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STEP 3: Neoplasia PATHOMA > Neoplasia Principles and Oncogenes > Flashcards

Neoplasia Principles and Oncogenes Flashcards

1
Q

What are 3 features that distinguish NEOPLASIA from hyperplasia or repair?

A

IRREVERSIBLE
UNREGULATED
MONOCLONAL (neoplastic cells derived from single mother cell)

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2
Q

How can clonality of cells be determined to differentiate between NEOPLASIA and HYPERPLASIA/REPAIR? (2) Which chromosome are these two genes on?

A
  1. G6PD ISOFORMS - Maintained 1:1 ratio in POLYCLONAL HYPERPLASIA, not maintained ratio - only 1 isoform in MONOCLONAL NEOPLASIA
  2. ANDROGEN RECEPTOR ISOFORM

Both present on X-chromosome

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3
Q

What is the Ddx of an ENLARGED LYMPH NODE (Proliferation of lymphocytes)?

A
  1. Metastatic Cancer
  2. Reactive Hyperplasia - Lymph node enlargement in response to an infection
  3. Lymphoma (only tumor of the lymph node)
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4
Q

Pt has an enlarged lymph node. Biopsy shows lymphocytic proliferation. Light chain study shows a Kappa:Lambda ratio of 20:1. What is my diagnosis?

A

STEP 1: Lymphocytic proliferation: 3 Ddx - Metastatic cancer, Reactive hyperplasia, and lymphoma
STEP 2: K:L ratio >6:1 = MONOCLONAL PROLIFERATION of B-lymphocytes

Diagnosis = LYMPHOMA

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5
Q

How can clonality of B-lymphocytes be determined?

A

Ig LIGHT CHAIN PHENOTYPE

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6
Q

What differentiates a POLYCLONAL HYPERPLASIA of B cells versus MONOCLONAL NEOPLASIA of B cells?

A

POLYCLONAL HYPERPLASIA: Normal kappa:lambda ratio - 3:1

MONOCLONAL NEOPLASIA: kappa:lambda > 6:1 (usually 20:1) OR inverted ratio (kappa:lambda = 1:3)

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7
Q

Which of the following neoplasias are monoclonal: BENIGN neoplasia or MALIGNANT neoplasia?

A

BOTH are monoclonal

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8
Q

What is the main distinguishing character of BENIGN tumors vs MALIGNANT tumors?

A

BENIGN: Absolutely do NOT metastasize
MALIGNANT: Have the POTENTIAL to metastasize

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9
Q

What are the most common cancers by INCIDENCE in adults?

A
  1. BREAST/PROSTATE
  2. LUNG
  3. COLORECTAL
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10
Q

What are the most common cancers by MORTALITY in adults?

A
  1. LUNG - Less common than breast/prostate BUT highest mortality BECAUSE of lack of early detection (NO PRACTICAL SCREENING MECHANISM) - Presents clinically LATE
  2. BREAST/PROSTATE
  3. COLORECTAL
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11
Q

How many divisions occur from the SINGLE MUTATED CANCER CELL (monoclonal proliferation) before clinical symptoms arise?

A

30 DIVISIONS

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12
Q

What is the difference between DYSPLASIA and CANCER?

A

Dysplasia: REVERSIBLE accumulation of mutations
Cancer: IRREVERSIBLE accumulation of mutations, grows unregulated and # of mutations increases with each division

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13
Q

What is the purpose of a PAP SMEAR?

A

To detect dysplastic precursor (CIN - cervical intraepithlial neoplasia I, II, III) before it becomes carcinoma

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14
Q

What is the purpose of a MAMMOGRAPHY?

A
  1. To detect ductal carcinoma in situ (DCIS) before it invades the BV and lymph - Calcifications often seen within DCIS
  2. To detect invasive carcinoma (>1cm) before it becomes clinically palpable (>2cm)
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15
Q

What is the purpose of a PSA and DRE?

A

To detect prostate carcinoma before it spreads
Prostate carcinoma arises on the POSTERIOR PERIPHERAL aspect and is thus clinically silent (unlike BPH which arises in the center and compresses on urethra)

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16
Q

What is the purpose of a HEMOCCULT TEST and COLONOSCOPY?

A
  1. To detect colonic adenoma before it progresses into colonic carcinoma (Adenoma-carcinoma sequence)
  2. To detect carcinoma before it spreads and shows clinical Sx
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17
Q

What is AFLATOXIN? What is the associated cancer?

