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MOD (Mechanisms of Disease) Exam 2 > Robbins Chapter 7 > Flashcards

Robbins Chapter 7 Flashcards

1
Q

What are 4 improper uses of “-oma”? (LMMS)

A

lymphoma, mesothelioma, melanoma, seminoma

  • “-oma” means benign but these are MALIGNANT
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2
Q

What is anaplasia?

A

complete lack of differentiation (malignant neoplasms composed of poorly differentiated cells)

  • IRREVERSIBLE; hallmark of malignancy
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3
Q

What do teratomas originate from?

A

totipotent germ cells

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4
Q

What are characteristics of a malignant nucleus? (4)

A

large nucleus (1:1 nucleus:cytoplasm ratio)

variable/irregular nuclear shape

coarsely clumpled chromatin

hyperchromatic (dark staining)

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5
Q

Difference between:

  1. Well Differentiated
  2. Moderately Differentiated
  3. Poorly Differentiated
  4. Undifferentiated
A
  1. looks like parent tissue
  2. original tissue not dominant pattern, some atypia
  3. small # of parent features, cellular anaplasia
  4. tissue of origin CANNOT be discerned, anaplasia
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6
Q

What is Carcinoma In Situ?

A

pre-invasive neoplasms involving full epithelial thickness but DO NOT penetrate basement membrane

  • becomes invasive once it has penetrated BM
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7
Q

Tumor Capsules (Local Invasion) and the one exception

A
  • rim of compressed fibrous tissue seen around benign tumors that separate them from host tissue (malignant have pseudo-capsules)
  • created by fibroblasts due to hypoxia from growing tumor pressing on healthy tissue (makes tumor easy to find and feel)

Hemangiomas do NOT have a capsule and are not discrete

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8
Q

What is the only ABSOLUTE criterion for Malignancy?

A

Metastasis (strongly reduced possibility of cure)

  • invasiveness is 2nd best characteristic
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9
Q

What are common pathways of spread for:

  1. Ovarian Carcinomas
  2. Breast Cancer
  3. Carcinomas of the lung
A
  1. Direct Seeding into potential space (“heavy glaze”)
  2. Lymphatic Spread (axillary LNs)
  3. Lymphatic Spread (perihilar tracheobronchial and mediastinal LNs)
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10
Q

What are the two most common ways carcinomas and sarcomas spread?

A

Lymphatic Spread –> mainly carcinoma, some sarcoma

Hematogenous Spread –> mainly sarcomas, some carcinomas

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11
Q

What is a Sentinel Node and why is important?

A

first node in a regional lymphatic basin that receives lymph from from the PRIMARY tumor

  • biopsy to detect absence/presence of metastatic lesions
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12
Q

What cancers embolize through the paravertebral plexus?

A

vertebral carcinomas of prostate and thyroid

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13
Q

What are two cancers that mainly invade veins?

A

renal cell carcinoma –> to heart

hepatocellular carcinomas

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14
Q

Where do these cancers normally spread to:

  1. Breast Cancer
  2. Bronchogenic Carcinomas
  3. Neuroblastomas
A
  1. bone
  2. adrenals and brain
  3. liver and bones
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15
Q

What are the 3 most common cancers of Men and Women in developed nations?

A

Men: prostate, lung, colorectal
Women: breast, lung, colorectal

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16
Q

What are the 3 most common cancers of Men and Women in developing nations?

A

Men: lung, stomach, liver
Women: breast, cervix, lung

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17
Q

What age range in Men and Women is cancer seen to be the main cause of death in?

A

Men: 60-79 yo
Women: 40-79 yo

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18
Q

What causes:

  1. Squamous Metaplasia of the bladder
  2. Colonic Metaplasia of the stomach
A
  1. schistosomiasis infection

2. pernicious anemia and chronic atrophic gastritis

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19
Q

What cancer does exposure to Beryllium, Radon, and Chromium make workers more prone to?

A

Lung Cancer

B: missles, space fuels, nuclear reactors
R: uranium decay (quarries and mines)
C: metal alloys, pigments, preservatives

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20
Q

What are the two main steps of Chemical Carcinogenesis?

