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Henrys 23rd Ed > Chapter 77 > Flashcards

Chapter 77 Flashcards

1
Q

Genetic mutations, PTC

A

Ret/Ptc rearrangement
Raf mutation
Ras mutation

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2
Q 
Chr 10q11.2
20% sporadic PTC
Exposed to rad.
Younger age
LN mets.
A

Ret/Ptc rearrangement

Ret/Ptc 1 - classic PTC
Ret/Ptc3 - solid variant PTC

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3
Q

20-40% follicular adenoma
Follicular variant PTC
FTC
Predispose well-diff. to dediff. resulting in anaplastic tumor

A

Ras mutation

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4
Q

B-catenin accumulation

A

Cribriform morular cariant of PTC

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5
Q

Direct target of ras-p21 (encoded by hras, kras and nras)

A

Raf mutation

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6
Q

MC genetic alteration in ptc (45%)

A

Braf gene mutation

T1799A transversion mutation in exon 15 of the gene —> braf v600e
Braf k601e pt. mutation
Akap9-braf rearrangement

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7
Q 
Classic ptc
Talk variant ptc
Aggressive (extrathyroidal extension, advance tumor stage, recurrence, + LN, distant mets)
20-40% dediff. 
30/40% anaplastic 
Tx failure (dec. trap of radioiodine)
A

Braf v600e

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8
Q

Braf; Follicular variant if ptc

A

Braf k601e

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9
Q

Braf; assoc. w/ rad. exposure PTC

A

Akap9-braf rearrangement

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10
Q

Pt. mutation codon 12, 13, 61
10-20% ptc
Almost always found in follicular variant of ptc

A

Nras, hras, kras

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11
Q

Genetic mutations, FTC

A

Ras pt. mutation

Pax8-ppary gene rearrangement

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12
Q

40-50% ftc
20-40% adenomas
Tumor dediff., less favourable prognosis, nets. to bone

A

Ras mutation

Mc site: codon 61 for nras and hras

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13
Q 
t(2;3)(q13;p25)
35% conventional ftc
13% follicular adenomas
5% follicular variant of ptc
Younger age, smaller, solid or nested patterns, + lvi
A

Pax8-ppary rearrangement

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14
Q

Genetic mutation, medullary ca (mca)

A

75% sporadic - somatic ret mutation; hras/ kras mutation
Men2a and men 2b
Familial mtc - germ line ret mutation (aggressive)

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15
Q

Genetic mutations, lung ca (adenoca)

A

Egfr mutations 10-40% -membranous oncoproteins
Alk gene chromosomal rearrangement - ~5%
Ros-1, ret, met, erbb2, braf, pic3ca - ~2%
Kras - 30%

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16
Q

Increase egfr overexpression

A

Egfr gene amplification
Chons overexpression
Specific activation mutations (10-40%)
-2 major hot spots:
90%: 1. exon 21 (l858r), exon 19 (15-bp and 18-bp deletion)
10%: 2. exon 18 (e709, g719), exon 20 (t790m)

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17
Q

Asian, Female, nonsmoker w/ AdenoCA

A

Egfr mutation

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18
Q 
Young, +/- smoker, AdenoCA 
Solid, cribriform, signet ring histology
Tx resonse crizotinib
Adenosq ca
Fish (gold standard)
A

Alk gene chromosomal rearrangement

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19
Q

Resistance to egfr-tkis in colorectal ca

A

Kras

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20
Q

Double stranded DNA virus

A

HPV infection

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21
Q

HPV Infection

> E7 binds to________

A

> E7 binds to retinoblastoma TSG (preferably the underphosphorylated form)

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22
Q

HPV Infection

> HPV E6 proteins associate with ______

A

> HPV E6 proteins associate with the p53 TSP

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23
Q

High risk HPV types

A

16, 18

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24
Q

Low risk HPV types

A

6, 11

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25
Q

cervical ca

> p16 (CDKN2A or MTS1) is located at 9p21.3 (group of TSG) regulate G1 phase of the cell cycle

A

p16 binds the cyclin-dependent protein kinases CDK4 and CDK6, inhibiting their interactions with cyclin D1.
inhibiting phosphorylation of RB gene and E2F transcription factors are sequestered, blocking G1 to S phase progression.
p16 expression loss allows cell to escape G1 arrest.
The E7 oncoprotein binds pRb causing E2F release resulting to G1 to S phase progression despite p16 expression

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26
Q

T/F: high p16 expression is a sensitive marker for HPV E7 protein expression

A

T

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27
Q 
Endometrial ca
Endometrioid adenocarcinoma (Type 1) exhibits \_\_\_\_ and \_\_\_\_ mutations  (26 and 17% respectively)
A

Endometrioid adenocarcinoma (Type 1) exhibits KRAS and TP53 mutations (26 and 17% respectively)

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28
Q

Endometrial ca

Approximately 5% of endometrioid carcinomas are associated with Lynch syndrome

A

mutations in ARID1A protein

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29
Q

Ovarian ca

____gene mutations are extremely common in high-grade serous carcinomas, while low-grade serous,

A

TP53 gene mutations

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30
Q

Ovarian ca

mucinous adenocarcinomas have a high prevalence of ____ and ___ mutations (75% in primary mucinous adenocarcinomas)

A

KRAS and B-RAF mutations

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31
Q 
endometrial ca
Serous adenocarcinoma (Type 2) exhibits \_\_\_\_ and \_\_\_\_ mutations                 (2 and 93% respectively)
A

KRAS and TP53 mutations

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32
Q

Ovarian ca

Mutations of _____, the gene encoding β-catenin and PTEN, are common in endometrioid adenocarcinoma

A

CTNNB1

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33
Q

ovarian ca
Mutations of ______, which encodes the catalytic subunit of PI3K (phosphoinositide 3-kinase), are observed most frequently in clear cell carcinomas.