A

AFLATOXIN = CHEMICAL TOXIN released by ASPERGILLUS that contaminated stored rice/grains

HEPATOCELLULAR CARCINOMA

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18
Q

Pt had chemotherapy. 5 years later, pt develops LEUKEMIA/LYMPHOMA. What is the most likely cause?

A

ALKYLATING AGENT DRUG

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19
Q

What are the 2 most common carcinogens that increase the risk of SQUAMOUS CELL CARCINOMA OF THE OROPHARYNX?

A

ALCOHOL

TOBACCO

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20
Q

ALCOHOL is a carcinogen that increases the risk of which cancers?

A

SQUAMOUS CELL CARCINOMA OF OROPHARYNX
SQUAMOUS CELL CARCINOMA OF UPPER ESOPHAGUS
PANCREATIC CARCINOMA [Alcoholism -> Pancreatitis]
HEPATOCELLULAR CARCINOMA [Alcoholism -> Cirrhosis]

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21
Q

How do you test for ARSENIC POISONING?

A

Clip the fingernails and sometimes remove the hair - ARSENIC can be found in the hair [HAIR and FINGERNAILS = derivatives of skin]

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22
Q

ARSENIC is a carcinogen that increases the risk of which 3 carcinomas?

A
  1. SQUAMOUS CELL CARCINOMA OF THE SKIN [Determine As poisoning by removing fingernails/hair - skin derivatives]
  2. LUNG CANCER [As - present in cigarette smoke]
  3. LIVER ANGIOSARCOMA
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23
Q

ASBESTOS exposure increases the risk of which 2 carcinomas?

A
  1. LUNG CARCINOMA

2. MESOTHELIOMA (Cancer that arises in the mesothelial cells of the pleura)

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24
Q

Is ASBESTOS exposure more likely to lead to LUNG CANCER or MESOTHELIOMA?

A

LUNG CANCER

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25
Q

What is the most carcinogenic component of CIGARETTE SMOKE?

A

POLYCYCLIC HYDROCARBONS

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26
Q

CIGARETTE SMOKE increases the risk of which 5 carcinomas?

A 
SQUAMOUS CELL CARCINOMA OF OROPHARYNX
SQUAMOUS CELL CARCINOMA OF ESOPHAGUS
LUNG CARCINOMA 
RENAL CELL CARCINOMA 
BLADDER CARCINOMA 
(Urothelium - lines kidneys, ureters, bladders; cigarette smoking = most carcinogenic component enters blood, filtered, concentrated in urine and entire urothelial system is bathed in smoke)
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27
Q

What are NITROSAMINES? Which carcinoma does this increase the risk of?

A

CARCINOGEN found in smoked foods - Associated with STOMACH CARCINOMA
Responsible for high rate of stomach carcinoma in Japan

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28
Q

Which type of STOMACH CARCINOMA (Intestinal type OR diffuse type) are NITROSAMINES associated with?

A

INTESTINAL TYPE STOMACH CARCINOMA - 3 risks: Chronic h.pylori gastritis + nitrosamines + Blood type A

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29
Q

What is NAPHTHYLAMINE? Which carcinoma is it most associated with?

A

NAPHTHYLAMINE - Derived from cigarette smoke

Most associated with UROTHELIAL CARCINOMA OF BLADDER

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30
Q

What is the carcinogen present in PLASTIC PIPES? (History/Epidemiological Study: Occupational exposure of this carcinogen resulted in a HIGH INCIDENCE of which cancer?)

A

PVC - POLYVINYL CHLORIDE

LIVER ANGIOSARCOMA

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31
Q

Occupational exposure of Ni, Cr, Be, or SILICA increases the risk of which carcinoma?

A

LUNG CARCINOMA

32
Q

CHINESE MALE or AFRICAN INDIVIDUAL with an EBV infection is most at risk for developing which carcinoma?
What other carcinomas is EBV infection related to?

A

NASOPHARYNGEAL CARCINOMA-Chinese male/Individual in Africa [NECK MASS - very early metastasis to the localized lymph nodes]
Also associated with BURKITT LYMPHOMA + LYMPHOMA (in AIDS pt)

33
Q

Which carcinoma is HHV-8 infection most related to? What are the 3 most common pt populations

A

KAPOSI SARCOMA = Low-grade malignant proliferation of endothelial cells
OLD EASTERN EUROPEAN MALES, AIDS, Tx RECIPIENTS

34
Q

Which carcinoma is HBV and HCV most associated with?

