Neoplasia/Hematology - Mechanisms of Disease - Neoplasia; Cancer Genetics Flashcards
1
Q
Name the leading three cancers causing death in women.
A
- Lung
- Breast
- Colon
2
Q
Name the leading three cancers causing death in men.
A
- Lung
- Prostate
- Colon
3
Q
What behavior indicates that a tumor is ‘cancerous’?
A
It can invade and metastasize
4
Q
What suffix is typically given to benign tumors?
And malignant epithelial tumors?
And malignant mesenchymal tumors?
A
‘-oma’
‘-carcinoma’
‘-sarcoma’
5
Q
Name a few of the misnomers for malignant tumors that end in ‘-oma’ (not ‘-sarcoma’ or ‘-carcinoma’).
A
Glioma;
mesothelioma;
lymphoma;
melanoma
6
Q
What is tumor differentiation?
A
The degree of tumor resemblence to normal tissue
(typically, either well-, moderately-, or poorly-differentiated)
7
Q
Benign tumors are typically ______-differentiated.
A
Benign tumors are typically well-differentiated.
8
Q
Name some of the histological features of malignant tumors:
__________ nuclei and nucleoli
__________ cytoplasm
__________ nucleus/cytoplasm ratio
A
Name some of the histological features of malignant tumors:
Enlarged nuclei and nucleoli
Decreased cytoplasm
Increased nucleus/cytoplasm ratio
9
Q
Name some of the histological features of malignant tumors:
Abnormal ________
Architectural ________
____plasia
____morphic cells
A
Name some of the histological features of malignant tumors:
Abnormal mitoses
Architectural disarray
Anaplasia
Pleomorphic cells
10
Q
What does it mean that malignant cells are often pleomorphic?
A
They are bizarrely shaped
11
Q
Malignant tumor cells often have nuclei with what appearance?
A
Hyperchromatic;
enlarged
12
Q
A tissue has many cells undergoing mitoses. Does this indicate malignancy?
A
It is suggestive but not definitive
13
Q
What does it mean that malignant cells may show abnormal mitoses and/or architectural disarray?
A
They may show tri- or tetra-polar mitotic spindles;
many cells may be undergoing mitosis at once
14
Q
What are the main three routes of metastatic spread?
A
Seeding (more rare);
lymphatic spread (typically carcinomas);
hematogenous spread (typically sarcomas)
15
Q
What is unique about the lymphatics of malignant tumors?
A
They are nonfunctional/absent
(lymphatic spread occurs via lymphatics in surrounding tissues)
16
Q
What are the two main organ systems to which metastases land via hematogenous spread?
A
Lungs;
liver
17
Q
True/False.
Hematogenously spread metastases often come to rest in the first capillary bed they find.
A
True.
18
Q
What is dysplasia?
A
Reversible and disordered growth
19
Q
What often comes before dysplasia?
A
Metaplasia
20
Q
Dysplasia most often arises following chronic irritation/damage in what tissue types?
A
Mucosal tissues
(and more broadly, epithelial)
21
Q
True/False.
Dysplasia is often characterized by increased epithelial mitoses, including an increase in those outside the basal layer.
A
True.
22
Q
Malignancy = ____plasia + ______
A
Malignancy = dysplasia + invasiveness
23
Q
Is ductal carcinoma in-situ (DCIS) considered invasive?
A
No; it is pre-invasive
(the basement membrane has not yet been breached)
24
Q
Normal function for what four main gene types are often disrupted in neoplasms?
________-_______genes
_______ _________ genes
Apoptosis genes
DNA repair genes
A
Normal function for what four main gene types are often disrupted in neoplasms?
Proto-oncogenes
Tumor suppressor genes
Apoptosis genes
DNA repair genes
25
Normal function for what four main gene types are often disrupted in neoplasms?
**Proto**-**onco**genes
**Tumor** **suppressor** genes
\_\_\_\_\_\_\_\_\_ genes
\_\_\_\_\_\_ ______ genes
Normal function for what four main gene types are often disrupted in neoplasms?
**Proto**-**onco**genes
**Tumor suppresso**r genes
**_Apoptosis_** genes
**_DNA_** **_repair_** genes
26
In order to increase cell growth, a cell needs how many mutations of a particular proto-oncogene's alleles (one or two) to become an oncogene?
