Hematology/Oncology Exam 3
What are the two types of cancer mutations? - 1. inherited
2. acquired (errors during cell division or environmental exposure)
What are the types of cancer genes and their functions? - 1. tumor suppressor genes (slow down cell
division, repair DNA error, regulate apoptosis): ex BRCA1
2. oncogenes (typically help cells grow): ex MYC
**mutations in these lead to cancer
What is a De novo genetic variation? - -variations that are new in a family generation (ie no other
members have had this variation)
-can be neutral and advantageous to evolution
-damaging mutations can lead to disease
When do we do genetic testing of cancer in patients with a family history of the disease? - -one first
degree relative with the same or related tumor
-2+ first degree relatives with tumors of the same site
-2+ first degree relatives with tumor types belonging to a known familial cancer syndrome
-2+ first degree relatives with rare tumors
-3+ relatives in 2 generations with tumors of the same site or etiologically related sites
Listen to recording on how to interpret dbSNP -
What is the BRCA 1/2 gene? - -tumor suppressor gene
-causes 3% of breast cancers and 10% of ovarian cancers
What are breast cancers classified as? - -estrogen receptor positive
-estrogen receptor negative
, What can decrease risk of cancer from BRCA 1/2 gene? - -tamoxifen treatment
Who are ultrarapid metabolizers of tamoxifen via cyp2d6? normal metabolizers? intermediated
metabolizers? poor metabolizers? - -UR: person with duplicate functional alleles (ex *1/*1xN)
-NM: person with 2 normal functional alleles, 1 normal and 1 decreased function allele, 2 decreased
function alleles, or 1 normal function and 1 no function allele (ex *1/*1, *1/*41, *41/*41, *1/*4)
-IM: personal carrying 1 decreased function and 1 no function (Ex *4/*10)
-PM: person carrying only no function alleles (ex *4/*4)
Is smoking heritable? - -yes: PK and PD response is influenced by many genes
-pharmacogenetics also influences smoking cessation therapies (ie data suggests CYP2B6 and
Bupropion)
What is the pathway of NTRK signaling? - 1. ligand binding and dimerization
2. trans-autophosphorylation
3. downstream kinase activity
How does the Ph + chromosome result (Philadelphia chromosome) - -from gene fusion of normal
chromosome 9 and normal chromosome 22
-results in the Ph + chromosome with brc-abl gene leading to unchecked kinase activity
What are NTRK fusions? - -drivers of various types of adult and pediatric tumors
-fusion of 5' gene partner with 3' NTRK
-fusion leading to activated NTRK kinase domain
-these lead to signaling following dimerization without the ligand
-3 different types
What are the 4 genomic classes of melanomas (where mutations occur)? - 1. BRAF (majority at V600)
2. RAS (majority at Q61)
,3. NF1
4. Triple WT
What are the apparent resistance mechanisms of melanomas? - -PTEN
-JAK/STAT
-MEK
In the BRAF subtype, what does treatment resistance revolve around? - -BRAF inhibition
What are the BRAF inhibitors? - -vemurafinib
-dabrafenib
How can we regain treatment response in the BRAF melanoma if we are having resistance? - -
downstream inhibitor of MAPK pathway
Where does treatment occur in the RAS melanoma subtype? - -downstream in MAPK pathway
What are the NF1 melanoma subtypes characterized by and how does this affect treatment? - -
heterogenous and loss of function
-loss of function in NF1 removes RAS inhibition
-treatment occurs via inhibition of MAPK pathway
What is the Triple WT melanoma subtype defined by? - -defined by lack of mutations in BRAF, RAS , or
NF1
-driven by driver mutations in other oncogenes (KIT)
-more structural rearragnements
What is the treatment of Triple WT melanoma subtype? - -receptor tyrosine kinase inhibitors
, Which treatments required genetic testing? - -BRAF inhibitors: vemurafenib, dabrafenib (can't use in
patients with wild type BRAF melanoma)
-MEK inhibitors: cobimetinib, trametinib (should be used in combo with BRAF inhibitor? not as single
agent?)
