Chapter 77 Flashcards
1
Q
Genetic mutations, PTC
A
Ret/Ptc rearrangement
Raf mutation
Ras mutation
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
3
Q
20-40% follicular adenoma
Follicular variant PTC
FTC
Predispose well-diff. to dediff. resulting in anaplastic tumor
A
Ras mutation
4
Q
B-catenin accumulation
A
Cribriform morular cariant of PTC
5
Q
Direct target of ras-p21 (encoded by hras, kras and nras)
A
Raf mutation
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
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
8
Q
Braf; Follicular variant if ptc
A
Braf k601e
9
Q
Braf; assoc. w/ rad. exposure PTC
A
Akap9-braf rearrangement
10
Q
Pt. mutation codon 12, 13, 61
10-20% ptc
Almost always found in follicular variant of ptc
A
Nras, hras, kras
11
Q
Genetic mutations, FTC
A
Ras pt. mutation
Pax8-ppary gene rearrangement
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
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
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)
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%
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)
17
Q
Asian, Female, nonsmoker w/ AdenoCA
A
Egfr mutation
18
Q
Young, +/- smoker, AdenoCA Solid, cribriform, signet ring histology Tx resonse crizotinib Adenosq ca Fish (gold standard)
A
Alk gene chromosomal rearrangement
19
Q
Resistance to egfr-tkis in colorectal ca
A
Kras
20
Q
Double stranded DNA virus
A
HPV infection
21
Q
HPV Infection
> E7 binds to________
A
> E7 binds to retinoblastoma TSG (preferably the underphosphorylated form)
22
Q
HPV Infection
> HPV E6 proteins associate with ______
A
> HPV E6 proteins associate with the p53 TSP
23
Q
High risk HPV types
A
16, 18
24
Q
Low risk HPV types
A
6, 11
25
cervical ca
| > p16 (CDKN2A or MTS1) is located at 9p21.3 (group of TSG) regulate G1 phase of the cell cycle
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
26
T/F: high p16 expression is a sensitive marker for HPV E7 protein expression
T
27
```
Endometrial ca
Endometrioid adenocarcinoma (Type 1) exhibits ____ and ____ mutations (26 and 17% respectively)
```
Endometrioid adenocarcinoma (Type 1) exhibits KRAS and TP53 mutations (26 and 17% respectively)
28
Endometrial ca
| Approximately 5% of endometrioid carcinomas are associated with Lynch syndrome
mutations in ARID1A protein
29
Ovarian ca
| ____gene mutations are extremely common in high-grade serous carcinomas, while low-grade serous,
TP53 gene mutations
30
Ovarian ca
| mucinous adenocarcinomas have a high prevalence of ____ and ___ mutations (75% in primary mucinous adenocarcinomas)
KRAS and B-RAF mutations
31
```
endometrial ca
Serous adenocarcinoma (Type 2) exhibits ____ and ____ mutations (2 and 93% respectively)
```
KRAS and TP53 mutations
32
Ovarian ca
| Mutations of _____, the gene encoding β-catenin and PTEN, are common in endometrioid adenocarcinoma
CTNNB1
33
ovarian ca
Mutations of ______, which encodes the catalytic subunit of PI3K (phosphoinositide 3-kinase), are observed most frequently in clear cell carcinomas.
PIK3CA
34
ovarian ca
| LGSC have _____ mutations, but lack TP53 mutations
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.
35
ovarian ca
| HGSCs are often identified in advanced stage and have a high prevalence (50% to 70%) of ____ mutations
TP53 gene
| > Most HGSC cancers further lack Wnt/β-catenin or PI3K/PTEN signaling pathway defects.
36
ovarian ca
| Most HGSCs have genetic and somatic alterations of _______ and _______.
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)
37
several genetic alterations in various thyroid tumors have been well-documented, including translocations and point mutations
involves RET, BRAF, RAS, and PAX8
38
RET/PTC rearrangement and point mutations of RAF (BRAF) and RAS genes — found in more than ___ of cases of papillary thyroid carcinoma
(70%)
39
gene
located on chromosome 10q11.2
encodes tyrosine kinase receptor
highly expressed in parafollicular C cells and very low in thyroid follicular cells
RET gene
40
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
RET/PTC rearrangements
41
RET/PTC1 was found to be associated with ________, and RET/PTC3 more among ________
> classic papillary histology
| > solid variants
42
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
Human HRAS, KRAS, and NRAS genes
43
with regard to the rare but important cribriform morular variant of PTC, ______ accumulation is a defining feature
β-catenin
44
most common genetic alteration in PTC (45%)
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
45
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
BRAF V600E
46
follicular thyroid ca
| most frequent alterations:
RAS point mutations and PAX8-PPARƔ rearrangements
47
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)
RAS mutation
48
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
PAX8-PPARƔ gene rearrangement
> result of translocation t(2;3)(q13;p25)
fusion between PAX8 gene and PPARƔ gene
49
Medullary or PTC: RET point mutation
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
50
Medullary or PTC: RET chromosomal rearrangement
PTC
51
Lung ca
| membranous oncoprotein that induces cell proliferation upon activation
EGFR
increased EGFR signaling can be result of EGFR gene amplification, protein over expression, or specific activation mutations in EGFR gene
52
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
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
53
_____ and ____ testing are the most important uses of the diagnostic sample after diagnosis of adenocarcinoma is established
EGFR and ALK testing
54
lung ca
| other less common alterations
> 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%)
55
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.
