Genetics: 2-Hit Model Flashcards
What is the sporadic tumor model?
assumes that the patient starts out with 2 normal copies of the the tumor suppressor gene (TSG) and all malignant changes will occur as somatic mutations
What are the first and second “hits” to genes?
each hit is an independent mutational event that renders one allele nonfunctional
In sporadic tumors, what is the risk to family members?
nothing - because each mutation/hit was somatic
What is the major difference in hereditary vs. sporadic tumors?
in sporadic tumors, the TSG hits are somatic only and not passed on; in hereditary tumors/cancers, the individual inherits a first hit and thus every cell in the body is heterozygous for a nonfunctional TSG allele
In a person with hereditary cancer, where does the second hit to TSG occur?
Within the tumor cells only, hence the development of cancerous proliferation
The majority of hereditary cancers segregate through families as ____ ____. with ____ penetrance.
autosomal dominant; reduced
How would an individual with an inherited nonfunctional TSG allele not develop cancer?
by inheriting one hit (nonfunctional allele) and [somehow] avoiding the second hit needed to develop a tumor
True or false: cancer families are not at risk for sporadic tumors; any tumor they develop wouldn’t be sporadic since they are already heterozygous for the nonfunctional TSG alleles.
False - cancer families are STILL at risk for sporadic tumors since these are somatic mutations that occur (randomly)
What is the mutation rate like in many cancers?
High
Acquired [cancerous] somatic mutations will be passed on to where?
to its own daughter cells via clonal expansion only
What is a constitutional mutation?
mutation (cancerous) that occurs in all cells of the body, including germline and somatic; can be inherited r new mutations
In the case of hereditary cancers, a constitutional mutation confers a ____ risk of cancer.
high - because it’s in all cells and includes inherited mutation AND multiple acquired mutations.
What is a driver mutation?
mutations in “cancer genes” that confers growth advantage through effects on a critical pathway
Typically, there are ____ driver mutations per tumor.
multiple
What is a passenger mutation?
mutation in cancer cells that confers no apparent growth advantage; these random mutations are carried along by clonal expansion; “along for the ride”
True or false: an evolving tumor is homogenous with respect to genotype of the cells comprising the tumor.
False - an evolving tumor is genetically heterogenous
What is the relationship between rounds of tumor cell division and acquired mutations?
more rounds of cell division = more acquired mutations
Do advanced malignancies exhibit heterogenous or homogenous genomic instability?
heterogenous
What are the 2 broad classes of cancer genes?
- oncogenes - when on they promote growth; mutated to gain of function
- TSG - when on they restrict growth; mutated to loss of function
RB1 and NF1 are ____ ____ TSGs that when mutated can lead to ____ and ____, respectively.
cell cycle; retinoblastoma; neurofibromatosis type 1
MLH1/MSH2/MSH6 are ____ ____ TSGs that when function is lost can lead to ____ and ____ respectively.
DNA repair; Lynch syndrome; Breast & Ovarian cancer
TP53 is an ____ ___ (gene type) that when mutated to loss of function can lead to ____ syndrome.
apoptotic TSG; Li-Fraumini
Tumor suppressor genes segregate as AD disease with reduced penetrance. The phenotype is ____ at the patient level and ____ at the tumor level.
dominant; recessive
Dominant at pt level because while most cells remain heterozygous, the tumor phenotype is present.
Recessive at the tumor level because it takes 2 mutations to create the tumor phenotype.
What are 3 mechanisms for acquiring the second hit in sporadic cancers?
- loss of heterozygosity (ie, microdeletion, mitotic nondisjunction, mitotic recombination)
- point mutation (typical LOF mutation)
- epigenetic silencing (normal allele is methylated)
Is penetrance usually high in familial cases of hereditary cancer?
yes
What are some characteristics that accompany hereditary cancers?
- multiple affected family members
- risk of multiple primary tumors
- increased risk of other types of cancer
- earlier age of onset
- may be other phenotypic features in addition to cancer
- reduced penetrance
Describe 3 genetic mechanisms for activation of oncogenes.
- point mutation
- somatically acquired reciprocal translocation
- gene amplification
Somatically acquired reciprocal translocation of the ABL and BCR genes, creating a fusion gene, occurs between which 2 chromosomes?
9 and 22
What does the fusion protein encoded by the BCR-ABL fusion gene do?
it’s a constitutively expressed tyrosine kinase that confers potential for malignant transformation and result in CML
____ is a drug used to treat CML and it specifically targets the fusion protein (ABL-BCR).
Imatinib
What is gene amplification?
abnormal copy number variants of a proto-oncogene, causing the protein product to be hyperexpressed and leading to malignancies
What are two types of gene amplifications seen in oncogene amplification?
- HSR - homogenously staining regions; visible in chromosomes as an extra non-banded region (picture long adjacent repeated gene)
- DM - double minutes; extrachromosomal genes that are circular without centromeres or telomeres and segregate randomly at cell division
When is gene amplification constitutional?
Never. Just like outlawing guns or cheese.
HER2 is a member of the ____ family.
EGFR
What 2 drugs target HER2 to treat HER2-positive cancers?
Herceptin
Kadcyla