**One**
(I.e. only one allele needs to be mutated.)
27
In order to increase cell growth, a cell needs how many inactivating mutations of a particular tumor supressor gene's alleles (one or two)?
**Two**
(I.e. both alleles needs to be mutated.)
28
Tumor suppressor gene mutations that result in increased cell growth are \_\_\_\_\_\_-of-function mutations.
Oncogenes are \_\_\_\_\_\_-of-function mutations.
Tumor suppressor gene mutations that result in increased cell growth are **_loss_**-of-function mutations.
Oncogenes are **_gain_**-of-function mutations.
29
In order to increase cell growth, a cell needs how many inactivating mutations of a particular apoptosis gene's alleles (one or two)?
**Two** (typically)
| (I.e. both alleles need to be mutated.)
30
What is the main issue seen in cells with mutated apoptosis genes?
Inability to undergo apoptosis
31
In order to increase cell growth, a cell needs how many inactivating mutations of a particular DNA repair gene's alleles (one or two)?
**Two** (typically)
| (I.e. both alleles need to be mutated.)
32
What are the three main categories of carcinogens?
**Chemical** carcinogens;
**radiation** carcinogens;
**microbial** carcinogens
33
What is a direct-acting chemical carcinogen?
One that **requires** **no metabolic** **conversion** to its carcinogenic form
34
What is an indirect-acting chemical carcinogen?
One that **requires metabolic conversion** to its carcinogenic form
35
What is the size of detection of most tumors on either palpation or imaging?
1 cm
36
How many cells are in the average 1 cm tumor?
1 billion
37
\_\_\_% of patients already have metastases at the time of malignancy diagnosis.
**_30_**% of patients already have metastases at the time of malignancy diagnosis.
38
The proliferative pool of cells within a neoplasm is known as the what?
The growth fraction
39
The purpose of a mitotic figure count is to measure what?
What is the equation used?
A tumor's **cell** **proliferation rate**;
MFC = **# of mitoses / 10 hpf** (high power fields)
40
The purpose of a **proliferation** (mitotic) **index** is to measure what?
What is the ratio used?
A tumor's **cell** **proliferation rate**;
PI = **proliferating cells / G0 cells**
41
How are flow cytometry and immunohistochemistry used in assessing the proliferation rate of a particular tumor?
Flow cytometry --- analysis of **cells in S-phase**
Immunohistochemistry --- analysis of **cell proliferation markers** (e.g. PCNA, Ki-67 / MIB-1)
42
Are neoplasias typically painful or painless lumps?
Painless
43
What is tumor grade?
Evaluation of **differentiation**
(# of mitoses; architectural disarray; presence of necrosis; etc.)
44
What is tumor stage?
Assessment of tumor **size and spread**
45
What system is typically used in tumor staging?
The **TNM** system
**T**umor size
**N**odal involvement
**M**etastases
46
**True/False**.
Serum tumor markers are typically the first indication that a tumor is present.
**False**.
Serum tumor markers are typically low or not present early in the disease course.
47
What is the number one method of cancer diagnosis?
Biopsy
48
Activation of *RAS* causes what in tumors?
**Excess** **proliferation** signals
49
Inactivation of *RB* causes what in tumors?
**Inhibited tumor suppression**
| (and thus, excess growth)
50
Expression of PD-L1 causes what in tumors?
Immunoevasion
51
What enzyme do tumors overactivate to ensure replicative immortality?
Telomerase
52
Why do tumors produce VEGF?
To induce **angiogenesis**
53
Overexpression of BcL-2 does what for tumors?
**Inhibits** **apoptosis**
54
Why might a tumor overexpress GLUT-1?
To **deregulate cellular energetics**
55
What does decreased expression of E-cadherin do for tumors?
Allows for **invasion** and **metastases**
| (cells no longer bound together)
56
What does increased expression of CSF3 or G-CSF do for tumors?
**Increases tumor-promoting inflammation**
(these substances are pro-wound-healing / pro-growth)
57
What does inactivation of *MSH2* do for tumors?
**Increases the mutation rate**
(*MSH2* and *MLH1* are involved in mismatch repair)
58
Tumor cells typically use what metabolic process for most of their energy production?
Glycolysis
59
What are 'driver mutations'?