A
  1. Initiation - cell exposure to carcinogenic agent
    • permanent, nonlethal DNA damage
    • highly reactive electrophile (DNA bind/lesions)
  2. Promotion - induce tumors in initiated cells
    • chemical agents that stimulate cell proliferation
    • exposes carcinogenic potential of initiator
    • *only works on initiated cells**
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21
Q

Direct vs Indirect Initiating Chemicals

A

Direct: does NOT require metabolic activation
- ex: chemotherapeutic agents (low risk)

In-Direct: requires metabolic activation

  • products called “ULTIMATE CARCINOGENS”
  • activated by CYP450 normally
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22
Q

Benzo[a]pyrene (Indirect Initiating Chemical) and Aromatic Amines/Azo Dyes

A

active component in soot (tobacco combustion forms)

  • CYP1A1 (highly inducible form) metabolizes
  • smoked meats (from animal fat)

Aromatic Amines/Azo Dyes from rubber industries

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23
Q

What is Aflatoxin B1 and what cancer does it cause?

A

agent produced by Aspergillus that grows on improperly stored grains and nuts

  • hepatocellular carcinoma in Africa and Far East
  • Arginine –> Serine on Codon 249 (p53 protein mutation; infrequent in liver tumors from areas where this contamination does NOT occur)
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24
Q

UVB and Radiation Carcinogenesis

A

greatest risk of UV damage to the skin

  • produces Pyrimidine dimers that are repaired by Nucleotide Excision Repair

Xeroderma Pigmentosum: defect in NER pathway

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25
Q

What is Human T-Cell Leukemia Virus Type-1 (HTLV-1)?

A

oncogenic RNA virus –> adult T-cell leukemia/lymphoma (ATLL)

  • many tumors express FOXP3 (deaths from opportunistic infections)
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26
Q

How does HTLV-1 cause tumors to develop?

A

does NOT contain an oncogene; is a RETROVIRUS

  • viral replication of TAX = viral transcription of viral RNA from 5’ long terminal repeat
  • PI3K/AKT –> cell survival
  • inc. Cyclin D2, dec. CDK inhibitors
  • NF-kB –> cell survival
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27
Q

What is HPV and what is associated with Low-Risk Types and High-Risk Types?

A

oncogenic DNA virus that interrupts E1/E2 reading frame = lose E2 viral repressor and overexpress E6/7

Low Risk (6/11) = genital warts (nonintegrated genome)
High Risk (16/18) = squamous cell carcinomas
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28
Q

What are the oncogenic properties of HPV oncoproteins E6 and E7?

A

E6 - degradation of p53, stimulate TERT (inc. telomerase)
- p53 Arg72 polymorphism = CERVICAL CANCER

E7 - binds Rb and displaces E2F TF (G1-S phase) and inactivates p21 and p27

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29
Q

What is EBV (oncogenic DNA virus) associated with and how does it infect?

A

associated with: African Burkitt Lymphoma, nasopharyngeal cancer, and B Cell lymphomas

  • infects B cells by CD21 (latent, can propagate indefinitely in vitro = immortalized)
  • develops self-limited infectious mononucleosis in immunocompotent individuals
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30
Q

How do LMP-1, EBNA-2, and vIL-10 help with EBV B Cell proliferation?

A

LMP-1: oncogene (CD40 always on)
- inc. NF-kB/JAK STAT and inc. Bcl2

EBNA-2: Notch receptor always on
- inc. cyclin D and SRC proto-oncogenes

vlIL-10 - no T cell activation by monocytes

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31
Q

EBV and its association with Burkitt Lymphoma and Nasopharyngeal Carcinoma

A

Burkitt Lymphoma

  • no EBV protein expression (acts as B-cell mitogen)
  • t(8;14) seen in sporadic and endemic forms

Nasopharyngeal Carcinoma

  • infect epithelial cells via CD21
  • 100% of carcinomas contain EBV (express LMP-1)
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32
Q