What type of histology does lung cancer have? - -diverse
-ex adenocarcinoma, squamous cell carcinoma, small cell carcinoma, etc
-very few shared mutations
What pathways can we use for treatment of squamous cell carcinoma? - -SOX2 (3q amp)
-NOTCH alterations
-CDKN2A inactivation
What pathways can we use for treatment of small cell carcinoma? - -TP53 loss
-RB1 loss
What pathways can we use for adenocarcinoma treatment? - -EGFR-RAS pathway activation
In adenocarcinoma, what mutations do patients begin with? - -mutations in RAS, BRAF, EGFR + loss of
TP53
-clinical testing for EGFR mutations can guide first line therapy
What are the main EGFR mutations? - -Exon 19 microdeletions
-Exon 21 L858R
What are the EGFR inhibitors? (treatment for non-small cell lung cancers) - -afatinib (1st line for exon
19 and exon 21, safety and efficacy not established for other mutations)
-gefitinib (1st line for exon 19 and exon 21, safety and efficacy not established for other mutations)
-erlotinib (for patients who are receiving first line/maintenance/2nd line treatment after progression of
at least 1 chemo regiment; or first line for patients with metastatic pancreatic cancer)
What are the two types of cancer mutations? - 1. inherited
2. acquired (errors during cell division or environmental exposure)
What are the types of cancer genes and their functions? - 1. tumor suppressor genes (slow down cell
division, repair DNA error, regulate apoptosis): ex BRCA1
2. oncogenes (typically help cells grow): ex MYC
**mutations in these lead to cancer
What is a De novo genetic variation? - -variations that are new in a family generation (ie no other
members have had this variation)
-can be neutral and advantageous to evolution
-damaging mutations can lead to disease
When do we do genetic testing of cancer in patients with a family history of the disease? - -one first
degree relative with the same or related tumor
-2+ first degree relatives with tumors of the same site
-2+ first degree relatives with tumor types belonging to a known familial cancer syndrome
-2+ first degree relatives with rare tumors
-3+ relatives in 2 generations with tumors of the same site or etiologically related sites
Listen to recording on how to interpret dbSNP -
What is the BRCA 1/2 gene? - -tumor suppressor gene
-causes 3% of breast cancers and 10% of ovarian cancers
What are breast cancers classified as? - -estrogen receptor positive
-estrogen receptor negative
, What can decrease risk of cancer from BRCA 1/2 gene? - -tamoxifen treatment
Who are ultrarapid metabolizers of tamoxifen via cyp2d6? normal metabolizers? intermediated
metabolizers? poor metabolizers? - -UR: person with duplicate functional alleles (ex *1/*1xN)
-NM: person with 2 normal functional alleles, 1 normal and 1 decreased function allele, 2 decreased
function alleles, or 1 normal function and 1 no function allele (ex *1/*1, *1/*41, *41/*41, *1/*4)
-IM: personal carrying 1 decreased function and 1 no function (Ex *4/*10)
-PM: person carrying only no function alleles (ex *4/*4)
Is smoking heritable? - -yes: PK and PD response is influenced by many genes
-pharmacogenetics also influences smoking cessation therapies (ie data suggests CYP2B6 and
Bupropion)
What is the pathway of NTRK signaling? - 1. ligand binding and dimerization
2. trans-autophosphorylation
3. downstream kinase activity
How does the Ph + chromosome result (Philadelphia chromosome) - -from gene fusion of normal
chromosome 9 and normal chromosome 22
-results in the Ph + chromosome with brc-abl gene leading to unchecked kinase activity
What are NTRK fusions? - -drivers of various types of adult and pediatric tumors
-fusion of 5' gene partner with 3' NTRK
-fusion leading to activated NTRK kinase domain
-these lead to signaling following dimerization without the ligand
-3 different types
What are the 4 genomic classes of melanomas (where mutations occur)? - 1. BRAF (majority at V600)
2. RAS (majority at Q61)
,3. NF1
4. Triple WT
What are the apparent resistance mechanisms of melanomas? - -PTEN
-JAK/STAT
-MEK
In the BRAF subtype, what does treatment resistance revolve around? - -BRAF inhibition
What are the BRAF inhibitors? - -vemurafinib
-dabrafenib
How can we regain treatment response in the BRAF melanoma if we are having resistance? - -
downstream inhibitor of MAPK pathway
Where does treatment occur in the RAS melanoma subtype? - -downstream in MAPK pathway
What are the NF1 melanoma subtypes characterized by and how does this affect treatment? - -
heterogenous and loss of function
-loss of function in NF1 removes RAS inhibition
-treatment occurs via inhibition of MAPK pathway
What is the Triple WT melanoma subtype defined by? - -defined by lack of mutations in BRAF, RAS , or
NF1
-driven by driver mutations in other oncogenes (KIT)
-more structural rearragnements
What is the treatment of Triple WT melanoma subtype? - -receptor tyrosine kinase inhibitors
, Which treatments required genetic testing? - -BRAF inhibitors: vemurafenib, dabrafenib (can't use in
patients with wild type BRAF melanoma)
-MEK inhibitors: cobimetinib, trametinib (should be used in combo with BRAF inhibitor? not as single
agent?)
What type of histology does lung cancer have? - -diverse
-ex adenocarcinoma, squamous cell carcinoma, small cell carcinoma, etc
-very few shared mutations
What pathways can we use for treatment of squamous cell carcinoma? - -SOX2 (3q amp)
-NOTCH alterations
-CDKN2A inactivation
What pathways can we use for treatment of small cell carcinoma? - -TP53 loss
-RB1 loss
What pathways can we use for adenocarcinoma treatment? - -EGFR-RAS pathway activation
In adenocarcinoma, what mutations do patients begin with? - -mutations in RAS, BRAF, EGFR + loss of
TP53
-clinical testing for EGFR mutations can guide first line therapy
What are the main EGFR mutations? - -Exon 19 microdeletions
-Exon 21 L858R
What are the EGFR inhibitors? (treatment for non-small cell lung cancers) - -afatinib (1st line for exon
19 and exon 21, safety and efficacy not established for other mutations)
-gefitinib (1st line for exon 19 and exon 21, safety and efficacy not established for other mutations)
-erlotinib (for patients who are receiving first line/maintenance/2nd line treatment after progression of
at least 1 chemo regiment; or first line for patients with metastatic pancreatic cancer)