MEN 1
> encodes menin (chromosome 11)
Rules of 1, Panay 1 (MEN 1, Chromosome 11)
56
Based on the risk for pheochromocytoma or hyperparathyroidism and the presence or absence of characteristic physical features
MEN 2
> RET proto-oncogene on chromosome 10
MEN 2 --> 2=R = RET (MED-RET)
57
– Most common Subtype: 95% detectable RET mutation.
| Can be stratified into 3 levels of risk for MTC development based on mutation sites and numbers
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.
58
MEN 2
| Highest risk
883, 918
59
Similarities MEN 1 and MEN 2a
Pituitary hyperpasia
60
Similarities MEN 2a and MEN 2b
Pheochromocytoma
| Medullary thyroid CA
61
Other hereditary diseases included in MEN SYNDROMES
VHL Syndrome
Familial Paraganglioma Syndrome
Cowden Syndrome
Li fraumeni
62
VHL syndrome
```
VHL gene
V = VHL gene
H =Hemangioblastoma
L = Lots of catecholamines = Pheochromocytoma
VHL = 3 letters = RCC
VHL = 3 letters = chromosome 3
```
63
Familial Paraganglioma Syndrome
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.
64
Cowden syndrome
```
PTEN gene (deleted chromosome 10)
PTEN = TEN = chromosome 10
PTENg *na, ang baho ng COW sa DEN
```
65
85% of patients with with Cowden mutation have an identifiable mutation or deletion within ____.
PTEN.
66
Li Fraumeni Syndrome
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.
67
Neurofibromatosis 1
```
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
68
```
CAFE SPOT
Cafe au lait spots
Axillary freckling
Fibromas
E lisch nodules in the eye
Skeletal bowing
Pseudoarthrosis of tibia
Optic Tumor
```
NF type 1
69
Neurofibromatosis 2
```
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
Schwanomatosis
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
ER + PR+ HER2 neg, ki 67 low
Luminal A
72
ER + PR + HER2 +/- high ki67
Luminal B
73
HER2 Immunohistochemical staining
Herceptest (Dako) = _____
Pathway (Ventana) = ______
Monoclonal
| Polyclonal
74
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: ____
CEP17 probe
| Her2/neu probe
75
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
```
BRCA1
76
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
BRCA2
77
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
TP53
78
____ = Activates BRCA1 and p53
Induces cell cycle arrest
ATM = Senses DNA damage
PTEN
CHEK2
79
Gene Assays
PAM50 gene expression signature
Oncotype Dx
Mammaprint
80
Expression levels of 50 genes
Classify tumor as 1 out of four intrinsic subtypes
Luminal A, luminal B, HER2- enriched, basal like
PAM50 gene expression signature
81
10 year risk recurrence in patients
| with ER +, lymph node negative tumor
Oncotype Dx
82
Pure prognostic assay
Prognosticc test for a lymph node
negative breast cancer for a < 61 yr old
70 genes tested
Mammaprint
83
Pancreatic ductal AdenoCA
| > Genetic alterations
> Most common: Allelic loss of chromosome 18
| > 1/3 have homozygous deletion at 18q21
84
Pancreatic ductal AdenoCA
Present in 95% of cases
Occurs commonly in codon 12
>Mutated KRAS P21 , with val for gly 12
85
Pancreatic ductal AdenoCA
> Tumor suppressing genes
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
Pancreatic dustal AdenoCA
common in Ashkenazi Jewish population (10%)
> telomerase, MSI
> BRCA2:
87
Precancerous lesions of the pancreas
Pancreatic intraductal neoplasia and intraductal papillary mucinous neoplasms may also have ___, ___, ___ and ____ mutations
KRAS, TP53, SMAD4 and p16/ CDKN2A
88
Precancerous lesions of the pancreas
| Intestinal type IPMNs always have intact ___ and harbor ____ mutations in 10% of cases
SMAD4/DPC4 and harbor PI3KCA
89
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
MSI
e-cadherin
B-catenin
90
Pancreatic CA
| ____ loss is usually associated with death related to multiple metastases
SMAD4/ DPCR
91
Pancreatic CA
| Alterations in ___ and ___ has a worse outcome
p16 and hTERT
92
Pancreatic CA
| Amplification of ___ and ___ and loss of TP53 genes are correlated with tumor grade and survival
KRAS2 and CMYC
93
Mouse- human hybrid monoclonal antibody
Cetuximab
94
Fully human immunoglobulin G2 monoclonal antibody
Panitumumab
95
Mutation status of ____ has become an important predictive marker for the effectiveness of Cetuximab or Panitumumab on metastatic CRCs.