Mutations that give tumors **growth advantages**
60
**True/False**.
The progression of a cell from normal to malignant is always a multistep process.
True.
61
\_\_\_\_\_\_\_\_\_ cells are the cells in a newly forming neoplasm.
\_\_\_\_\_\_\_ is the death of most of these cells.
\_\_\_\_\_\_\_\_\_tion is the growth of the cells that can divide indefinitely.
**Transform**ed cells become independent of anchorage and serum.
**Metastatic** cells are fully tumorigenic that can migrate and form distant colonies.
**_Primary_** cells are the cells in a newly forming neoplasm.
**_Crisis_** is the death of most of these cells.
**_Immortaliza_**tion is the growth of the cells that can divide indefinitely.
**Transform**ed cells become independent of anchorage and serum.
**Metastatic** cells are fully tumorigenic cells that can migrate and form distant colonies.
62
**Primary** cells are the cells in a newly forming neoplasm.
**Crisis** is the death of most of these cells.
\_\_\_\_\_\_\_\_tion is the growth of the cells that can divide indefinitely.
\_\_\_\_\_\_\_\_ed cells become independent of anchorage and serum.
\_\_\_\_\_\_\_\_\_\_ cells are fully tumorigenic that can migrate and form distant colonies.
**Primary** cells are the cells in a newly forming neoplasm.
**Crisis** is the death of most of these cells.
**_Immortaliza_**tion is the growth of the cells that can divide indefinitely.
**_Transform_**ed cells become independent of anchorage and serum.
**_Metastatic_** cells are fully tumorigenic cells that can migrate and form distant colonies.
63
**True/False**.
Tumor suppressor mutations can be thought of as 'autosomal recessive'.
**True**.
| (Two hits needed)
64
**True/False**.
Proto-oncogene to oncogene mutations can be thought of as 'autosomal recessive'.
**False**.
Proto-oncogene to oncogene mutations can be thought of as 'autosomal ***dominant***'.
(Only one hit needed)
65
Do most inherited syndromes that increase risk of cancer development involve tumor suppressor genes or oncogenes?
Tumor suppressor genes
| (two hits needed)
66
**True/False**.
Oncogenes usually have tissue 'preferences'.
(I.e. a predilection for occurring in certain tissues)
**False**.
***Tumor suppressor genes*** usually have tissue 'preferences'.
(less common in oncogenes)
67
Defects in which gene(s) is(are) associated with hereditary non-polyposis colon cancer (Lynch syndrome)?
***MLH1*** and ***MSH2***
| (mismatch repair genes)
68
Defects in which gene(s) is(are) associated with Li Fraumeni syndrome?
*P53*
69
In addition to point mutations or chromosomal rearrangement, what other mutation might lead to oncogene formation?
Amplification;
70
What is the normal function of the Ras protein?
It is a GTPase and effector molecule that **promotes cell growth**
71
The Ras protein is active and _______ cell growth when bound to \_\_\_\_\_\_\_.
The Ras protein is active and **_stimulates_** cell growth when bound to **_GTP_**.
72
What is the most common mutation type (e.g. point, amplification, deletion, translocation, etc.) in tumorigenesis?
**Point** mutations (single bases substitutions)
73
**True/False**.
The term 'oncogenes' refers to a relatively narrow category of proto-oncogenes that increase cell growth by increasing production of growth factors.
**False**.
Oncogenes are a broad category of overexpression/overactivity of any of the following:
**Growth factors**
**Growth factor receptors**
**Signal transducers**
**Transcription factors**
74
Name the generic components of the cell proliferation pathway starting with a growth factor.
Growth factors --\>
Growth factor **receptors** --\>
**Signal** **transducers** --\>
**Transcription** **factors**
75
What enzyme type increases Ras activation?
What enzyme type decreases Ras activation?
**GEFs**
(guanine nucleotide exchange factors);
**GAPs**
(GTPase-activating proteins)
76
The *N-Myc* gene is responsible for synthesizing what?
The N-Myc **transcription factor**
77
In addition to the mutations that produce oncogenes (point mutations, translocations, deletions, amplifications etc.), what other mutation type is associated with the inactivation of tumor suppressor genes?
DNA methylation
78
Name a few examples of the general types of products made by tumor suppressor genes.
79
What is the NF-1 protein?
A GAP
(a GTPase-activating protein that acts to **inhibit cell proliferation**)
80
What is the APC protein?
