Nelson- Neoplasm Flashcards
Define Neoplasm
New growth
Abnormal mass of tissue
Growth exceeds and is uncoordinated w/ normal tissue
Persists once the stimuli stops that invoked the change
What is the pathogenic mechanism of neoplasia?
Genetic alterations in a single cell>
passed to progeny thrpugh clonal proliferation>
tissue mass
What is the key difference between benign and malignant neoplasms?
Benign
CAN’T spread to other tissues (don’t metastasize)
NOT locally invasive
Malignant
CAN spread to other tissues
Locally invasive and destroys adjacent structures
What are the 4 types of genes that are typically mutated in cancer?
- Proto-oncogenes (growth promoting)
- Tumor suppressor genes (growth inhibiting)
- Genes that regulate apoptosis
- Genes involved in DNA repair.
What are the 8 essential alterations involved in the malignant transformation of cells?
- Self-sufficiency in growth signals (proliferate w/out external stimuli)
- Insensitivity to growth-inhibitory signals (TSGs)
- Evasion of apoptosis
- Limitless replicative potential (telomeres)
- Sustained angiogenesis
- Ability to invade and metastasize
- Defects in DNA repair
- Escape from immune attack
What is a proto-oncogene?
Make the proteins involved in growth signaling pathways
What are oncogenes?
Created by mutated proto-oncogenes–> oncoproteins
Gene that has the potential to cause cancer.
What’s an oncoprotein?
Oncoproteins resemble the normal products of proto-oncogenes except they’re devoid of regulatory elements–> autonomous growth.
How many alleles are typically mutated in order to generate an activating mutation?
Only ONE allele needs to be mutated.
Which fusion gene results in increased tyrosine kinase activity?
ABL-BCR
Which gene results in the over expression of cell membrane epidermal growth factor receptor?
Her2/NEU
In breast cancer
*Treat w/ monoclonal Ab to Her2/NEU receptor (trastuzumab)
What does the RAS mutation cause and how does it relate to colon cancer?
Persistent activation of the RAS signal
KRAS for colon cancer
What gene mutation is associated w/ melanomas?
BRAF
What gene is mutated in gastro-intestinal tumors?
KIT–> activation of tyrosine kinase receptor (c-KIT)
CML is associated w/ what mutation?
ABL Translocation y(9:22)
Breast carcinoma is associated w/ what mutation?
HER
Amplification
Burkitt’s lymphoma is associated w/ what mutation?
MYC Translocation t (8:14)
Neuroblastoma is associated w/ what mutation?
N-MYC
Amplification
Leukemia is associated w/ what mutation?
RAS
Point mutation
Osteogenic sarcoma is associated w/ what mutation?
SIS
Why do you perform a her2/neu test in breast cancer?
Because 25% of breast cancers over express an epidermal GF called HER-2/NEU.
Pts with this GF can be treated w/ a monoclonal Ab (Trastuzumab)
Why do you perform a KRAS mutation analysis in colon cancer?
Because KRAS mutations are found in 40% of CRC.
What is a tumor suppressor gene?
Genes that inhibit cell proliferation and prevent uncontrolled growth
What are the functions of TSGs?
Regulate the cell cycle at checkpoints
Regulate nuclear trxn
Regulate cell differentiation
What is the two hit hypothesis for suppressor gene defects?
Explains sporadic and inherited occurence of tumors.
- homozygous for a mt allele
- One mutant allele is inherited and the second loses it’s heterozygosity for the normal gene
How can an inherited mutation of a suppressor gene give rise to an increased risk of familial cancer?
You only need to get the gene from one parent to inherit the disease.
*Autosomal dominant
What are malignancy is associated w/ inheritance of BRCA1/2?
Women w/ this mut have a greatly increased risk of developing breast cancer in their life time (60%).
What are malignancy is associated w/ inheritance of APC mutations?
APC mut–> loss of tumor supressor function–> large numbers of adenomatous polyps in the colon and rectum
100% risk of colorectal adenocarcinoma
How does the over-expression of BCL-2 lead to follicular lymphoma?
BCL-2 usually regulated and prevents apoptosis by limiting the release of cyt c.
Overexpressed BCL2–>
Protects lymphocytes from apoptosis>
Reduced B cell death (rather than explosive proliferation).
slow growing lymphoma
How does the over expression of telomerase lead to limitless replication?
All malignant neoplasms maintain telomeres through the up-regulation of telomerase.
Telomeres prevent gene loss after multiple cell divisions and generally shorten over time. When they’re too short they’re considered damaged and sensce.
How do cancer cells initiate neoangiogenesis?
Angiogenesis is controlled by an increased production of VEGF/ loss of angiogenesis inhibitors.
What cytokine is involved w/ neoangiogenesis?
VEGF
What are the steps involved in invasion and metastases?
- Invasion of ECM:
dissociaton of tumor>
degradation of basement membrane/connective tissue>
attachment of tumor cells to ECM proteins, migration of tumor cells w/in ECM, enter into vasculature - Vascular dissemination and colonization:
Tumor cells attach to endothelial cells of capillary bed. Colonization occurs d/t tumor cells secreting cytokines, GFs and ECM molecules that make metastatic site habitable for tumor cells.
What are some of the ways that cancer cells can evade immunologic detection?
o Outgrowth of antigen negative variants o Loss/reduction of expression of MHC molecules o Immunosuppression o Antigen masking (glycocalyx molecules) o Apoptosis of cytotoxic T cells
What are some of the structural chromosomal changes that can be seen in malignancies?
Translocations
Deletions
Amplifications
**Accumulation of multiple mutations
How are gene expression profiles used in the assessment of breast cancer?
Breast cancer assays are used to determine the expression of 21 genes in tumor tissue. A recurrence score is calculated from the gene expression results. Based on a genetic profile you can calculate the % of recurrent cancer after 10 years of first incident.