A

HEPATOCELLULAR CARCINOMA

35
Q

Which carcinoma is HLTV-1 infection most associated with?

A

ADULT T-CELL LEUKEMIA/LYMPHOMA

36
Q

Which carcinomas are HIGH RISK HPV (16,18,31,33) most associated with?

A

SQUAMOUS CELL CARCINOMA OF VULVA/ ANUS/ CERVIX

ADENOCARCINOMA OF CERVIX

37
Q

IONIZING RADIATION increases the risk of which 3 carcinomas? How does ionizing radiation do this?

A

AML
CML
Papillary carcinoma of thyroid

Ionizing radiation generates OH free radicals in the water within tissue -> Damages DNA -> Accumulation of mutations -> Carcinoma

38
Q

What is the most common source of NON-IONIZING RADIATION? Which 3 carcinomas does this increase the risk of? How?

A

UVB Sunlight -> Results in formation of TOO MANY PYRIMIDINE DIMERS in DNA (normally excised by restriction endonuclease) -> Increases risk of:

SQUAMOUS CELL CARCINOMA
BASAL CELL CARCINOMA
MELANOMA OF SKIN

39
Q

Which genetic disorder results in a predisposition to SQUAMOUS CELL/BASAL CELL CARINOMA/MELANOMA OF SKIN with exposure to UVB sunlight (NON-IONIZING RADIATION)?

A

XERODERMA PIGMENTOSUM: Deficiency of RESTRICTION ENDONUCLEASE - that is involved in nucleotide excision repair (nicking the pyrimidine dimers formed by sunlight)

40
Q

What are the 5 possible categories of PROTO-ONCOGENES?

A
  1. GROWTH FACTOR
  2. GROWTH FACTOR RECEPTOR
  3. SIGNAL TRANSDUCER
  4. NUCLEAR REGULATORS
  5. CELL CYCLE REGULATORS
41
Q

How does a proto-oncogene mutation result in CANCER?

A

Proto-oncogene normally is essential for cell growth and differentiation. Mutation of proto-oncogene -> ONCOGENE

ONCOGENE = undifferentiated cell growth

42
Q

PROTO-ONCOGENE CLASS 1: What mutation causes an ASTROCYTOMA?

A

RENAL CELL CARCINOMA
ASTROCYTOMA = Over-expression of Growth factor PLATELET-DERIVED GROWTH FACTOR B (PDGFB) -> Results in an AUTOCRINE LOOP

AUTOCRINE LOOP: PDGFB binds to PDGFB-R on astrocytes -> Signals to nucleus -> overgrowth of astrocytes (uncontrolled growth)

43
Q

PROTO-ONCOGENE CLASS 2: What mutation causes a SUBSET OF BREAST CARCINOMA?

A

BREAST CARCINOMA (subset) = AMPLIFICATION of EPIDERMAL GROWTH FACTOR RECEPTOR (ERBB2 [HER2/NEU])

44
Q

Which medication is indicated for breast carcinomas that overexpress HER2/neu epidermal GROWTH FACTOR RECEPTOR?

A

TRASTUZUMAB = anti-Her2/neu mAb

45
Q

What mutation is associated with MEN2A, MEN2B, and SPORADIC MEDULLARY CARCINOMA of the THYROID?

A

Point mutation in RET (TYROSINE KINASE RECEPTOR = NEURAL GROWTH FACTOR RECEPTOR) of neural crest cell origin

46
Q

What is MEN2A? What is MEN2B? What is MEN1? What is the inheritance pattern of all 3 of these?

A

MEN1= 3P’s - PANCREATIC ADENOMAS, PITUITARY ADENOMAS, PARATHYROID

MEN 2A = 2P’S - PARATHYROID + PHEOCHROMOCYTOMA + MEDULLARY CARCINOMA OF THYROID
MEN2B = 1P - PHEOCHROMOCYTOMA + MEDULLARY CARCINOMA OF THYROID + MUCOSAL NEUROMAS (Oral/intestinal ganglioneuromatosis)

All AUTOSOMAL DOMINANT: “Men think that they’re dominant”

47
Q

Pt presents with PARATHYROID ADENOMA and PHEOCHROMOCYTOMA. Why is it important to do a RET testing?

A

Do RET testing to test for MEN2A

If RET is +, do a PROPHYLACTIC THYROIDECTOMY BEFORE a medullary carcinoma of the thyroid (FATAL) presents!