A

PIK3CA

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34
Q

ovarian ca

LGSC have _____ mutations, but lack TP53 mutations

A

KRAS or BRAF
> Low-grade tumors have also been found to contain mutations that deregulate the canonical Wnt/β-catenin and PI3K/PTEN signaling pathways and typically lack TP53 mutations.

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35
Q

ovarian ca

HGSCs are often identified in advanced stage and have a high prevalence (50% to 70%) of ____ mutations

A

TP53 gene

> Most HGSC cancers further lack Wnt/β-catenin or PI3K/PTEN signaling pathway defects.

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36
Q

ovarian ca

Most HGSCs have genetic and somatic alterations of _______ and _______.

A

BRCA1 and BRCA2

  • genes encode proteins that are required for DNA double-strand break repair by homologous recombination
  • Cells lacking BRCA1- or BRCA2-dependent DNA repair tend to develop chromosomal rearrangements and genomic instability.
  • lifetime risk for developing ovarian cancer in mutation carriers varies with the genetic defect (for BRCA1, 30% to 60%, and for BRCA2, 15% to 30%)
  • BRCA-related familial ovarian cancers are more frequently multifocal and progress faster (almost invariably high grade serous type)
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37
Q

several genetic alterations in various thyroid tumors have been well-documented, including translocations and point mutations

A

involves RET, BRAF, RAS, and PAX8

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38
Q

RET/PTC rearrangement and point mutations of RAF (BRAF) and RAS genes — found in more than ___ of cases of papillary thyroid carcinoma

A

(70%)

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39
Q

gene
located on chromosome 10q11.2
encodes tyrosine kinase receptor
highly expressed in parafollicular C cells and very low in thyroid follicular cells

A

RET gene

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40
Q

PTC mutation
very early event in thyroid cancer development
high prevalence in occult or microscopic PTC
twelve forms have been reported to date, linking the 3’ portion of the RET gene with the 5’ portion of various different genes of the PTC family (2 MC: PTC1 (70%) and PTC3 (30%))
more frequent in individuals exposed to ionizing radiation (50-80%)
more frequent in children (40-70%) as compared with general population (15-30%)
typically presents in younger individuals and exhibit a high rate of lymph node metastasis with classical papillary histology and lower stage at presentation

A

RET/PTC rearrangements

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41
Q

RET/PTC1 was found to be associated with ________, and RET/PTC3 more among ________

A

> classic papillary histology

> solid variants

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42
Q

PTC mutation
encode the ras-p21 proteins
point mutations involving several specific sites (codons 12, 13, and 61) in NRAS and HRAS are more common in thyroid cancer
(10-20%) of papillary carcinoma
(40-50%) of follicular carcinomas
(20-40%) of poorly differentiated and anaplastic carcinoma

A

Human HRAS, KRAS, and NRAS genes

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43
Q

with regard to the rare but important cribriform morular variant of PTC, ______ accumulation is a defining feature

A

β-catenin

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44
Q

most common genetic alteration in PTC (45%)

A

BRAF mutation
most common genetic alteration in PTC (45%)
a majority of mutations involve T1799A transversion mutation in exon 15, causing amino acid change from valine to glutamine at amino acid residue 600 (V600E) — highly prevalent in PTC with classical histology and tall cell variant
K601E point mutation — typically follicular variant of PTC
AKAP9-BRAF rearrangement — more commonly associated with radiation exposure

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45
Q

PTC gene mutation
correlated with extra thyroid extension, advanced tumor stage at presentation, recurrence, and lymph node involvement and/or distant spread
20-40% of poorly differentiated thyroid carcinomas
30-40% of anaplastic thyroid carcinomas
cancers with this mutations have decreased ability to trap radio iodine and lead to treatment failure and more aggressive behavior

A

BRAF V600E

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46
Q

follicular thyroid ca

most frequent alterations:

A

RAS point mutations and PAX8-PPARƔ rearrangements

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47
Q

FTC gene mutation
found in 40-50% of conventional follicular carcinomas
20-40% of adenomas
most occur at codon 61 for NRAS and HRAS
associated with tumor dedifferentiation, and bone metastasis
potentially transformative (20-40% prevalence in poorly differentiated and undifferentiated carcinoma)

A

RAS mutation

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48
Q

FTC gene mutation
(35%) of conventional follicular carcinomas
lower prevalence in oncocytic (Hürtle cell) carcinoma
(13%) of follicular adenomas
(5%) of follicular variants of PTC
younger age group; smaller; exhibit solid or nested patterns; more frequent vascular invasion

A

PAX8-PPARƔ gene rearrangement
> result of translocation t(2;3)(q13;p25)
fusion between PAX8 gene and PPARƔ gene

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49
Q

Medullary or PTC: RET point mutation

A

Medullary
in sporadic MTC, somatic mutations of RET are found in (20-80%) of cases without a germ-line mutation
in familial forms, germ-line mutations are found in almost all patients

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50
Q

Medullary or PTC: RET chromosomal rearrangement

A

PTC

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51
Q

Lung ca

membranous oncoprotein that induces cell proliferation upon activation

A

EGFR
increased EGFR signaling can be result of EGFR gene amplification, protein over expression, or specific activation mutations in EGFR gene

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52
Q

Lung ca
more frequent in younger patients with either no or light smoking history
recent guidelines suggest ALK molecular testing should be done in all patients with lung adenocarcinoma
associated with solid, mucinous, cribriform and/ or signet ring histology
FISH using break apart probes is considered gold standard in detection of ALK rearrangements

