Lecture 9: Oncology Flashcards
1
Q
What must B and T cells be able to recognize?
A
a wide variety of antigens (diversity)
2
Q
What allows for even more diversity in B and T cells?
A
Somatic mutation
3
Q
How are surface immunoglobulin and T-cell receptors structurally similar?
A
Heterodimer proteins, disulfide bonds, have variable (V) and constant (C) regions
4
Q
How are surface immunoglobulin and T-cell receptors genetically similar?
A
Have large number of exons DNA recombination to functional receptor
5
Q
Surface Immunoglobulin and T-cell receptors are involved in what process?
A
antigen recognition (by normal B & T-cells)
6
Q
For DNA recombination in B and T cells what are the segments that can be transcribed and translated to millions of antigen receptors?
A
V, D, J, and C
7
Q
What can increase the sensitivity of T cells to peptide antigen MHC complexes by ~100 fold?
A
CD4 and CD8
8
Q
What are gene rearrangements?
A
normal events, can occur in lymphocytes
9
Q
What are the classes of immunoglobulins?
A
IgG, IgD, IgA, IgM, and IgE respectively
10
Q
What are the immunoglobulin light chain genes?
A
k, λ (kappa and lambda)
11
Q
What are immunoglobulin light chain genes encodes by?
A
immunoglobulin kappa and lamnda
12
Q
Does rearrangement in each cells occur independently? or dependently?
A
independently
13
Q
What genes rearrange?
A
T-cell receptor genes (α, β, γ, δ) rearrange
14
Q
What defines the classes of immunoglobulins?
A
Antibody genes immunoglobulin heavy chain genes IgH (γ, δ, α, μ, ε)
15
Q
What is the variable domain of heavy chain made of?
A
three segments (V, D, & J)
16
Q
What residues does VH genes encodes?
A
residues 1-94
17
Q
What residues does JK encode?
A
residues 98-113
18
Q
What residues does D gene encode?
A
residues 95-97
19
Q
51 V x 27 D x 6 J =8262 ???
A
Heavy chain??? idk about this one
Sarahboo it’s 8262 different combinations silly
20
Q
What do heavy and light Ig chains undergo?
A
random gene rearrangement
21
Q
TCR rearrangement vs. Ig rearrangement
A
they are VERY similar
22
Q
What are the 7 means of generating antibody diversity?
A
- Multiple germ-line gene segments
- Combinatorial V-(D)-J- joining
- Junctional flexibility
- P-region nucleotide addition (P-addition)
- N-region nucleotide addition (N-addition)
- Somatic hypermutation
- Combinatorial association of light and
heavy chains
23
Q
Population of cells with similar characteristics that are all derived from a single precursor cell
A
clonality
24
Q
Normal lymphocyte populations are ____ with respect to Ig and TCR genes
A
polyclonal
25
Leukemia or lymphoma is ______ with regard to Ig or TCR rearranged genes
monoclonal
26
Neoplastic transformation of B and T lymphocytes occurs at different stages of B-cells and T-cell development at which the disordered lymphoid cells ______ in the normal differentiation scheme
arrested
27
B lymphocyte: Benign (Clonality of Lymphoid Proliferation Disorder)
Ig Light Chain, Heterogeneity
28
Plasma Cells: Benign (Clonality of Lymphoid Proliferation Disorder)
Heterogeneous Ig Electrophoresis
29
T Lymphocyte: Benign (Clonality of Lymphoid Proliferation Disorder)
Heterogeneous Variable Regions
30
B lymphocyte: Malignant (Clonality of Lymphoid Proliferation Disorder)
Ig Kappa or Lambda Only
31
Plasma Cells: Malignant (Clonality of Lymphoid Proliferation Disorder)
Monoclonal Ig Spike
32
T Lymphocyte: Malignant (Clonality of Lymphoid Proliferation Disorder)
Homogeneous Variable Regions
33
What is tumor cell clonality caused by?
gene rearrangement
34
Are rearrangements unique in each cell?
yes
35
What do rearrangements display?
allelic exlusion
36
Techniques for Clonality Determination
Morphology
Immunopathology
Cytogenetics
Molecular genetics
37
What is Morphology?