KRAS
96
Glioblastoma Multiforme
| GENETIC MUTATIONS:
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
Oligodendroglioma
| GENETIC MUTATIONS
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
IDH mutations
IDH1 (R132H) (50% - 93%)
IDH2 (R172) (3% to 5%)
99
rhabdoid tumor
| genetic mutations
> 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
HCC (HBV vs HCV)
| genetic mutations
>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
HCC
| genetic mutations
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
HCC
independent risk factor for a shorter postoperative disease-free survival, recurrence, and for a decreased overall survival
High level of GPC3 in tissue
103
HA
| ____ = increases lipogenesis (fatty acid synthesis and downregulation of L-FABP --> diffuse intralesional steatosis
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
HA
| Decreased degradation, sustained activation, and nuclear accumulation of β-catenin protein:
Mutation of the β-catenin gene, OR
| Mutations in the axin, APC, or GSK3 genes
105
HA
| more frequently associated with malignant transformation
HA-B subtype
| > β-Cateningene (CTNNB1)
106
HA-I
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
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
Intestinal type
108
Gastric CA
Intestinal type
genetic mutations
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
Gastric Cancer
Less clear
Not related with H. pylori infection
Part of a hereditary gastric cancer predisposition syndrome
Diffuse type
110
Gastric Cancer
Diffuse type
genetic mutation
E-cadherin gene (CDH1) mutations
Met proto-oncogene --> encoding the hepatocyte growth factor receptor
SC-1 antigen --> apoptosis receptor
111
Gastric CA
prognosis
Expression caudal-type homeobox transcription factor 2 (CDX2) + normal E-cadherin + non-expression of the transmembrane protein mucin 1 (MUC1)
favorable prognostic factor
112
____ in gastric carcinoma is warranted for determination of treatment eligibility
HER2 testing
113
Tumor marker
| Epidermal Growth Factor (EGF)
> 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
Tumor marker
| Her2
> 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
tumor marker
| ras-p21 protein
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
tumor marker
| Raf
> Western blot analysis showed that activated Raf was overexpressed in tissues obtained from cirrhosis and HCC patients
> V600E (Valine to Glutamine) --> PTC
117
tumor marker
| p53
```
Hepatocellular Carcinoma
Breast and Lung Cancers
Lung Cancers
Leukemia (B-CLL)
> antioncogene protein
```
118
tumor marker
| myc
> 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
tumor marker
| NMP-22
> Excellent Biomarker for Bladder and Urothelial Cancers
| > Used to monitor the recurrence or bladder cancer after resection
120
Sarcoma
EWSR1-FLI1 (85-90%)
EWSR1-ERG (9-14%)
t(11;22)(q24;q12)
EWING’S SARCOMA FAMILY TUMORS (ESFT)
| > IHC: CD99 and FLI1
121
Sarcoma
EWSR1-AFT1
EWSR1-CREB1
t(12;22)(q13;q13)
Clear cell sarcoma
| > Malignant neoplasm with melanocytic differentiation (Malignant melanoma of soft parts)
122
Sarcoma
EWSR1-NR4A3
t(9;22)(q22;q12)
Extraskeletal myxoid chondrosarcoma
| > Aggressive with a high rate of metastasis and local recurrence
123
Sarcoma
| q14 to q15 amplification
Atypical lipomatous tumor/well-differentiated AND DEDIFFERENTIATED LIPOSARCOMA
124
Sarcoma
DDIT3-TLS (90%)
t(12;16)(q13;q11)
MYXOID / ROUND CELL LIPOSARCOMA
125
Sarcoma
FUS-CREB3L2 = t(7;16)(q32-34;p11)
FUS-CREB3L1 = t(11;16)(p11;p11)
Low-grade fibromyxoid sarcoma
126
sarcoma
EWSR1-NFATC1
t(18;22)(q23;q12)
Hemangioma of bone
127
Sarcoma
ETV6-NTRK3
t(12;15)(p13;q25)
CONGENITAL FIBROSARCOMA (CFS)
128
Sarcoma
SS18-SSX1, SS18-SSX2, SS18-SSX4
t(X;18)(p11.2;q11.2)
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
Sarcoma
COL1A1-PDGFB
t(17;22)(q11;q13.1)
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
Sarcoma
PAX3-FOXO1A (70%) = t(2;13)(q35;q14)
PAX7-FOXO1A (10%) = t(1;13)(p36;q14)
Subtype: ARMS
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
Sarcoma
WWTR1-CAMTA1
t(1;3)(p36.3;q25)
Epithelioid hemangioendothelioma
> Epithelioid hemangioma with atypical morphology contains a YAP-TFE3 fusion partner
> IHC for TFE3 is diffusely and strongly positive
132
Sarcoma
cKIT (75-80%)
PDGFRA (5-10%)