A

ALK gene chromosomal rearrangement
> found in ~5% of lung adenocarcinoma
most commonly in form of an intrachromosomal inversion leading to EML4-ALK fusion product associated with ALK protein over expression

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53
Q

_____ and ____ testing are the most important uses of the diagnostic sample after diagnosis of adenocarcinoma is established

A

EGFR and ALK testing

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54
Q

lung ca

other less common alterations

A

> ROS1 chromosomal rearrangements (~2%)
RET chromosomal rearrangements (~2%)
increased copies of MET
sequence-altering mutations in ERBB2, BRAF, and PIK3CA
KRAS mutations (codons 12 and 13)
reported in up to 30% of cases of lung adenocarcinoma
usually found in cancers of smokers and are more common in adenocarcinoma than in NSCLC (15-20%)

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55
Q

encodes a gene product that is involved in the regulation of gene transcription menin, DNA replication and repair, and chromatin modification.
10% patients: first affected in the family
80% patients: with mutation in the MEN1 gene will develop disease at age 50.

A

MEN 1
> encodes menin (chromosome 11)
Rules of 1, Panay 1 (MEN 1, Chromosome 11)

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56
Q

Based on the risk for pheochromocytoma or hyperparathyroidism and the presence or absence of characteristic physical features

A

MEN 2
> RET proto-oncogene on chromosome 10
MEN 2 –> 2=R = RET (MED-RET)

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57
Q

– Most common Subtype: 95% detectable RET mutation.

Can be stratified into 3 levels of risk for MTC development based on mutation sites and numbers

A

MEN 2A
Genetic testing for for germ line RET mutations is available for a definitive diagnosis of MEN2 in patients who have an equivocal presentation or family history.

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58
Q

MEN 2

Highest risk

A

883, 918

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59
Q

Similarities MEN 1 and MEN 2a

A

Pituitary hyperpasia

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60
Q

Similarities MEN 2a and MEN 2b

A

Pheochromocytoma

Medullary thyroid CA

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61
Q

Other hereditary diseases included in MEN SYNDROMES

A

VHL Syndrome
Familial Paraganglioma Syndrome
Cowden Syndrome
Li fraumeni

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62
Q

VHL syndrome

A 
VHL gene
V = VHL gene
H =Hemangioblastoma
L = Lots of catecholamines = Pheochromocytoma
VHL = 3 letters = RCC
VHL = 3 letters = chromosome 3
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63
Q

Familial Paraganglioma Syndrome

A

Succinate dehydrgenase pathway (mitochondria II)
SDHD; pGL type 1 (MC, low risk)
Unk: PGL type 2
SDHC: PGL type 3 (rare, paragangliomas, head and neck)
SDHB: PGL type 4

SaD yung FAMILY dahil may PARANGLIOMA SYNDROME anak nila.

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64
Q

Cowden syndrome

A 
PTEN gene (deleted chromosome 10)
PTEN = TEN = chromosome 10
PTENg *na, ang baho ng COW sa DEN
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65
Q

85% of patients with with Cowden mutation have an identifiable mutation or deletion within ____.

A

PTEN.

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66
Q

Li Fraumeni Syndrome

A

Tp53 protein (chromosome 17p13.1)
Other show mutations in CHEK2
Invert “Li” = chromosome 17

Also known as sarcoma, breast, leukaemia and adrenal gland (SBLA) syndrome.

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67
Q

Neurofibromatosis 1

A 
NF1 gene (chromosome 17q11.2)
> encodes for neurofibromin
> Types of mutations f NF1 include complete gene deletions, insertions, stop codons, spicing mutations, amono acid mutations and chromosomal rearrangements.

NEUROFIBROMATOSIS = 17 letters

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68
Q 
CAFE SPOT
Cafe au lait spots
Axillary freckling
Fibromas
E lisch nodules in the eye
Skeletal bowing
Pseudoarthrosis of tibia
Optic Tumor
A

NF type 1

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69
Q

Neurofibromatosis 2

A 
NF2 gene (chromosome 22)
> tumor suppressor

RULE of 2s = NF 2; Chromosome 22q12; bilateral vestibular schwannomas; 2nd ro 4th decades of life (around 20 years); prevalence 1:25000

70
Q

Schwanomatosis

A

NF2 gene
3rd major form of NF
Multiple NONvestibular schwannomas in the absence of meningiomas, intraspinal ependymomas and otehr clinical signs of NFs
SCHWANOMA”TWO”SIS = NF2 gene

71
Q

ER + PR+ HER2 neg, ki 67 low

A

Luminal A

72
Q

ER + PR + HER2 +/- high ki67

A

Luminal B

73
Q

HER2 Immunohistochemical staining
Herceptest (Dako) = _____
Pathway (Ventana) = ______

A

Monoclonal

Polyclonal

74
Q

FISH method
Determine copy number of HER2neu gene
Uses chromosome probe 17 for centromere CEP17
Interpretation: >2.0 : abnormal
Her2/neu amplification compared with normal cells: Green: ___, Red: ____

A

CEP17 probe

Her2/neu probe

75
Q

Functions: repair of DNA damage, cell cycle check point control
Cumulative risk of developing breast cancer by age 70: 50-70%
Ovarian cancer: 30-40%

Likely to stain for basal cytokeratins 5/6 and 14 
Negative for ER
Stain for EGFR
P53 mutated
Younger women
A

BRCA1

76
Q

Involved in DNA repair, cytokinesis and meiosis
Cumulative risk of developing cancer by age 70:
Breast cancer:40-50%
Ovarian cancer: 10-15
Increased risk for other cancers:
Male breast cancer (75 fold relative risk)
Pancreas 4-8 fold
Prostate: 2 fold to 4 fold