48
Q

Pt presents with PHEOCHROMOCYTOMA and ORAL GANGLIONEUROMATOSIS. Why is it important to do a RET testing?

A

Do RET testing to test for MEN2B

If RET is +, do a PROPHYLACTIC THYROIDECTOMY BEFORE a medullary carcinoma of the thyroid (FATAL) presents!

49
Q

Which MEN syndrome is associated with MARFAN?

A

MEN2B = PHEOCHROMOCYTOMA + MEDULLARY CARCINOMA OF THYROID + MUCOSAL NEUROMA

50
Q

What mutation is associated with GI STROMAL TUMOR?

A

Point mutation in KIT = stem cell GROWTH FACTOR RECEPTOR

51
Q

PROTO-ONCOGENE CLASS 3: What mutation is associated with a very BROAD range of carcinomas [eg. colonic adenocarcinoma], melanomas, and lymphomas?

A

Point mutation in RAS-gene family protein (=GTP-binding protein SIGNAL TRANSDUCER molecule)

52
Q

Explain the biochemistry of how RAS over-activation can result in an oncogenic transformation to cancer.

A

INACTIVE Ras: Ras-GDP
ACTIVE Ras: Ras-GTP -> Can transduce signal to nucleus (Do NOT want too much signal to be transduced to the nucleus)

GTP-ase associated protein (GAP) closely linked to Ras: Hydrolyzes and inactivates Ras-GTP to Ras-GDP

GAP mutation -> Ras persistently in ACTIVE form [Ras-GTP] -> Excessive signal transduction to nucleus -> CANCER

53
Q

What mutation DEFINES CML and adult form of ALL (poor prognosis)?

A

t(9;22) translocation with BCR -> Results in mutation and overexpression of ABL (=TYROSINE KINASE SIGNAL TRANSDUCER)

54
Q

PROTO-ONCOGENE CLASS 4: What mutation is associated with BURKITT LYMPHOMA?

A

t(8;14) translocation with IgH = heavy chain (Chrom14) and c-Myc (Chrom 8) -> Mutation and over-expression of c-MYC (=NUCLEAR TRANSCRIPTION FACTOR)

55
Q

What mutation is associated with NEUROBLASTOMA?

A

Amplification of N-MYC (NUCLEAR TRANSCRIPTION FACTOR)

N-myc for Neuroblastoma

56
Q

What mutation is associated with LUNG CARCINOMA (small cell) - associated with lambert-eaton, SIADH, cushing?

A

Amplification of L-myc (=NUCLEAR TRANSCRIPTION FACTOR)

Lung for L-myc

57
Q

PROTO-ONCOGENE CLASS 5: What is the mutation associated with MANTLE CELL LYMPHOMA?

A

t(11;14) translocation of Cyclin D1 (=CELL CYCLE REGULATOR) on Chrom 11 with IgHeavy chain locus on Chrom 14 -> Massive overexpression of cyclin D1 = CHECKPOINT ALLOWS G1 -> S phase transition
**G1->S phase is the most regulated step of the cell cycle

58
Q

Which mutation (HINT: cell cycle regulator) is most commonly associated with MELANOMA?

A

Amplification of CDK4 (cyclin dependent kinase)

59
Q

How does a proto-oncogene mutation result in CANCER?

A

Proto-oncogene normally is essential for cell growth and differentiation. Mutation of proto-oncogene -> ONCOGENE

ONCOGENE = undifferentiated cell growth

60
Q

PROTO-ONCOGENE CLASS 1: What mutation causes an ASTROCYTOMA?

A

ASTROCYTOMA = Over-expression of Growth factor PLATELET-DERIVED GROWTH FACTOR B (PDGFB) -> Results in an AUTOCRINE LOOP

AUTOCRINE LOOP: PDGFB binds to PDGFB-R on astrocytes -> Signals to nucleus -> overgrowth of astrocytes (uncontrolled growth)

61
Q

PROTO-ONCOGENE CLASS 2: What mutation causes a SUBSET OF BREAST CARCINOMA?

A

BREAST CARCINOMA (subset) = AMPLIFICATION of EPIDERMAL GROWTH FACTOR RECEPTOR (ERBB2 [HER2/NEU])

62
Q

Which medication is indicated for breast carcinomas that overexpress HER2/neu epidermal GROWTH FACTOR RECEPTOR?

A

TRASTUZUMAB = anti-Her2/neu mAb

63
Q

What mutation is associated with MEN2A, MEN2B, and SPORADIC MEDULLARY CARCINOMA of the THYROID?