Monomorphous cell population
38
What is Immunopathology?
Monotypic Sig
39
What is Cytogenetics?
Recurrent chromosomal alteration (e.g., translocation)
40
What is Molecular genetics?
Clonal B- or T-cell gene rearrangements methods
41
What are all the clonal B- or T-cell gene rearrangements methods?
-Hybridization, blotting
-Standard PCR, RT-PCR, electrophoresis
-PCR with heteroduplex analysis, SSCP
-Real-time PCR with gene or patient-specific probes
42
What is an increasingly popular method to evaluate for the presence of B- or T cell clonality?
Polymerase Chain Reaction
43
What is the polymerase chain reaction analogous to?
Southern blot
44
Polymerase Chain Reaction uses _______ V and J segment primers (recognize shared DNA sequences)
consensus
45
Polymerase Chain Reaction may detect a _____ clonal population?
0.1%
46
Involves evaluation of segments of DNA that code for variable regions of immunoglobulin and T-cell receptors (V and J segments)
Polymerase Chain Reaction
47
What is an example of PCR?
Poly/Monoclonal Lymphocyte Populations by PCR
48
Monoclonal populations are detected by _____ unique to the tumor cell population
Sharp bands
49
What will normal (polyclonal) population yield? (PCR)
A polyclonal PCR product
50
What will monoclonal populations will yield? (PCR)
a single PCR product
51
What are the 3 classes of cancer?
Carcinomas, Sarcomas, and Hematopoietic and lymphoid malignant neoplasm such as leukemia and lymphoma
52
What classes of cancer are solid tumors?
Carcinomas and Sarcomas
53
Originate in epithelial tissue, such as the cells lining the intestine, bronchi, or mammary ducts
Carcinomas
54
The tumor has arisen in mesenchymal tissue, such as bone muscle or connective tissue, or in nervous system tissue
Sarcomas
55
Spread throughout the bone marrow, lymphatic system, peripheral blood
Hematopoietic and lymphoid malignant neoplasms, such as leukemia and lymphoma
56
What class of cancer are circulating tumors?
lymphoid tumors
57
Tumors arise from a ______ that has accumulated critical initiating mutations (genetic changes) and perhaps other epigenetic alterations.
single ancestral cell
58
Is the number of mutations dependent on the tumor type?
no it is independent
59
How many mutations needed for tumor formation?
multiple
60
In some cases, mutations causing tumors are
present in all cells (genetic predisposition)
61
What are the multistage process of carcinogenesis?
normal cell to initiated cell to preneoplastic lesion to malignant tumor
62
What is the clonal basis of cancer development?
-Defects in cellular differentiation
-Defects in growth control
-Resistance to cytotoxicity
-Activation of Protooncogenes
-Inactivation of of Tumor Suppressor Genes
63
Molecular Detection- Differential PCR for Her2/neu Amplification. What is the process used?
Co-amplify by PCR and analyze by gel electrophoresis
64
Hereditary Cancer Characters
* Multiple affected relatives
* Early age of cancer onset (clinical disease)
* Bilaterally affected organs (such as in breast cancer)
* Multiple primary cancers in the same individual
* Known associated cancers occurring in the same family (such as breast and
ovarian cancers)
* Autosomal dominant of inheritance
65
Mutations in what genes are inherited in an autosomal dominant pattern? What does that mean?
BRCA1 & BRCA2
one copy of altered gene in each cell is sufficient to increase a person's chance of developing cancer
66
What chromosome arm is breast cancer susceptibility gene: BRCA1 localized to?
arm 17q
67
How many different mutations have been identified in BRCA1 gene?
120
68
The BRCA1 gene is mutated in what percentage of hereditary breast cancers?
45%
69
The BRCA1 gene is mutated in what percentage of patients with breast/ovarian cancer?
90%
70
What are the features of the BRCA1 gene?