A

BRCA2

77
Q

Tumor suppressor involved in cell cycle control, DNA repair and apoptosis
Most commonly mutated gene in sporadic breast cancer
Associated with Li- Fraumeni syndrome
Also associated with sarcoma, leukemia, brain tumors, adrenocortical adenoma

A

TP53

78
Q

____ = Activates BRCA1 and p53
Induces cell cycle arrest
ATM = Senses DNA damage
PTEN

A

CHEK2

79
Q

Gene Assays

A

PAM50 gene expression signature
Oncotype Dx
Mammaprint

80
Q

Expression levels of 50 genes
Classify tumor as 1 out of four intrinsic subtypes
Luminal A, luminal B, HER2- enriched, basal like

A

PAM50 gene expression signature

81
Q

10 year risk recurrence in patients

with ER +, lymph node negative tumor

A

Oncotype Dx

82
Q

Pure prognostic assay
Prognosticc test for a lymph node
negative breast cancer for a < 61 yr old
70 genes tested

A

Mammaprint

83
Q

Pancreatic ductal AdenoCA

> Genetic alterations

A

> Most common: Allelic loss of chromosome 18

> 1/3 have homozygous deletion at 18q21

84
Q

Pancreatic ductal AdenoCA

Present in 95% of cases
Occurs commonly in codon 12

A

> Mutated KRAS P21 , with val for gly 12

85
Q

Pancreatic ductal AdenoCA

> Tumor suppressing genes

A

CDKN2A, at chromosome 9p, inactivated in 95%
Encodes p16/ INK4a AND ARF
TP53, at chromosome 17p, inactivated in 70-75%
SMAD4: inactivated in 55%

86
Q

Pancreatic dustal AdenoCA

common in Ashkenazi Jewish population (10%)

> telomerase, MSI

A

> BRCA2:

87
Q

Precancerous lesions of the pancreas
Pancreatic intraductal neoplasia and intraductal papillary mucinous neoplasms may also have ___, ___, ___ and ____ mutations

A

KRAS, TP53, SMAD4 and p16/ CDKN2A

88
Q

Precancerous lesions of the pancreas

Intestinal type IPMNs always have intact ___ and harbor ____ mutations in 10% of cases

A

SMAD4/DPC4 and harbor PI3KCA

89
Q

Other pancreatic cancers:

Medullary carcinoma : ____

Colloid CarcinomaL CDX2/ MUC22

Undifferentiated carcinoma: ____

Acinar carcinoma: inactivation of TP53, p16/CDKN2A or SMAD4

Solid pseudopapillary neoplasms commonly have abnormal expression of ____

Pancreaticoblastoma: loss of one copy of the short arm of chromosome 11 near the WT locus

A

MSI
e-cadherin
B-catenin

90
Q

Pancreatic CA

____ loss is usually associated with death related to multiple metastases

A

SMAD4/ DPCR

91
Q

Pancreatic CA

Alterations in ___ and ___ has a worse outcome

A

p16 and hTERT

92
Q

Pancreatic CA

Amplification of ___ and ___ and loss of TP53 genes are correlated with tumor grade and survival

A

KRAS2 and CMYC

93
Q

Mouse- human hybrid monoclonal antibody

A

Cetuximab

94
Q

Fully human immunoglobulin G2 monoclonal antibody

A

Panitumumab

95
Q

Mutation status of ____ has become an important predictive marker for the effectiveness of Cetuximab or Panitumumab on metastatic CRCs.

A

KRAS

96
Q

Glioblastoma Multiforme

GENETIC MUTATIONS:

A

LOH 10q –> most frequent genetic loss (60-80%)
EGFR amplification (40%) –> chromosome 7; primary GBM
Tp53 mutation –> secondary GBM
Loss of MGMT
Allelic losses on 1p and 7q
CDK4, SAS (15%), MDM2, GLI, PDGFRA, MYC, N-MYC, MYCL1, MET, GADD153, cKIT amplification
1p/19q co-deletion –> rare

97
Q

Oligodendroglioma

GENETIC MUTATIONS

A

1p/19q co-deletion [ (1; 19)(q10; p10) translocation ] –> 50-80%; better prognosis and chemotherapy response
IDH mutations –> strong, independent positive prognostic biomarker
LOH mutations in p53 and p16 –> survival

98
Q

IDH mutations

A

IDH1 (R132H) (50% - 93%)

IDH2 (R172) (3% to 5%)

99
Q

rhabdoid tumor

genetic mutations

A

> 90% demonstrate loss of all or part of chromosome 22, particularly involving 22q11.2
INI1 (hSNF5/SMARCB1/BAF47), a putative suppressor gene, is mapped

100
Q

HCC (HBV vs HCV)

genetic mutations

A

> Genomic abnormality:
HCV-related HCC = exclusive gain at 10q
HBV-related HCC = loss of 4q and 16q; gain of 11q
Dysregulation of the major signal transduction pathways:
HCV-associated HCC = Wnt/β-catenin and MAPK pathways
HBV-related HCCs = Wnt/β-catenin, p53, pRb, MAPK, cytokine signaling

101
Q

HCC

genetic mutations

A

Chromosome 1q –> most common aberration in several geographic locations

Frequently deleted chromosome regions by LOH contain
TSGs: p53, Rb, p16, PTEN, and DLC1
Oncogenes: insulin-like growth factor-2 receptor IGF2R

LOH 1p –> early, small, or well-differentiated HCC
LOH 16p & 17p –> advanced stage and poor prognosis
Abnormalities in 8p, 17p, and 19p –> metastasis of HCC

102
Q

HCC
independent risk factor for a shorter postoperative disease-free survival, recurrence, and for a decreased overall survival