Hepatitis B and Hepatitis C viruses (HBx protein)

A

associated w/hepatocellular carcinoma

no viral oncogenes (effects are multifactorial)

cause chronic inflammation –> regeneration and genomic damage over time

produce HBx = activates TF and signal transduction pathways –> cancer development

33
Q

H. pylori and development of Gastric Adenocarcinoma and Gastric Lymphoma

A

GA: CagA gene penetrates gastric epi cells –> stimulate growth factors

GL: B cell lymphoma lookin’ like Peyers Patches

  • reactive T Cells stim B Cell proliferation (MALToma)
  • monoclonal B cell proliferation

can eliminate H. pylori but B cells could acquire mutation that keeps them on WITHOUT T cell stimulus

34
Q

Cushings Syndrome and Hypercalcemia of Malignancy (Paraneoplastic Syndromes)

A

CS: most common endocrinopathy

  • small cell carcinoma of lung
  • lots of corticotropin and POMC (lung cancer)
  • puititary problems only have inc. corticotropin

HM: most common paraneoplastic syndrome

  • breast, lung, kidney, ovary carcinomas
  • extraosseus neoplasms (osteolysis/PTHRP)
  • symptomatic hypercalcemia = CANCER
35
Q

What is the most common lung neoplasm associated with Hypercalcemia?

A

squamous cell carcinoma

36
Q

What two cancers would cause migratory thrombophlebitis (Trousseau Syndrome)?

A

pancreas and lung carcinomas

37
Q

What two cancers is DIC associated with?

A

acute premyelocytic leukemia and prostatic adenocarcinoma

38
Q

What are cancer Gradings and Stagings based on?

A

Grading: differentiation, architecture, mitosis

Staging: size of primary lesion, spread to LNs, blood-borne metastasis presence
- MOST IMPORTANT CLINICALLY

T (primary tumor), N (LN involvement), M (metastasis)

39
Q

Where should a cancer biopsy be taken from?

A

between the outside edge and the necrotic center

periphery may not represent the tumor well

40
Q

What cancers are indicated by antibodies for:

  1. cytokeratins
  2. desmin
  3. anti-CD20
  4. PSA
  5. Thyroglobulin
  6. ALK
A
  1. epithelial carcinomas
  2. muscle cancer
  3. B cell tumors
  4. prostate carcinomas
  5. thyroid carcinomas
  6. lung cancers and lymphoma expressing ALK fusion proteins

abs can also check for estrogen/progesterone receptors and HER2 receptors

41
Q

When would you want to use:

  1. Quick Freeze
  2. Fine Needle aspiration
  3. Cytological Smears
A
  1. determine nature of mass lesion
  2. gather surrounding fluids from easily palpable lesions
    • less invasive than needle biopsy
    • usually from LNs
  3. pap smears (IN SITU STAGE)
    • ID tumors of abdominal, pleural, joint, CS fluids
    • tumors from easily shed locals
42
Q

What does Flow Cytometry and Circulating Tumor methods provide to cancer diagnosos?

A

FC: look at multiple antigens of blood-borne cancers at the same time (rapid and quantitative)

CT: find rare cancers cells in blood using 3D flow cells coated in antibodies

43
Q

How are PCR, FISH, DNA Microarrays useful in cancer diagnosis?

A

PCR - ID monoclonal (neoplastic) or polyclonal (reactive) T and B cell proliferations

FISH - ID characteristic translocations

DNA Microarray - genome-wide amps/deletions

44
Q

What cancers do these tumor biomarkers help identify:

  1. PSA
  2. CEA (Carcinoembryonic Antigen)
  3. AFP (alpha fetoprotein)
  4. HCG
  5. CA-125
A
  1. prostatic carcinomas
  2. colon, pancreas, lung, stomach, breast carcinomas
  3. hepatocellular carcinomas
  4. testicular tumors
  5. ovarian tumors

none are useful for DEFINITIVE diagnosis of cancer

45
Q

Driver Mutations and Loss of Function Mutations

A

DM: mutations that contribute to the malignant phenotype
- accumulation rate = speed of dz progression

LoF Mutations in genomic integrity genes are common early step on road to malignancy

46
Q

What does a mutation in ERBB1 and an amplification in ERBB2 lead to?