A

Point mutation in RET (TYROSINE KINASE RECEPTOR = NEURAL GROWTH FACTOR RECEPTOR) of neural crest cell origin

64
Q

What is MEN2A? What is MEN2B? What is MEN1? What is the inheritance pattern of all 3 of these?

A

MEN1= 3P’s - PANCREATIC ADENOMAS, PITUITARY ADENOMAS, PARATHYROID

MEN 2A = 2P’S - PARATHYROID + PHEOCHROMOCYTOMA + MEDULLARY CARCINOMA OF THYROID
MEN2B = 1P - PHEOCHROMOCYTOMA + MEDULLARY CARCINOMA OF THYROID + MUCOSAL NEUROMAS (Oral/intestinal ganglioneuromatosis)

All AUTOSOMAL DOMINANT: “Men think that they’re dominant”

65
Q

Pt presents with PARATHYROID ADENOMA and PHEOCHROMOCYTOMA. Why is it important to do a RET testing?

A

Do RET testing to test for MEN2A

If RET is +, do a PROPHYLACTIC THYROIDECTOMY BEFORE a medullary carcinoma of the thyroid (FATAL) presents!

66
Q

Pt presents with PHEOCHROMOCYTOMA and ORAL GANGLIONEUROMATOSIS. Why is it important to do a RET testing?

A

Do RET testing to test for MEN2B

If RET is +, do a PROPHYLACTIC THYROIDECTOMY BEFORE a medullary carcinoma of the thyroid (FATAL) presents!

67
Q

Which MEN syndrome is associated with MARFAN?

A

MEN2B = PHEOCHROMOCYTOMA + MEDULLARY CARCINOMA OF THYROID + MUCOSAL NEUROMA

68
Q

What mutation is associated with GI STROMAL TUMOR?

A

Point mutation in KIT = stem cell GROWTH FACTOR RECEPTOR

69
Q

PROTO-ONCOGENE CLASS 3: What mutation is associated with a very BROAD range of carcinomas [eg. colonic adenocarcinoma], melanomas, and lymphomas?

A

Point mutation in RAS-gene family protein (=GTP-binding protein SIGNAL TRANSDUCER molecule)

70
Q

Explain the biochemistry of how RAS over-activation can result in an oncogenic transformation to cancer.

A

INACTIVE Ras: Ras-GDP
ACTIVE Ras: Ras-GTP -> Can transduce signal to nucleus (Do NOT want too much signal to be transduced to the nucleus)

GTP-ase associated protein (GAP) closely linked to Ras: Hydrolyzes and inactivates Ras-GTP to Ras-GDP

GAP mutation -> Ras persistently in ACTIVE form [Ras-GTP] -> Excessive signal transduction to nucleus -> CANCER

71
Q

What mutation DEFINES CML and adult form of ALL (poor prognosis)?

A

t(9;22) translocation with BCR -> Results in mutation and overexpression of ABL (=TYROSINE KINASE SIGNAL TRANSDUCER)

72
Q

PROTO-ONCOGENE CLASS 4: What mutation is associated with BURKITT LYMPHOMA?

A

t(8;14) translocation with IgH = heavy chain (Chrom14) and c-Myc (Chrom 8) -> Mutation and over-expression of c-MYC (=NUCLEAR TRANSCRIPTION FACTOR)

73
Q

What mutation is associated with NEUROBLASTOMA?

A

Amplification of N-MYC (NUCLEAR TRANSCRIPTION FACTOR)

N-myc for Neuroblastoma

74
Q

What mutation is associated with LUNG CARCINOMA (small cell) - associated with lambert-eaton, SIADH, cushing?

A

Amplification of L-myc (=NUCLEAR TRANSCRIPTION FACTOR)

Lung for L-myc

75
Q

PROTO-ONCOGENE CLASS 5: What is the mutation associated with MANTLE CELL LYMPHOMA?

A

t(11;14) translocation of Cyclin D1 (=CELL CYCLE REGULATOR) on Chrom 11 with IgHeavy chain locus on Chrom 14 -> Massive overexpression of cyclin D1 = CHECKPOINT ALLOWS G1 -> S phase transition
**G1->S phase is the most regulated step of the cell cycle

76
Q

Which mutation (HINT: cell cycle regulator) is most commonly associated with MELANOMA?

A

Amplification of CDK4 (cyclin dependent kinase)

STEP 3: Neoplasia PATHOMA (3 decks)

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