A

High level of GPC3 in tissue

103
Q

HA

____ = increases lipogenesis (fatty acid synthesis and downregulation of L-FABP –> diffuse intralesional steatosis

A

TCF1 or HNF1A (chromosome 12)

Biallelic inactivating mutations in the TCF1 (HNF1A) gene (homogenous)
85% –> somatic in origin
Few cases –> mutation is somatic + other is germ-line

Heterozygous germ-line mutations –> associated with occurrence of a rare autosomal dominant condition (MODY3), which presents in early adulthood (usually < 25 y/o)

104
Q

HA

Decreased degradation, sustained activation, and nuclear accumulation of β-catenin protein:

A

Mutation of the β-catenin gene, OR

Mutations in the axin, APC, or GSK3 genes

105
Q

HA

more frequently associated with malignant transformation

A

HA-B subtype

> β-Cateningene (CTNNB1)

106
Q

HA-I

A

Some hepatic adenomas show sustained activation of interleukin 6 (IL-6) receptor signaling
Somatic gain-of-function mutations of the IL-6 signal transducer gene (IL6ST) encodes glycoprotein-130 (gp130)

107
Q

Gastric CA

Main causes: dietary habits, environmental factors, and H. pylori infection

Multistep process: gastritis (chronic or atrophic) and related changes (e.g., pernicious anemia) –> intestinal metaplasia, dysplasia –> carcinoma

A

Intestinal type

108
Q

Gastric CA
Intestinal type
genetic mutations

A

Inactivation mutation p53 –> early stage of carcinogenesis

Mutation in p73 –> associated with H. pylori infection (mouse model)

High-level of microsatellite instability (MSI-H)
Hypermethylation of the promoter regions of mismatch repair genes (most commonly, MLH1 and MSH2), OR
Gene mutations (in a small percentage of GCs)

24% to 47%: CpG island methylator phenotype (originally found in colorectal cancer)

LOH or mutation of APC genes

LOH at the bcl-2 locus
Amplification of cyclin D1 and E
Oncogene product Her2/neu

109
Q

Gastric Cancer
Less clear
Not related with H. pylori infection
Part of a hereditary gastric cancer predisposition syndrome

A

Diffuse type

110
Q

Gastric Cancer
Diffuse type
genetic mutation

A

E-cadherin gene (CDH1) mutations

Met proto-oncogene –> encoding the hepatocyte growth factor receptor

SC-1 antigen –> apoptosis receptor

111
Q

Gastric CA
prognosis
Expression caudal-type homeobox transcription factor 2 (CDX2) + normal E-cadherin + non-expression of the transmembrane protein mucin 1 (MUC1)

A

favorable prognostic factor

112
Q

____ in gastric carcinoma is warranted for determination of treatment eligibility

A

HER2 testing

113
Q

Tumor marker

Epidermal Growth Factor (EGF)

A

> Both diagnostic and therapeutic(EDGFr inhibitors-colon CA)
Suggest that the primary effect of asbestos as a carcinogen is to cause mutations in the EGFr gene (>636 fmol/mL)
Prostate cancer (cutoff value of 67.9 ng/mL for serum EGFr)

114
Q

Tumor marker

Her2

A

> Independent prognosticator of disease free survival in early breast cancer(Stage I-III breast cancer)*
Used as screening method for patients with known predisposition, such as pneumoconiosis
Elevated serum p185 erbB2 ECD levels in almost 100% of patients with predisposing factor who have lung cancer
Elevated in almost 100% of East Asian people who have known risk factors for developing HCC

115
Q

tumor marker

ras-p21 protein

A

Angiosarcoma
Lung and Colon Cancer
Pancreatic Cancer
> This mechanism has been well documented for the ras-oncogene encoded p21 protein, for which substitutions of most amino acids for glycine 12 or glutamine 61 result in an oncogenic protein.

116
Q

tumor marker

Raf

A

> Western blot analysis showed that activated Raf was overexpressed in tissues obtained from cirrhosis and HCC patients
V600E (Valine to Glutamine) –> PTC

117
Q

tumor marker

p53

A 
Hepatocellular Carcinoma
Breast and Lung Cancers
Lung Cancers
Leukemia (B-CLL)
> antioncogene protein
118
Q

tumor marker

myc

A

> breast (about 20%) and colon cancers
Burkitt’s lymphoma (myc gene, chromosome 8 is translocated to a long terminal repeat–like region of an immunoglobulin-coding region of chromosome 14)

119
Q

tumor marker

NMP-22

A

> Excellent Biomarker for Bladder and Urothelial Cancers

> Used to monitor the recurrence or bladder cancer after resection

120
Q

Sarcoma
EWSR1-FLI1 (85-90%)
EWSR1-ERG (9-14%)
t(11;22)(q24;q12)

A

EWING’S SARCOMA FAMILY TUMORS (ESFT)

> IHC: CD99 and FLI1

121
Q

Sarcoma
EWSR1-AFT1
EWSR1-CREB1
t(12;22)(q13;q13)

A

Clear cell sarcoma

> Malignant neoplasm with melanocytic differentiation (Malignant melanoma of soft parts)

122
Q

Sarcoma
EWSR1-NR4A3
t(9;22)(q22;q12)

A

Extraskeletal myxoid chondrosarcoma

> Aggressive with a high rate of metastasis and local recurrence

123
Q

Sarcoma

q14 to q15 amplification

A

Atypical lipomatous tumor/well-differentiated AND DEDIFFERENTIATED LIPOSARCOMA

124
Q

Sarcoma
DDIT3-TLS (90%)
t(12;16)(q13;q11)

