MOLECULAR DIAGNOSTICS EXAM #4
MATERIAL QUESTIONS AND
ANSWERS
________________ genes normally arrest cell division. - ANSWER-Oncogenes
(Oncogene mutations are usually a gain of function and dominant).
Tumor suppressor (usually a loss of function and recessive).
Understand how proliferation and apoptosis changes lead to tumor development. -
ANSWER-Cell growth exceeds cells arrest/apoptosis. Uncontrolled cell growth.
State the four reasons molecular testing is performed on solid and hematologic
malignancies. - ANSWER-1. Directing treatment.
2. Diagnosis.
3. Prognosis.
4. Risk.
Molecular oncology testing: risk
--what is the purpose of this?
--give examples of how this is used. - ANSWER---certain mutations may place
individuals at an incr risk of developing cancer.
--Ex: BRCA1/2 mutations increases lifetime risk of breast cancer to 80%; (general
population is 12%). 60% lifetime risk of uterine cancer (general population <2%).
In a breast cancer workup, molecular testing is performed on invasive breast cancer.
Results of this dictate treatment.
What receptors are tested for?
What % are positive?
What is the treatment for pos? - ANSWER-Step 1: test for estrogen receptor
(ER)/progesterone receptor (PR) by immunohistochemistry.
60% are positive.
Tamoxifen treatment.
When doing a breast cancer workup, if the ER/PR is negative, what should be tested
for next? What % are pos? What is the treatment for pos? - ANSWER-HER2
amplification by FISH and IHC.
20% are positive.
Candidate for Herceptin.
,EGFR and HER2 are strong promoting growth factors. Not turned on all the time,
only when the cells need to grow. Always on for tumor formation. Nothing you can do
to turn them off cellularly, must target with _______________. - ANSWER-specific
drugs.
It is extremely rare to be positive for both ER/PR and HER2 in breast cancer testing.
- ANSWER-True.
The ______________ gene encodes one of a family of human epidermal growth-
factor receptors. This gene is frequently amplified in breast cancer cells, resulting in
increased amounts of ___________ cell surface protein and faster cell growth. -
ANSWER-HER2/neu.
HER2.
HER2-expressing tumors are sensitive to _______________, a monoclonal antibody
therapy. HER2/neu gene amplification is detected by __________________-. -
ANSWER-Herceptin.
in situ hybridization (ISH).
Describe how HER2 amplification is diagnosed and how this impacts treatment of
breast cancer. - ANSWER-Test for HER2 amplification by FISH and IHC.
HER2-expressing tumors are sensitive to Herceptin, a monoclonal antibody therapy
HER2 amplification can be detected by CISH and FISH. Compare and contrast CISH
and FISH. - ANSWER-FISH (fluorescence in situ hybridization). FISH probes are
generally labelled with a variety of different fluorescent tags and can only be
detected under a fluorescence microscope.
CISH (chromagenic in situ hybridization). CISH probes are labelled with biotin or
digoxigenin and can be detected using a bright-field microscope after other treatment
steps have been applied.
________________ are tumor-suppressor genes encoding proteins that participate
in DNA repair. Inherited mutations in these genes significantly increase risk of breast
cancer and ovarian cancer.
Small deletions and insertions are found (187delAG and 5382insC in BRCA1 and
6174delT in BRCA2). Hundreds of mutations identified therefore... mutations are
detected by ____________________. - ANSWER-BRCA1 and BRCA2.
DNA sequencing of the entire genes. (Sanger Sequencing).
Upon identifying non-small cell lung cancer by morphology, what molecular tests are
then ordered? - ANSWER-1. EGFR mutation analysis
2. ALK rearrangement
Explain the genetic changes by which EGFR can drive tumor progression. -
ANSWER-The EGFR oncogene encodes epidermal growth factor receptor that can
, be a driver gene when active. This gene is mutated or amplified in several types of
cancer cells.
