Neoplasia 1

Question 1

How does a receptor tyrosine kinase mutation affect cancer?

Answer 1

Serves as an oncogene. It is a growth factor receptor, so if mutated to have ligand-independent activation lead to constitutive cell proliferation by activating nuclear transcription factors

Question 2

Name the three common RTKs mutated in cancer.

Answer 2

1. EGFR (ERB1 gene): point mutation -> lung adenocarcinoma 2. HER2 (ERB2 gene): gene amplification -> breast carcinoma 3. ALK: translocation -> lung adenocarcinoma

Question 3

What are two EGFR inhibitors used to treat tumors? What is the HER2 inhibitor?

Answer 3

Erbitux (cetuximab): monoclonal antibody that binds and inhibits extracellular domain Iressa (gefitinib): smallm olecule nihibotr binds and inhibits intracellular ATP binding domain HER2 – Herceptin (trastuzumab): monoclonal antibody

Question 4

How do Ras point mutations result in constitutive signaling?

Answer 4

mutate it so that it’s permanently in GTP bound form

Question 5

GAP is a tumor ___ gene. Thus, loss/gain of function prmotes pro proliferation

Answer 5

It is a tumor suppressor, so loss of function Because RAS GTP -> Ras GDP (reduction of proliferation)

Question 6

Why does resistance evolve to RTK inhibtors

Answer 6

Downstream path has a lot of points of modification/evolution

Question 7

Downstream of Ras, signal transduction proteins are within what two pathways? What is a major inhibitor of one of these pathways? Explain how mutations can result in problems for cancer.

Answer 7

BRAF pathway: serine-threonine cascade (oncogene—melanoma, thyroid carcinoma, some leukemias)

PI3k: kinase and signal cascade activator (oncogene – breast carcinoma) – inhibited by PTEN (tumor suppressor gene – endometrial carcinoma )

Question 8

Where are non-receptor tyrosine kinases located? What are major classes?

Answer 8

cytoplasm:

Src

Abl

Jak

Question 9

How do alterations of non-receptor tyrosine kinases result in cancer?

Answer 9

Alterations are usually translocations or rearrangements that create fusion genes

Question 10

What drives chronic myelogenous leukemia (CML)?

Answer 10

ABL on Chr9 is fused to BCR on Chr 22

On chromosome 22, the fusion protein kinase that is made is constitutively active

This is the “Philadelphia chromosome”

Question 11

How does Gleevec target the fusion kinase produced in the Philadelphia chromosome?

Answer 11

It is specific to inhibit bcr-abl, or a couple of other tyrosine kinases

BUT NO OTHERS

Question 12

What is the most commonly involved transcription factor?

Answer 12

MYC, which is activated in RAS/MAPK pathway

it activates D cyclins, upregulates rRNA gene transcription (for ribosome assembly), and upregulates metabolism and telomerase genes

Question 13

What are the classes of G1-S checkpoint regulators mutated in cancer?

Answer 13

D-cyclins and CDKs, if gof -> promote cell ycle

CDK inhibtors, if lof -> promote cell cycle

Question 14

How do we detect point mutations? (Three ways)

Answer 14

Detect oncoprotein: stain for mutated protein cytoplasm with IHC using a targeted antibody

OR

detect oncogene with sequencing, allele specific PCR

Question 15

How do we detect amplifications of DNA? Her2 is an example, amplified in ____ cancers. Three ways

Answer 15

Her2 is amplified in breast, gastric carcinoma, treatable with Herceptin

Detect the oncoprotein with IHC by using a targeted antibody

Detect the oncogene: Fluorescence in-situ hybdridization (FISH) labels gene with probe and detects copy #

Array CGH: comparative genomic hybridization, compares number of tumor genes to reference genome

if you have fresh cells…

cytogenetics (karytoyping): stain with Giemsa, amplified cells have DMs or HSRs

Question 16

How do we detect translocations?

Answer 16

Break-apart FISH: put dual color on one gene. if a gene is broken apart, you’ll see that the two colors are far from one antoher

Dual-fusion FISH: different colored probes on two genes of interest, if brought together by rearrangement, hybrid

Question 17

What is Multiple Endocrine Neoplasia Type 2?

Answer 17

Mutation in RET gene (Chr 10): constitutive tyrosine kinase activity

Can result in three syndromes depending on which axon, which all include medullary thyroid carcinoma (malignant tumor of C cells)

A: parathyroid adenoma, adrenal phreochromocytoma (bening tumor of adrenal medulla)

B: adrenal phreochromocytoma, mucosal neuroma

or just FMTC (familial medullary thyroid carcinoma)

Question 18

Functional obstruction in color + proximal dilation–related to what gene, and what is the disease name?

Answer 18

Hirschsprung disease, LOSS of functino of RET (an oncogene)…so neural network doesn’t go to colon, can’t really contract correctly