A

MYXOID / ROUND CELL LIPOSARCOMA

125
Q

Sarcoma
FUS-CREB3L2 = t(7;16)(q32-34;p11)
FUS-CREB3L1 = t(11;16)(p11;p11)

A

Low-grade fibromyxoid sarcoma

126
Q

sarcoma
EWSR1-NFATC1
t(18;22)(q23;q12)

A

Hemangioma of bone

127
Q

Sarcoma
ETV6-NTRK3
t(12;15)(p13;q25)

A

CONGENITAL FIBROSARCOMA (CFS)

128
Q

Sarcoma
SS18-SSX1, SS18-SSX2, SS18-SSX4
t(X;18)(p11.2;q11.2)

A

SYNOVIAL SARCOMA
> Monophasic variant: Vimentin-expressing spindle cells usually carrying SS18-SSX2 translocation
> Biphasic variant: Mixture of vimentin-expressing spindle cells and keratin-expressing glandular epithelial cells harboring the SS18-SSX1 or SS18-SSX2 translocation; May resemble adenocarcinoma or carcinosarcoma and carries a worse prognosis in early-stage patients
> IHC for TLE1 distinguishes synovial sarcoma from other soft-tissue malignancies

129
Q

Sarcoma
COL1A1-PDGFB
t(17;22)(q11;q13.1)

A

DERMATOFIBROSARCOMA PROTUBERANCE / GIANT CELL FIBROBLASTOMA
> Imatinib mesylate – inhibitor of tyrosine kinases with a dramatic response to treatment in adults
> Other PDGFR inhibitors (sunitinib and sorafenib) for patients with metastatic DFSP

130
Q

Sarcoma
PAX3-FOXO1A (70%) = t(2;13)(q35;q14)
PAX7-FOXO1A (10%) = t(1;13)(p36;q14)
Subtype: ARMS

A

RHABDOMYOSARCOMA
> PAX7-FOXO1A: less common but better prognosis
> ARMS tend to have a poor prognosis overall and genetic testing may be moot in stage IV patients

131
Q

Sarcoma
WWTR1-CAMTA1
t(1;3)(p36.3;q25)

A

Epithelioid hemangioendothelioma
> Epithelioid hemangioma with atypical morphology contains a YAP-TFE3 fusion partner
> IHC for TFE3 is diffusely and strongly positive

132
Q

Sarcoma
cKIT (75-80%)
PDGFRA (5-10%)

A

KIT and PDGFRA in Gastrointestinal Stromal Tumor
> cKIT protein encodes a TKR for stem cell/PDGFR –> mutated receptors transmit growth signals in a ligand-independent manner, inducing dysregulated cell proliferation
> Imatinib mesylate used to treat patients with metastatic GIST
> D816V point mutations in cKIT exon 17 are responsible for resistance to targeted therapy

133
Q

sarcoma

> GIST negative for both KIT and PDGFRA mutations

A

WILD-TYPE GISTs
> Common in stomach (5-10%) of all gastric GISTs
> SDH-deficient GISTs cannot be predicted based on size and mitotic activity (unlike conventional GISTs)
> Resistant to imatinib but have an indolent clinical course
> May occur as part of Carney triad or Carney-Stratakis syndrome or occur sporadically

134
Q

Sarcoma

USP6-MYH9 (90%)

A

NODULAR FASCIITIS
>Rearrangement of USP6 (ubiquitin-specific peptidase 6)
> Fusion with MYH9 (myosin heavy chain 9, non-muscle)
> Translocation leads to overexpression of USP6, a protein shown to be involved in proliferation, inflammation, and cell signaling

135
Q

sarcoma
ALK gene
2p23 region rearrangement
Fusion: TPM3, TMP4, CLTC, RANBP2, ATIC, CARS, SEC31L1, PPFIBP
* All share an N-terminal oligomerization motif that leads to ALK kinase catalytic activation
Other molecular changes: p53 mutation
MDM2 amplification

A

INFLAMMATORY MYOFIBROBLASTIC TUMOR
> Large percentage are ALK-negative and should be diagnosed morphologically and with IHC
> RANBP2-ALK: worse prognosis
> ALK expression: perinuclear or nuclear membrane

136
Q

Sarcoma
CDH11-USP6
t(16;17)(q22;p13)

A

ANEURYSMAL BONE CYST

> FISH break-apart USP6 probe

137
Q

Sarcoma
Chromosomal breakpoints are widely scattered, with no predilection for any recurrent breakpoints and no losses to any of the morphologic subtypes

A

Sarcomas with variable complex genetic alterations with no specific pattern

138
Q 
Sarcoma
Chromosomal change:
1p12-pter loss of 2p
Loss of 13q14-21 = Targets the Rb pathway
Loss of 10q = Targets PTEN
Loss of 16q
Gains of 17p, 8q, and 5p14 pter
A

leiomyosarcoma
> Complex karyotypic alterations (gains, losses, and amplifications)
> Activation of P13K-AKT through different mechanisms – plays a crucial role in development and maintenance of LMS
> Activation leads to concomitant activation of downstream effectors such as mTOR (target of rapamycin protein) and its targets (B-catenin, pS6, p4E-BP), as well as stabilization of HDM-2
> Analogs of rapamycin such as everolimus (mTOR inhibitor) have some efficacy in patients with LMS
> Myocardin –> transcriptional cofactor for regulating smooth muscle differentiation, and its inactivation is associated with less differentiated histology; Amplification/overexpression: LMS tends to behave more aggressively