A protein that normally **inhibits signal transduction**
(inhibiting cellular proliferation)
81
What is the Rb protein?
A protein that binds **E2 F** proteins to **inhibit** progression from **G1 to S**
82
What are the two normal functions of the p53 protein?
1. Inhibiting cell growth
2. Inducing BAX (pro-apoptotic)
83
What is the normal function of the p16 protein?
Rb protein hypophosphorylation
(thus Rb binds E2 F, pausing the cell cycle at G1)
(Technically, it inhibits the cyclin-dependent kinase complex that phosphorylates Rb.)
84
What is the normal purpose of the *ATM* gene?
DNA repair
85
The product of what gene activates p53 in response to double-stranded breaks in DNA?
(thus, signalling for p53's pro-apoptotic effects)
*ATM*
(This is in addition to its function as a DNA repair gene.)
86
What is the gene that is most commonly mutated in associated with tumor development?
*p53*
87
\_\_\_\_\_\_\_ age of onset of malignancy is a potential indicator for a hereditary cancer syndrome.
**_Early_** age of onset of malignancy is a potential indicator for a hereditary cancer syndrome.
88
**True/False**.
Multiple primary tumors and/or bilateral organ development are potential indicators for a hereditary cancer syndrome.
True.
89
The _________ model of cancer heritability pertains to an inherited mutation that follows an autosomal recessive pattern (two-hit hypothesis).
*(E.g. retinoblastoma is more common in individuals born with an* Rb1 *gene mutation, but they still need one more mutation of the alternate allele.)*
The **_Knudson_** model of cancer heritability pertains to an inherited mutation that follows an autosomal recessive pattern (two-hit hypothesis).
*(E.g. retinoblastoma is more common in individuals born with an* Rb1 *gene mutation, but they still need one more mutation of the alternate allele.)*
90
Describe how the Knudson model relates to disorders such as retinoblastoma.
Retinoblastoma is more common in individuals born with an *Rb1* gene mutation, but they still need one more mutation of the alternate allele
91
What does it mean if cancer cases are said to be 'familial'?
A clustering of cancer (usually the same type) in a family
(NOTE: not necessarily heritable --- due to **multifactorial causes**)
92
\_\_\_\_\_\_\_\_\_ cancers --- not related to a family history and no known inherited component.
**_Sporadic_** cancers --- not related to a family history and no known inherited component.
93
\_\_\_\_\_\_\_\_ --- clustering of cancer (usually the same type) in a family.
**_Familial_** --- clustering of cancer (usually the same type) in a family.
94
\_\_\_\_\_\_\_\_ --- germline (constitutional) mutation in a single gene leads to a greatly increased risk of cancer
**_Hereditary_** --- germline (constitutional) mutation in a single gene leads to a greatly increased risk of cancer
95
# Fill in the blanks for indicators of hereditary cancer syndromes:
\_\_\_\_\_\_\_ age of onset (premenopausal breast cancer for example)
Several ________ with the same or related cancers
Excess of \_\_\_\_\_focal or \_\_\_lateral tumors
Excess of multiple _________ tumors
Autosomal __________ inheritance (usually)
# Fill in the blanks for indicators of hereditary cancer syndromes:
**_Early_** age of onset (premenopausal breast cancer for example)
Several **_relatives_** with the same or related cancers
Excess of **_multi_**focal or **_bi_**lateral tumors
Excess of multiple **_primary_** tumors
Autosomal **_dominant_** inheritance (usually)
96
**True/False**.
Screening for genes associated with certain cancers and heritable syndromes (e.g. *BRCA1*) is a way of indicating a person's _susceptibility_ and _overall lifetime risk_.
True.
97
Familial adenomatous polyposis is caused by a mutation in the ___ gene on chromosome \_\_\_.
Familial adenomatous polyposis is caused by a mutation in the ***_APC_*** gene on chromosome **_5q_**.
98
What are the two main causes of hereditary colon cancer?
Lynch syndrome (HNPCC);
familial adenomatous polyposis
99
How is familial adenomatous polyposis typically diagnosed?
**Colonoscopy**
(100+ and even thousands of polyps by a very early age)
100
How is familial adenomatous polyposis treated?
What is the patient's risk of colon cancer development if not treated?
