. Mutations in this gene correlate with poor prognosis in neuroblastomas
  4. EGF-R (ERB-B, epidermal growth factor receptor)
    1. Chromosome
    2. Function: epidermal growth factor (EGF) receptor
    3. Mutations found in gliomas, squamous (skin) cancers, others
    4. Mechanism of activation: gene amplification
  5. Neu (Her2, Erb-B2)
    1. Chromosome
    2. Function: growth factor receptor
    3. Mutations found in breast, ovarian, gastric, other carcinomas
    4. Mechanism of activation: gene amplification
    5. Amplifcation of this gene associated with increased relapse risk in breast cancer
  6. C-MYC
    1. Chromosome 8
    2. Function: transcription factor
    3. Mutations found in Burkitt Lymphoma, Small Cell Lung Ca (SCLC), others
    4. Mechanism of activation: chromosomal translocation, gene amplification
  7. L-MYC
    1. Chromosome
    2. Function: transcription factor
    3. Mutations found in SCLC
    4. Mechanism of activation: amplification
  8. N-MYC
    1. Chromosome
    2. Function: transcription factor
    3. Mutations found in neuroblastoma, SCLC
    4. Mechanism of activation: amplification
  9. BCL-2 (B-cell lymphoma 2)
    1. Chromosome 18
    2. Function: blocks apoptosis (programmed cell death)
    3. Mutations found in follicular type B cell lymphomas
  10. BCL-3 (B-cell lymphoma 3)
    1. Chromosome
    2. Function:
    3. Mutations found in
  11. BCL-6 (B-cell lymphoma 6)
    1. Chromosome 3
    2. Function: zinc-finger transcription factor
    3. Mutations found in large cell lymphomas
    4. Chromosomal Translocation t(3;14) found in ~33% of large cell lymphomas
  12. CYCD1 (Cyclin D1, BCL-1)
    [Figure] "Cell Cycle Control Proteins"
    1. Chromosome 11
    2. Function: cell cycle control protein interacts with Cyclin E, Cdk2
    3. Mutations found in breast, other carcinomas, B-cell lymphoma, parathyroid adenoma
    4. Mechanism of activation: amplification, chromosomal translocation
  13. RET
    1. Chromosome 10q11.2
    2. Function: glial-derived neurotropic factor (GDNF) receptor protein kinase
    3. Mutations: papillary thyroid (translocation); medullary thyroid Ca (point mutation) [24]
    4. Familial Syndrome: Multiple Endocrine Neoplasia II [5]
  14. BCR-ABL (Breakpoint Cluster Region - Abl Fusion)
    1. Chromosome 22 (BCR) and Chromosome 9 (ABL)
    2. Function: non-receptor tyrosine kinase, chronic activation
    3. Mutations found in CML, T Cell ALL
    4. This fusion is produced by the Philadelphia Chromosome t(9;22) translocation
  15. CDK4 (cyclin dependent kinase)
    1. Chromosome
    2. Function: cyclin-dependent kinase, cell cycle regulation
    3. Mutations found in sarcomas
    4. Mechanism of activation: amplification
  16. MET
    1. Chromosome 7
    2. Function: hepatocyte growth factor (HGF) receptor tyrosine kinase
    3. Mutations found in hereditary papillary renal cancer
    4. Mechanism of activation: point mutations
  17. SMO
    1. Chromosome
    2. Function: transmembrane signalling, sonic hedgehog pathway
    3. Mutations found in basal cell skin carcinomas
    4. Mechanism of activation: point mutations
  18. ß-CAT
    1. Chromosome
    2. Function: transcriptional coactivator, links E-cadherin to cytoskeleton
    3. Mutations found in melanoma, colorectal cancer
    4. Mechanism of activation: point mutations, in frame deletion
  19. HST
    1. Chromosome
    2. Function: appears similar to fibroblast growth factor (FGF)
    3. Mutations found in gastric cancers
    4. Mechanism of activation: amplification
  20. PML-RARa
    1. Chromosome
    2. Function: chimeric transcription factor
    3. Mutations found in acute promyelocytic (M4) leukemia
    4. Mechanism of activation: chromosomal translocation
  21. MWA-PBX1
    1. Chromosome
    2. Function: chimeric transcription factor
    3. Mutations found in Pre-B acute lymphocytic leukemia
    4. Mechanism of activation: chromosomal translocation
  22. MDM-2
    1. Chromosome
    2. Function: p53 binding protein
    3. Mutations found in sarcomas
    4. Mechanism of activation: amplification
  23. GL1 (glioma 1)
    1. Chromosome
    2. Function: transcription factor
    3. Mutations found in gliomas, sarcomas
    4. Mechanism of activation: amplification
  24. TTG
    1. Chromosome
    2. Function: transcription factor
    3. Mutations found in T-cell acute lymphocytic leukemia
    4. Mechanism of activation: chromosomal translocation
  25. Survivin [23]
    1. Chromosome 17q25
    2. Function: Member of inhibitor of apoptosis gene family
    3. Mechanism of activation: overexpression, probably induced by ß-catenin
    4. Overexpression in soft tissue sarcomas predicts high risk of death [21]
    5. Not expressed in normal colonic epithelium, but increased in colon cancer
    6. High expression in colon cancer corelates with reduced survival, reduced tumor apoptosis
  26. Telomerase (TERT) [2]
    1. Chromosome
    2. Function: extension of telomeres during cell division
    3. Mechanism of activation: overexpression
    4. Overexpression in soft tissue sarcomas predicts high risk of death [21]
    5. Overexpression is required for preventing normal senescence