139
Q

Clear cell RCC

A

Most common subtype, 50-70%
Encapsulated solid mass with alveolar or acinar arrangement of clear polygonal cells
Chromosome 3p deletion, majority of cases 70-90%
TSG von Hippel-Lindau (VHL) located on 3p25 in activated in:
100% of familial renal cancer sydromes
57% of sporadic cases
VHL Protein –regulates expression of the transcription factor, hypoxia-inducible factor (HIF), implicated in tumor growth and angiogenesis.
VHL syndrome associated clear cell carcinoma is caused by germ-line mutation at birth in one copy of the VHL gene,
Second hit can result from deletion, non sense mutations, allelic loss or hypermethylation of the VHL promoter region

140
Q

PAPILLARY RENAL CELL CARCINOMA

A

PAPILLARY RENAL CELL CARCINOMA
Second most common type of renal carcinoma
Most common chromosomal: Trisomies of Chromosome 7 and 17 and loss of chromosome Y.
Loss of 9q – reduced survival
Chromosome 7 and 17 frequent in type I papillary RCC
With mixed features
Type II usually associated with more aggressive behavior: higher stage, worst survival

Hereditary Papillary Renal cell and Hereditary Leiomyomatosis RCC (HLRCC)
MET proto-oncogene and FH mutations

141
Q

Chromophobe Tumors

A

Chromophobe Tumors
Widespread chromosomal abnormality :
Chromosome 1, 2, 6, 10, 13 and 17
Birt-Hogg Dube Syndrome (BHD) = hereditary form
30% of tumors with chromophobe morphology
FLCN gene mutation

142
Q

Microphthalmia Transcription Factor (MiT)

A

Involves somatic translocations of transcription factors that are members of MiT family.
Included:
Transcription factor binding to IGHM enhancer 3 (TFE3)
Transcription factor EB(TFEB)- located on chromosome Xp11 and 6p21
** Translocation leads to = HIGH LEVELS OF TFE3 or TFEB fusion proteins with increased nuclear localization leading to activation of their target genes.

More common in women
Cytotoxic therapy, risk factor
Most common renal malignancies in adolescents and young adults = 1/3 cases
Aggressive and early nodal involvement

143
Q

Xp11 Translocation or TFE 3-Associated RCC

A 
Xp11.2 = TF 3 gene
17q25, or 1q21 = ASPL gene (Alveolar soft part sarcomas)
Common translocation: 
T (X;17)(p11.2;q25)
ASPL-TFE3, PRRCC-TFE3 fusion gene

TFE3 protein migrate to the nucleus and participate in transcriptional activation of target genes.
Grossly appearance: RCC
Histopathologic appearance: Papillary Carcinoma
Voluminous, clear to eosinophilic cytoplasm of the cells, discrete cell borders, vesicular nuclei chromatin and prominent nuclei
Psammoma bodies

144
Q

Difference ASPL-TFE3 vs PRCC-TFE3

A

ASPL-TFE3

Voluminous
Clear to eosinophilic cytoplasm of the cells,
Discrete cell borders,
vesicular nuclei chromatin and prominent nuclei
Psammoma bodies constant and extensive within hyaline nodules

UNDEREXPRESS: CK, EMA, VIMENTIN
CONSTANT: CD 10, RCC

145
Q

(6;11) Translocation TFEB-Associated RCC

A

t(6;11) (p21;q12) = Alpha-TFEB gene fusion
Biphasic morphology: larger and smaller epitheliod cells (forming clusters around the BM)
Cases: without small cells, instead dominated by sclerosis, clear cells, or papillary architecture
Consistently express: HMB45 and Melan-A
Focal or negative for epithelial markers.

146
Q

Succinate Dehydrogenase B (SDHB) Mutation Associated RCC

A

Germline mutation of SDHB that are associated with:
Pheochromocytoma/paraganglioma syndrome type 4 (PGL 4)
Predilection to form pheochromocytoma, paraganglioma, type 2 GIST
14% risk to for renal neoplasia
Morphology: vacuolated cytoplasm, or distinctive pale eosinophilic cytoplasmic inclusions
Corresponds to: GIANT MITOCHONDRIA by EM

147
Q

ALK translocation RCC

A

t(2;10)(p23;q22) resulting in a fusion gene of vinculin (VCL) with Anaplastic Kinase (ALK)
2 cases, both associated with Sickle Cell Trait
Morphology: Polygonal to spindle cells, with abundant eosinophilc cytoplasm and frequent intracytoplasmic lumina.
Different clinical outcomes: clear cells, papillary architecture

148
Q

HYBRID ONCOCYTIC TUMORS (HOT)

A

5% of cases with RCC
chromophobe and oncocytoma components
BHD patient s with FLCN gene alteration
50% have HOT components

149
Q

HLRCC –Hereditary Leiomyomatosis and Renal Cell Cancer

A

Germline mutation in FH gene, associated with
Cutaneous leiomyomas, adrenal nodules and aggressive form of papillary kidney cancer
Distant metastasis in 50% of cases
Usually papillary type 2
Morphology: large nucleus containing prominent orangophilic nucleolus sorrounded by a Clear perinucleolar halo

150
Q

GENE EXPRESSION PROFILING by AFFTYMETRIX in RCC

A

Increased expression in immune response and angiogenesis
Clear Cell RCC – over expressed the proximal nephron markers megalin and cubilin
Papillary RCC – overexpressed proximal nephron markers, alpha methylacyl coenzyme (CoA) racemase
Chromophobe and Oncocytoma RCC – distal nephron markers, Beta Defensin 1, parvalbumin, chloride channel Kb, claudin 7, claudin 8, and epidermal growth factor
molecular classification of renal tumors
Useful in prognosis and therapeutic selections
Adipophilin - prognostic marker for RCC, discovered in clear cell RCC biomarker
Favorable outcome by IHC
Angiogenesis in Clear cell RCC, dysregulation in VHL and HIF1A, results in activation of multiple angiogenic tyrosine kinase molecules
Carbonic Anhydrase IX- use for targeted therapy, which expressed highly in cells with increase angiogenesis and immune response