Surgical resection of the colon;
## Footnote
**100%**
101
**True/False**.
Radiotherapy is contraindicated in individuals with an *Rb* mutation.
**True**.
Radiotherapy drastically increases their likelihood of cancer development.
102
What is the inheritance pattern for Lynch syndrome (HNPCC)?
Autosomal dominant
103
What is the range for the lifetime risk for colon cancer in patients with Lynch syndrome (HNPCC)?
And endometrial cancer?
50 - 80%;
25 - 60%
104
**True/False**.
Patients with Lynch syndrome (HNPCC) will almost certainly develop colon cancer later in life.
**False**.
HNPCC is associated with earlier onset (40s), but not all patients develop colon cancer.
105
Lynch syndrome (HNPCC) is _most_ associated with mutations in what gene(s)?
*MSH2* and *MLH1*
106
Via what two methods can a diagnosis of Lynch syndrome (HNPCC) be confirmed?
1. Microsatellite instability tests
2. Immunohistochemistry
107
What inheritance pattern does Lynch syndrome (HNPCC) show?
Autosomal dominant
108
What are the two main cancers associated with Lynch syndrome (HNPCC)?
Are there others?
**Colon**, **endometrial**;
**yes** (e.g. stomach, ovarian, urinary tract, billiary tract)
109
Wilm's tumor is a rapidly growing neoplasm of the kidney.
What is the normal function of the *WT1* gene on chromosome 11?
Tumor suppression
110
**True/False**.
The general lifetime cancer risk in individuals with Li Fraumeni syndrome is 50% by age 30 and 90% by age 60.
**True**.
111
A mutation in what gene causes Cowden syndrome?
*PTEN*
112
What syndrome predisposes individuals to tumors of the thyroid, breast, endometrium, adipose, and kidneys, as well as facial papules, papillomatous papules, hamartomas, and macrocephaly?
Cowden syndrome
| (*PTEN* deletion)
113
Name some of the tumors associated with Von Hippel-Lindau syndrome.
**Hemangioblastoma** (brain, spinal cord, retina);
**renal** **cell** carcinoma;
**pheochromocytoma**
114
**True/False**.
Most cancer syndromes (e.g. Von Hippel-Lindau; Cowden's; etc.) are asymptomatic until both alleles are mutated (two hits).
**False**.
Non-tumorigenic S/Sy are often present after a single mutation (e.g. macrocephaly, cutaneous lesions, etc.). Tumors typically only arise after two mutations.
115
What syndrome is characterized by mucocutaneous hyperpigmentation and multiple intestinal hamartomous polyps?.
Peutz-Jeghers syndrome
116
Peutz-Jeghers syndrome shows what inheritance pattern?
Autosomal dominant
117
What gene mutation is associated with Peutz-Jeghers syndrome?
*STK11*
118
A patient presents with macrocephaly, jaw cysts, and mutliple basal cell carcinomas. You note these basal cell carcinomas are in sun-exposed and non-sunexposed locations.
What syndrome do you suspect?
Basal cell nevus (Gorlin) syndrome
119
What gene is associated with basal cell nevus syndrome?
*PTCH*
120
What genes are associated with hereditary melanoma?
*CDKN2A*; *CDK4*
121
What type of gene is the *RET* gene?
A proto-oncogene
122
What is the main prophylactic treatment for a patient with a *RET* mutation?
Thyroidectomy
(e.g. in MEN 2a/b)
123
Ataxia telangiectasia results from a mutation in what type of gene?
DNA repair
| (*ATM* gene)
124
**True/False**.
Oster-Weber-Rendu syndrome is another name for ataxia telangiectasia.
**False**.
Oster-Weber-Rendu syndrome is another name for ***hereditary hemorrhagic*** telangiectasia.
125
Why is ataxia seen in ataxia telangiectasia?
Where are the telangiectasias in this disorder typically prominent?
Cerebellar dysfunction;
the eyes
126
What is the inheritance pattern of ataxia telangiectasia?
Autosomal recessive
127
Name a few syndromes with an increased risk of malignancy that result due to deficient DNA repair mechanisms.
## Footnote
**XAB**
Xeroderma pigmentosum;
ataxia telangiectasia;
Bloom syndrome
128
What might be indicated by a patient with bilateral tumor formation?
A hereditary cancer syndrome