A

ERBB1 –> EGFR = Adenocarcinoma of the Lung
- EGRF RTK always on

ERBB2 –> HER2 = breast carcinoma
- amplification of HER2 receptor, RTK always on

47
Q

What does a translocation and a point mutation in ALK Receptor Proto-oncogenes lead to?

A

ALK translocation = adenocarcinoma of lung

ALK point mutation = neuroblastoma

48
Q

What 2 growth factors do Glioblastomas and Sarcomas express?

A

G: PDGF and PDGF RTK

S: TGFa and EGFR

49
Q

What are the most common abnormalities in proto-oncogenes in human tumors?

A

Point Mutations in RAS

50
Q

What cancers develop from a translocation and point mutation of the proto-oncogene ABL (Nonreceptor Tyrosine Kinase)?

A

Translocation = chronic myelogenous leukemia (CML)

Point Mutation = acute lymphoblastic leukemia (AML)

51
Q

What cancers develop from a translocation and amplification of MYC proto-oncogenes?

A

Translocation –> Burkitt Lymphoma

Amplification –> Neuroblastoma
specifically NMYC amplification

52
Q

What cancer are BRAF mutations seen in 100% of the time?

A

hairy cell leukemia

53
Q

Rb gene mutation and the two cancers somatic mutations cause

A

two hits required at RB on C13q14

AD inherited or undergo 2 random somatic mutations when NOT inherited

Somatic Mutation = retinoblastoma and osteosarcoma

54
Q

What is the function of:

  1. p21
  2. p27
  3. p16
  4. p14
A
  1. induced by p53
  2. responds to TGF-b
  3. INK4 –> bind cyclin D-CDK4 (inhibitory to Rb)
  4. inc. p53 lvls by inhibiting MDM2
55
Q

MDM2 effect on p53

A

p53 normally cause apoptosis via BAX but is negatively inhibited by MDM2

MDM2 degrades p53 (hyperactivity of MDM2 could lead to cancer proliferation)

p53 virtually undetectable in normal cells

56
Q

How does HPV confer a high risk of cervical carcinoma?

A

if it expresses the E7 protein

57
Q

TP53 mutations and Li-Fraumeni Syndrome

A

“Guardian of the Genome” –> LoF in 50% of cancers (C17p13.1)

  • most likely NOT inherited (inheriting one defective allele = Li-Fraumeni Syndrome = 25x greater chance of cancer by 50)
  • loss of p53 causes driver mutation accumulation
58
Q

APC mutations and Familial Adenomatous Polyposis

A

“Gatekeeper of Colonic Neoplasm” –> locus on C5q21

helps with degradation of Beta-Catenin (WNT system)

APC loss = inc. Beta-Catenin (uncontested growth)

Familial Adenomatous Polyposis (start w/1 defective allele of APC) = malignant polyps –> colon cancer

59
Q

What is the WNT System?

A

WNT signals FRZ = prevents Beta-catenin from being degraded

Beta Catenin binds to TCF (DNA binding factor) = promotion of colonic epithelial growth (inc. MYC and Cyclin D1)

60
Q

What TP53 mutants are treated the best and what two cancers are caused by them?

A

wild-type mutations treated easier

cancers: testicular teratocarcinoma and lymphoblastic leukemias

61
Q

Von Hippel Lindau function and mutation (what 2 cancers are pts at risk for?)

A

component of ubiquitin ligase that normally degrades HIF and TFs that respond to hypoxia (Chromosome 3)

  • Von Hippel-Lindau Syndrome (AD inherited) w/inc. risk of renal cell carcinoma and pheochromocytoma
  • mutations associated with inc. lvls of angiogenic growth factors and metabolism alterations
62
Q

E-cadherin function and mutation (what cancer are pts at risk for?)