Tumors with activating mutations in EGFR are sensitive to tyrosine kinase inhibitors
(TKI). EGFR ACTIVATING gene mutations are detected by DNA sequencing.
Mutations cause unregulated cell growth.
What drug treats EGFR mutations in lung cancers? - ANSWER-Iressa.
List the two genes used to predict the risk of breast & ovarian cancer, what
methodology is used for testing and on what population the test is ordered. -
ANSWER-BRCA1 and BRCA2.
DNA sequencing on entire genome.
BRCA1/2 sequencing is ordered on women without breast cancer that have a family
history of the disease.
___________ is a kinase that controls cell growth. A small inversion of this kinase on
chr 2 causes a massive increase in protein expression, driving lung cell growth to
cancer. - ANSWER-ALK rearrangement.
The two separate genes are EML4 and ALK, rearrange to get EML4-ALK.
>60% of patients pos for ALK rearrangement have complete remission (2-3 years) of
lung cancer when treated with ____________. - ANSWER-Xalkori.
Molecular oncology testing: prognosis
--what is the purpose of this?
--give examples of how this is used. - ANSWER---PREDICTS how long pt. has to
live/how effective a therapy is, how well the drug works.
--Ex: DLBC lymphomas have 3 associated mutations (BCL2, BCL6 and MYC
rearrangements). MYC rearrangement alone and in combination with BCL2/6
decreases survival.
--Ex: MGMT methylation in gliomas. If the MGMT promoter is methylated the only
approved drug (Temadar) is ineffective.
Molecular oncology testing: diagnosis
--what is the purpose of this?
--give examples of how this is used. - ANSWER---specific molecular changes are
always associated with a type of cancer.
--Ex: EGFR amplification in glioblastomas.
--Ex: MDM2 amplification in liposarcomas. (100% of lipos have this amplification).
Molecular oncology testing: directing treatment.
--what is the purpose of this?
--give examples of how this is used. - ANSWER---helps determine drug
specificity/targeted therapy for specific driver mutations.
--Ex: HER2 amplification in breast cancer --> treat with Herceptin.
MATERIAL QUESTIONS AND
ANSWERS
________________ genes normally arrest cell division. - ANSWER-Oncogenes
(Oncogene mutations are usually a gain of function and dominant).
Tumor suppressor (usually a loss of function and recessive).
Understand how proliferation and apoptosis changes lead to tumor development. -
ANSWER-Cell growth exceeds cells arrest/apoptosis. Uncontrolled cell growth.
State the four reasons molecular testing is performed on solid and hematologic
malignancies. - ANSWER-1. Directing treatment.
2. Diagnosis.
3. Prognosis.
4. Risk.
Molecular oncology testing: risk
--what is the purpose of this?
--give examples of how this is used. - ANSWER---certain mutations may place
individuals at an incr risk of developing cancer.
--Ex: BRCA1/2 mutations increases lifetime risk of breast cancer to 80%; (general
population is 12%). 60% lifetime risk of uterine cancer (general population <2%).
In a breast cancer workup, molecular testing is performed on invasive breast cancer.
Results of this dictate treatment.
What receptors are tested for?
What % are positive?
What is the treatment for pos? - ANSWER-Step 1: test for estrogen receptor
(ER)/progesterone receptor (PR) by immunohistochemistry.
60% are positive.
Tamoxifen treatment.
When doing a breast cancer workup, if the ER/PR is negative, what should be tested
for next? What % are pos? What is the treatment for pos? - ANSWER-HER2
amplification by FISH and IHC.
20% are positive.
Candidate for Herceptin.
,EGFR and HER2 are strong promoting growth factors. Not turned on all the time,
only when the cells need to grow. Always on for tumor formation. Nothing you can do
to turn them off cellularly, must target with _______________. - ANSWER-specific
drugs.
It is extremely rare to be positive for both ER/PR and HER2 in breast cancer testing.
- ANSWER-True.