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
sarcoma
| > GIST negative for both KIT and PDGFRA mutations
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
Sarcoma
| USP6-MYH9 (90%)
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
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
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
Sarcoma
CDH11-USP6
t(16;17)(q22;p13)
ANEURYSMAL BONE CYST
| > FISH break-apart USP6 probe
137
Sarcoma
Chromosomal breakpoints are widely scattered, with no predilection for any recurrent breakpoints and no losses to any of the morphologic subtypes
Sarcomas with variable complex genetic alterations with no specific pattern
138
```
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
```
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
Clear cell RCC
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
PAPILLARY RENAL CELL CARCINOMA
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
Chromophobe Tumors
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
Microphthalmia Transcription Factor (MiT)
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
Xp11 Translocation or TFE 3-Associated RCC
```
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
Difference ASPL-TFE3 vs PRCC-TFE3
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
(6;11) Translocation TFEB-Associated RCC
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
Succinate Dehydrogenase B (SDHB) Mutation Associated RCC
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
ALK translocation RCC
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
HYBRID ONCOCYTIC TUMORS (HOT)
5% of cases with RCC
chromophobe and oncocytoma components
BHD patient s with FLCN gene alteration
50% have HOT components
149
HLRCC –Hereditary Leiomyomatosis and Renal Cell Cancer
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
GENE EXPRESSION PROFILING by AFFTYMETRIX in RCC
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
BLADDER CANCER
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
BLADDER CA
| ______ – associated with progression from urothelial hyperplasia to low grade non invasive papillary carcinoma
HRAS oncogene
153
BLADDER CA
______ - a tyrosine kinase receptor, have documented in 70-80% of non-invasive low-grade papillary Urothelial Ca
20% of invasive carcinomas
FGFR3 (Fibroblast growth factor receptor 3)
FGFR3 mutation Invasive carcinoma – bulky, exophytic, branching papillary architecture, irregular nuclei with koilocytic appearance
154
BLADDER CA
| ____ – high grade papillary UC and Flat carcinoma in situ
TP53, RB gene
155
BLADDER CA
______- genetic studies in flat and papillary urothelial hyperplasia in patients with low grade UC
Loss of 17p, 2q, 4, 11p = aggressive
Chromosome 9
156
BLADDER CA
| Criteria for abnormal results:
4 aneuploid cells
12 cells with deletion of 9p21 locus
10 cells with tetraploid, near tetraploid profile
157
PROSTATE CANCER
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
PROSTATE CA
| Fusion leads to over expression of ETS family genes:
ERG (21q22.2)
ETV1 (7q21.2)
ETV4 (17q21)
159
PROSTATE CA
| Myc oncogenes- expressed in 8q24
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
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
PTEN loss
161
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
LDT
162
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
Oncotype DX
163
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
Prolaris
164
percentage of individuals with a given genotype who exhibit the phenotype associated with that genotype.
Penetrance
165
genes of melanoma
```
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
_______ - major player in the induction and maintenance of sporadic melanoma. NRAS mutatios also occur most frequently in melanocytes.
RAS/RAF/MEK/ERK signaling pathway
167
Most important signaling molecule in melanoma downstream of RAS is _______
BRAF
168
_______ is deregulated in a high proportion of melanomas. (PTEN deleted: 45% of melanomas and the downstream AKT gene is amplified)
PI3K signaling
169
MYH POLYPOSIS / MYH INACTIVATION
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
SERRATED POLYPOSIS SYNDROME (PREVIOUSLY HYPERPLASTIC POLYPOSIS SYNDROME
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