23 exons, large exon 11 (100kb) that contains 60% of coding sequence
71
What is the BRCA1 protein expression and phosphorylation dependent on?
the cell cycle
72
What is BRCA1 protein?
large nuclear phosphoprotein
73
The BRCA1 Protein is probably a ____ and involved in ___
DNA- binding transcription factor; DNA repair ***
74
What arm is breast cancer susceptibility gene BRCA2 localized to?
arm 13q
75
What percentage of early onset hereditary breast cancer does BRCA2 gene account for?
40-45%
76
Do mutations in BRCA2 gene contribute significantly to risk for development of ovarian cancer?
NO
77
How big is the BRCA2 gene?
70 kb in size, 27 exons
78
BRCA2 is required to prevent breakdown of the stalled ______
replication forks***
79
BRCA2 gene and protein disruption of function leads to?
chromosomal rearrangements
80
Mutation in the BRCA2 gene and protein may cause ______ and predisposition to cancer.
genomic instability***
81
Prevalence of BRCA gene mutation is more common in what community?
Ashkenazi Jewish Community (185del AG; 5382ins C; 6174 del T)
82
How to know if there is a mutation of BRCA1 185delAG present by SSP-PCR?
The 180bp product indicates the present of mutation
83
What is the 3rd most common non-skin cancer diagnosed in men and women in the U.S and second highest cause of cancer deaths?
Colorectal Cancer
84
Is colorectal cancer?
highly curable when it is detected early enough
85
Molecular CRC Testing
* MSI, MMR IHC ***
– MSI-H Sporadic (15%)
– MSI-H Lynch (2-3%)
* KRAS ***
* BRAF ***
* PIK3CA
* PTEN
* APC, SMAD4, BMPRIA,STK11
* Septin 9
86
Detection Methods for CRC
Tumor screening assay (90% sensitivity)
87
Detect affected patients with tumor MSI by...
– PCR (paraffin works well)
– MMR Immunohistochemistry: MLH-1, MSH-2, MSH-6,
PMS2
– Blood germ line mutation analysis
– Detect affected family members
88
Tumor screening assays for CRC has ___% sensitivity
90%
89
KRAS mutation in ___-____% CRC's
30-40%
90
~__% of colorectal cancers have BRAF mutations?
10%
91
What does KRAS and BRAF Detection highly predict?
lack of response to anti-EGFR Rx
92
What plays a key role in determining proper and most cost-effective Rx in stage III-IV CRC?
Laboratory
93
What downstream marker may be useful in KRAS wild type tumors?
BRAD, PIK3CA, PTEN
94
What are molecular test for KRas?
-Sequencing, Sequenom, allele
-Specific PCR, and melt curve analysis
95
What predicts anti-EGFR non-response in KRAS WT?
KRAS and BRAF detection
96
What is the BRAF mutation (BRAF V600E)?
-T to A transversion
-Valine to glutamate at codon 600 (BRAF V600E)
97
What percentage of Hereditary Non-Polyposis Colorectal Carcinoma (HNPCC) have MSI?
85-90%
98
What is inferred by testing for MSI?
mutations in genes of the MMR system (loss of function)
99
What does MSI analysis determine?
gene function
100
What is direct sequencing used to detect?
actual gene mutation
101
What are the two major types of lung cancer?
Small Cell Lung Cancer (SCLC)
Non-Small Cell Lung Cancer (NSCLC)
102
What percentage of lung cancers are NSCLC?
85-90%
103
What is it called when lung cancer has characteristics of both types? Is it common?
mixed small cell/large cell cancer; NOT common
104
What is the leading cause of lung cancer?
Smoking
105
What percentage of lung cancer deaths are linked to smoking?
80% (many others are caused by exposure to secondhand smoke)
106
American Cancer Society Guideline 2018: Tests for Newly Diagnosed NSCLC Patients
-Low-dose CT scans for lung cancer screening
-Biomarker Detection
107
What is the minimum necessary for biomarker detection of NSCLC patients?
PD-L1 IHC, EGFR, ALK, ROS1, BRAF