151
Q

BLADDER CANCER

A

2nd most common malignancy affecting the urinary system
Urothelial – most common form, 90%
Squamous cell ca – 5% of the cases
caused by Schistosoma hematobium
Adnocarcinoma, small cell carcinoma
p16 tumor suppressor gene – used for early detection of bladder cancer

152
Q

BLADDER CA

______ – associated with progression from urothelial hyperplasia to low grade non invasive papillary carcinoma

A

HRAS oncogene

153
Q

BLADDER CA
______ - a tyrosine kinase receptor, have documented in 70-80% of non-invasive low-grade papillary Urothelial Ca
20% of invasive carcinomas

A

FGFR3 (Fibroblast growth factor receptor 3)

FGFR3 mutation Invasive carcinoma – bulky, exophytic, branching papillary architecture, irregular nuclei with koilocytic appearance

154
Q

BLADDER CA

____ – high grade papillary UC and Flat carcinoma in situ

A

TP53, RB gene

155
Q

BLADDER CA
______- genetic studies in flat and papillary urothelial hyperplasia in patients with low grade UC
Loss of 17p, 2q, 4, 11p = aggressive

A

Chromosome 9

156
Q

BLADDER CA

Criteria for abnormal results:

A

4 aneuploid cells
12 cells with deletion of 9p21 locus
10 cells with tetraploid, near tetraploid profile

157
Q

PROSTATE CANCER

A

Most common cancer among male
85% cases multifocal
PSA most common biomarker
50% of prostate cancer has recurrent chromosomal arrangement, resulting in fusion of androgen regulated TMPRSS2 (21q22.3) to E26 transforming sequence (ETS) family of TF

158
Q

PROSTATE CA

Fusion leads to over expression of ETS family genes:

A

ERG (21q22.2)
ETV1 (7q21.2)
ETV4 (17q21)

159
Q

PROSTATE CA

Myc oncogenes- expressed in 8q24

A

Amplified highly in primary and metastatic prostate
Detected in patients the sera (C-MYC) with prostate ca and not in normal controls
Correlated with Gleason Grade
Overexpression has been correlated with downregulation of FOXP3
X linked tumor suppressor gene
Binds to promoter region of Myc and represses its transcription

160
Q

PROSTATE CA
_____ – correlates with with high Gleason score and advanced stage.
Loss results to hyperactive PI3K/Akt pathway that promotes cancer progression.
Associated also with resistance to PI3K inhibitors and treatment failure

A

PTEN loss

161
Q

PROSTATE CA
____ – laboratory developed tests
Not approved by FDA
But are offered under laboratory’s CLIA certificate
Concern: variability of validation per laboratory to laboratory

A

LDT

162
Q

PROSTATE CA
________ - is an LDT
Test small (1 mm) fixed paraffin embedded tissue samples by needle biopsy
Measures 12 cancer related genes
Which are algorithmically combined with to calculate the Genomic Prostate Score (GPS)
With NCCN risk criteria, GPS improves risk discrimination of prostate cancer – active surveillance
Very low
Low
Modified intermediate risk

A

Oncotype DX

163
Q

prostate ca
_______ – directly measures tumor cell growth characteristics to stratify disease risk of progression
Formalin-fixed paraffin-embedded tissue by biopsy
46 gene expression, 31 cell cycle progression genes, 15 house keeper genes = correlated with proliferation of prostate cancer
Low expression, low risk for disease progression

A

Prolaris

164
Q

percentage of individuals with a given genotype who exhibit the phenotype associated with that genotype.

A

Penetrance

165
Q

genes of melanoma

A 
High petrance gene: 
CDKN2A (on chr 9P21, with p16 and p14 genes)
      - p16 = INK4a
       - p14 = ARF
CDK4 on chr 12q14

Low penetrance gene:
MC1R

166
Q

_______ - major player in the induction and maintenance of sporadic melanoma. NRAS mutatios also occur most frequently in melanocytes.

A

RAS/RAF/MEK/ERK signaling pathway

167
Q

Most important signaling molecule in melanoma downstream of RAS is _______

A

BRAF

168
Q

_______ is deregulated in a high proportion of melanomas. (PTEN deleted: 45% of melanomas and the downstream AKT gene is amplified)

A

PI3K signaling

169
Q

MYH POLYPOSIS / MYH INACTIVATION

A

Germ line mutation located on the short arm of chromosome 1, called MUTYH glycosylase/ MYH, most located at Y165C and G38D, found in 2% of population
Normal function of the gene is repair DNA damage as a result of oxidation
If not repaired, oxidized guanine is recognized by thymine during DNA replication and acts as a mutagen. Repair function is lost and C-G to T-A transversion persists.

Heterozygous MYH germ line mutations = 1.3x increase for CRC
Bi- allelic MYH mutations = 177x increase for CRC, low grade carcinomas

MYH- associated polyposis = extracolonic manifestations + duodenal adenomas or carcinomas in 17% of patients

PCR followed by denaturing HPLC is done to test germ line DNA mutation.

170
Q

SERRATED POLYPOSIS SYNDROME (PREVIOUSLY HYPERPLASTIC POLYPOSIS SYNDROME

A

Presents in the 6th decade with approximately 100 hyperplastic or serrated polyps or sessile adenomas on colonoscopy.

> 5 large hyperplastic polyps proximal to the sigmoid colon: Indication that syndrome is present in the patient

Autosomal recessive mode of transmission
Risk for developing colon cancer ranges from 37- 69%
Molecular trait: numerous sites of DNA and MLH1 methylation in the polyps

Henrys 23rd Ed (1 decks)

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