Summary
Summary Principles and practice of human pathology
- Course
- Institution
Short summary of the lectures and self study assignments of the course Principles and practice of human pathology.
[Show more]
Seller
Follow
elineedwards
Content preview
Benign neoplasia’s usually have simple genetic alterations:- Most common nevi (moles) have only one mutation > 60% BRAF, 20% NRAS
Clonal evolution model: every time a new mutation in one of the cells, there is a clone of this cell
within the tumour. This clone will have a proliferation or survival advantage over the rest of tumour.
Every time there is a new mutation, this mutation will have an advantage over the rest of the cells
Immunohistochemistry (IHC): Usage of an antibody directed against an antigen on a (tumor) cell.
Mutations/ Genes involved in the formation of cancer
1. (proto)oncogenes: main function is to promote cell proliferation and survival. When a
mutation or amplification occurs, it leads to a gain of function, activations or over expression.
This promotes more cell proliferation and survival.
2. Tumor suppressor genes: main function is to inhibit cell proliferation and induction of
apoptosis. When there is a mutation in these genes, this will lead to inactivation or loss of
function of the tumor suppressor gene, this then leads to the loss of induction of apoptosis
and loss of inhibition of cell proliferation.
3. Mutation/ mismatch repair genes (DNA repair genes): main function is to repair DNA
replication errors. When there is a mutation in the genes, this will lead to loos of function
and results in an accumulation of DNA errors.
MYC gene MYC enhances transcription. Important oncogene in some lymphomas.
BIRC3-MLT fusion inhibits apoptosis.
HER2 proto-oncogene. This gene makes protein receptors that are involved in the growth and division of cells
in the breast. Many people with breast cancer have a gene amplification mutation in their HER2 gene. This type
of breast cancer is often referred to as HER2-positive breast cancer.
JAK2 mutation constitutively activates the signal transduction pathways of RAS pathways
BRAF mutation = often a melanoma
BRAF mutated melanoma can be treated with BRAF inhibiting targeted therapy.
Mutant p53 proteins not only lose their tumor suppressive activities but often gain additional
oncogenic functions that endow cells with growth and survival advantages.
Skin cancer
CDKN2A gene: tumor suppressor gene:
- cell cycle + apoptosis
- Homozygous loss of function (mutations or CNVs) often occurs in melanoma
- Codes for p16 and p14 (regulators for cell cycle and can cause apoptosis)
BCC: sun-exposure, never metastasizes, CC to TT mutations/ Mutations in the tumor suppressor
gene p53.
SCC: sun-exposure/HPV, metastases (mostly nodal), dysplasia (abnormal development of cells), CC to
TT mutations, CC to TT mutations/ Mutations in the tumor suppressor gene p53.
Common Nevi: moedervlek, hotspot mutations BRAF/NRAS
Spitz nevus: rapid growth, Spitz tumors have fusion gene rearrangements forming active chimeric
oncogenes, instead of point mutations of oncogenes (which happens in the case of melanomas),
,Translocations in tyrosine kinase receptors e.g. ALK, ROS, RET, MET, NTRK. (fusion between parts of
two chromosomes).
Translocation of genes: occurs when one gene fuses with another gene > caused by a translocation of
the whole part of the chromosome. It translocate to another location and then it fuses with another
chromosome > this causes the fusion of genes, one of them being an oncogene. Because of the fusion,
the oncogene can be activated or it can be expressed. Then, the signal transduction pathway is
activated, causing cell survival, proliferation, inhibition of apoptosis and metastasis.
Melanocytic tumors: melanocytes make pigment (melanin),
- Driver mutations (Lead to a constant activated state of the oncogene and of the pathways.
Oncogenes in melanocytic tumors: BRAF, NRAS, HRAS, KIT, GNAG, GNA11)/ Loss of function
mutations in a tumor suppressor gene.
- Structural chromosomal alterations: translocations
- Copy number variations: loss or gain of part of a chromosome
Lentigo maligna (melanoma)
- Not arising from nevus
- UVB, age
- Face
- Often mutations in KIT (and NF1 and P53). No mutations in BRAF or NRAS
Stages melanoma
, Therapy of melanoma
- Primary melanoma: surgery
Metastatic melanoma: Surgery: few and operable metastases
- Systemic treatment:
- Targeted therapy: BRAF inhibitor: Hit this mutations → treat tumor. This treatment only last
for a few weeks/months and then the tumor can escape and the patient dies of the tumor.
- Immunotherapy: immune checkpoint inhibitor (ICI, anti-PD-1): longer survival than targeted
therapy. Tumor cells have molecules that bind CTLA4 that inhibit T cell function.
Treat patients with antibodies that bind CTLA-4. Instead of activating CTLA-4 they block CTLA-4 so it
cannot be bind by the tumor secreted molecules → constantly activated T cell response. They cannot
be inhibited anymore.
Tumor cells express PD-L1 that binds PD1 → inactivate T cells.
Therapy: antibodies that bind PD1 → block of PD1 signaling → activation of T cells → killing of tumor
cells.
- Chemotherapy is not effective for the treatment of melanomas.
Langerhans cells:
- Somatic muations
- Same functions as DC
- Mutation of BRAF (part of BRAF-MAPK pathway). Mostly also a drive mutation in LHCs
Merkel cell carcinoma (MCC):
- Only occurs in old patients who are immunosuppressed or immunocompromised.
- Very bad prognosis, grows very rapidly and quickly metastasizes. Quick progression
eventually leading to death.
- 20% sun-derived, whereas 80% are caused by the Merkel virus (viral protein).
Pathways
Non cell lung cancer
EGFR activated → ERK and AKT signaling
These patients have EGFR mutations and KRAS mutations
Most focus on EFGR pathway
Ligand binds →EGFR can bind → trigger to activate the pathways.
EFGR mutation → constant active (cells stay in a proliferate state
Drug: EGFR kinase inhibitor: These mutations inhibit the tyrosine kinase domain. The cleft where ATP
bind cannot bind and the inhibitor will bind. The inhibitor inhibit the pathways.
KRAS mutation: In the oncogene (like EGFR). KRAS can stimulate the pathway.
The benefits of buying summaries with Stuvia:
Guaranteed quality through customer reviews
Stuvia customers have reviewed more than 700,000 summaries. This how you know that you are buying the best documents.
Quick and easy check-out
You can quickly pay through credit card or Stuvia-credit for the summaries. There is no membership needed.
Focus on what matters
Your fellow students write the study notes themselves, which is why the documents are always reliable and up-to-date. This ensures you quickly get to the core!
Frequently asked questions
What do I get when I buy this document?
You get a PDF, available immediately after your purchase. The purchased document is accessible anytime, anywhere and indefinitely through your profile.
Satisfaction guarantee: how does it work?
Our satisfaction guarantee ensures that you always find a study document that suits you well. You fill out a form, and our customer service team takes care of the rest.
Who am I buying these notes from?
Stuvia is a marketplace, so you are not buying this document from us, but from seller elineedwards. Stuvia facilitates payment to the seller.
Will I be stuck with a subscription?
No, you only buy these notes for $7.49. You're not tied to anything after your purchase.
Can Stuvia be trusted?
4.6 stars on Google & Trustpilot (+1000 reviews)
53068 documents were sold in the last 30 days
Founded in 2010, the go-to place to buy study notes for 14 years now