The ______________ gene encodes one of a family of human epidermal growth-
factor receptors. This gene is frequently amplified in breast cancer cells, resulting in
increased amounts of ___________ cell surface protein and faster cell growth. -
ANSWER-HER2/neu.
HER2.
HER2-expressing tumors are sensitive to _______________, a monoclonal antibody
therapy. HER2/neu gene amplification is detected by __________________-. -
ANSWER-Herceptin.
in situ hybridization (ISH).
Describe how HER2 amplification is diagnosed and how this impacts treatment of
breast cancer. - ANSWER-Test for HER2 amplification by FISH and IHC.
HER2-expressing tumors are sensitive to Herceptin, a monoclonal antibody therapy
HER2 amplification can be detected by CISH and FISH. Compare and contrast CISH
and FISH. - ANSWER-FISH (fluorescence in situ hybridization). FISH probes are
generally labelled with a variety of different fluorescent tags and can only be
detected under a fluorescence microscope.
CISH (chromagenic in situ hybridization). CISH probes are labelled with biotin or
digoxigenin and can be detected using a bright-field microscope after other treatment
steps have been applied.
________________ are tumor-suppressor genes encoding proteins that participate
in DNA repair. Inherited mutations in these genes significantly increase risk of breast
cancer and ovarian cancer.
Small deletions and insertions are found (187delAG and 5382insC in BRCA1 and
6174delT in BRCA2). Hundreds of mutations identified therefore... mutations are
detected by ____________________. - ANSWER-BRCA1 and BRCA2.
DNA sequencing of the entire genes. (Sanger Sequencing).
Upon identifying non-small cell lung cancer by morphology, what molecular tests are
then ordered? - ANSWER-1. EGFR mutation analysis
2. ALK rearrangement
Explain the genetic changes by which EGFR can drive tumor progression. -
ANSWER-The EGFR oncogene encodes epidermal growth factor receptor that can
, be a driver gene when active. This gene is mutated or amplified in several types of
cancer cells.
Tumors with activating mutations in EGFR are sensitive to tyrosine kinase inhibitors
(TKI). EGFR ACTIVATING gene mutations are detected by DNA sequencing.
Mutations cause unregulated cell growth.
What drug treats EGFR mutations in lung cancers? - ANSWER-Iressa.
List the two genes used to predict the risk of breast & ovarian cancer, what
methodology is used for testing and on what population the test is ordered. -
ANSWER-BRCA1 and BRCA2.
DNA sequencing on entire genome.
BRCA1/2 sequencing is ordered on women without breast cancer that have a family
history of the disease.
___________ is a kinase that controls cell growth. A small inversion of this kinase on
chr 2 causes a massive increase in protein expression, driving lung cell growth to
cancer. - ANSWER-ALK rearrangement.
The two separate genes are EML4 and ALK, rearrange to get EML4-ALK.
>60% of patients pos for ALK rearrangement have complete remission (2-3 years) of
lung cancer when treated with ____________. - ANSWER-Xalkori.
Molecular oncology testing: prognosis
--what is the purpose of this?
--give examples of how this is used. - ANSWER---PREDICTS how long pt. has to
live/how effective a therapy is, how well the drug works.
--Ex: DLBC lymphomas have 3 associated mutations (BCL2, BCL6 and MYC
rearrangements). MYC rearrangement alone and in combination with BCL2/6
decreases survival.
--Ex: MGMT methylation in gliomas. If the MGMT promoter is methylated the only
approved drug (Temadar) is ineffective.
Molecular oncology testing: diagnosis
--what is the purpose of this?
--give examples of how this is used. - ANSWER---specific molecular changes are
always associated with a type of cancer.
--Ex: EGFR amplification in glioblastomas.
--Ex: MDM2 amplification in liposarcomas. (100% of lipos have this amplification).
Molecular oncology testing: directing treatment.
--what is the purpose of this?
--give examples of how this is used. - ANSWER---helps determine drug
specificity/targeted therapy for specific driver mutations.
--Ex: HER2 amplification in breast cancer --> treat with Herceptin.