C. Chromosomal Abnormalities

  1. Acute Myelogenous Leukemia (AML)
    1. M2 - t(8;21)
    2. M3 - t(15;17)
    3. M4 - inv(16)
    4. M5 - 11q23
    5. Secondary AML (drug, myelodysplasia) - del(5q) or -5, del(7q) or -7, or t(11,21)
  2. Philadelphia (Ph+) Chromosome [22]
    1. Ph+ is a translocation from chr 9 (3' portion of c-abl) to 22 (to proximal bcr)
    2. Forms constitutively active kinases of 210K or 190K molecular weight
    3. CML - Ph+ in >90%
    4. Adult ALL - Ph+ in 20%
    5. Childhood ALL - Ph+ in 5%
    6. AML - Ph+ in 2%
  3. Acute Lymphocytic Leukemia (ALL)
    1. t(4,11)
    2. t(9,22)
    3. t(1,19); Pbx1-E2A fusion
  4. Chronic Lymphocytic Leukemia (CLL)
    1. t(11,14); Bcl1-IgH fusion
    2. t(14,19); IgH-Bcl3(IFkB) fusion
    3. t(2,14)
    4. t(18,22); Bcl2-IgL fusion
  5. Non-Hodgkin's Lymphoma (NHL)
    1. t(14,18); IgH-Bcl1 fusion
    2. t(14,19); IgH-Bcl3(IFkB) fusion
    3. p53 mutations correlated with low rates of complete response and poor prognosis [10]
  6. Burkitt Lymphoma
    1. t(8,14); Myc-IgH fusion
    2. t(2,8); IgL-Myc fusion
    3. t(22,8); IgL-Myc fusion
  7. Solid Tumors
    1. Small Cell Lung Ca: del(3p) in ~90% of tumors
    2. Testicular: Isochromosome 12
    3. Colon (see below)
    4. Kidney: 3p-
    5. Ewing's Sarcoma: t(11,22); Fli-1 and Ews
    6. Melanoma: 6q-
    7. Retinoblastoma: del(13)
  8. Colon Cancer
    1. Del(5) APC
    2. Del(18) DCC
    3. DPC4 [9]
    4. Also, p53 mutations, c-ras mutations are found

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