A

normally anchors B-catenin to intracellular membrane and mediates cell-cell connections

Germline LoF (CDH1) = familial gastric carcinoma

SNAIL can downregulated E-cadherins

63
Q

CDKN2a function and mutation

A

encodes p16 and p14 (inhibits MDM2)

germline mutations

p16 methylated in some cervical cancers

64
Q

What cancers are associated with LoF in TGF-bR2 and inactivation of SMAD? (TGF-b pathway)?

A

LoF = colon, stomach, endometrium cancer

Inactivation = pancreatic cancer

SMAD normally upregulates CDKi/downregulates proliferative genes

65
Q

PTEN function and mutation

A

found on C10q23 –> normally halts PI3K/AKT

Cowden Syndrome

  • mutated –> skin appendages and tumors
  • inc. epithelial cancers (breast, endomet., thyroid)
66
Q

What are NF1 and NF2 associated with?

A

NF1 –> optic nerve gliomas

NF2 –> bilateral schwannomas of acoustic N.
- makes neurofibromin 2 (MERLIN)

67
Q

Patched (PTCH) function and Gorlin Syndrome

A

tumor suppressor that negatively regulates hedgehog

mutation = unopposed Hedgehog signaling (inc. NMYC and D cyclins)

Gorline Syndrome = germline mutations
- inc. risk of basal cell carcinoma and medulloblastoma

68
Q

Warburg Effect (PI3K, RTK, MYC)

A

inc. aerobic glycolysis and glutamine/glucose uptake
- provides intermediates for rapidly dividing cells that OxPhos cannot provide

PI3K –> upregulates GLUT, lipid/protein synth
RTK –> M2 isoform of pyruvate kinase
MYC –> support anabolic state and cell growth

69
Q

What affects does PTEN and STK11 have on the Warburg Effect?

A

PTEN = oppose PI3K pathway

STK11 = antagonizes Warburg changes

70
Q

What do the most common mutation of apoptosis in cancer involve?

A

caspase 9

71
Q

What do most B-cell lymphomas over-express in order to evade programmed cell death?

A

Bcl-2 due to t(14;18) translocation

72
Q

Cancer-Testis Antigens

A

MAGE-1 (Melanoma Antigen Gene)

  • only expressed in testis; silent in adults
  • tumor specific since sperm have no MHC1
73
Q

What two Mucin (glycoproteins/glycolipids) are expressed by ovarian Carcinomas?

A

CA-125 and CA-19-9

74
Q

What can kill mature B-cell lymphoma/leukemia and what CD is expressed by T cell lymphomas/Hodgkin lymphomas?

A

Anti-CD20 can kill B-cell lymphoma and leukemias

CD30 for T cell lymphomas and Hodgkins

75
Q

Hereditary Nonpolyposis Colon Cancer Syndrome

A

AD inherited cecum and proximal colon cancer
- defect in mismatch repair

microsatellite instability (1-6 nucleotide repeats inc/dec in disease)

76
Q

Why are COX2 inhibitors important?

A

decrease incidence of colonic adenomas and are approved for treatment of Familial Adenomatous Polyposis

77
Q

What cancers are epigentic methylation mutations (MLL1 and MLL2) and chromatin remodeling mutation (SNF5) related to?

A

MLL1 –> infants with acute leukemia

MLL2 –> follicular lymphoma

SNF5 –> malignant rhaboid tumor

78
Q

What miRNA are associated with B cell lymphomas and chronic lymphocytic leukemias?

A

BCL: miR-155 (indirectly upregulates MYC)

CLL: miR-15/16 (upregulation of Bcl-2)

79
Q

What translocation is associated with:

  1. CML (Chronic Myelogenous Leukemia)
  2. AML (Acute Myeloid Leukemia)
  3. Burkitt Lymphoma
  4. Mantle Cell Lymphoma
  5. Follicular Lymphoma
A
  1. t(9;22)
  2. t(8;21) OR t(15;17) –> PML-RARA gene
    • give All-trans RA to displace receptor repressors
  3. t(8;14)
  4. t(11;14)
  5. t(14;18)

MOD (Mechanisms of Disease) Exam 2 (4 decks)

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