Molecular Fundamentals - Cancer Genetics

cancer is what?

a genetic disease that develops in a predictable sequence of steps

mutations that result in oncogenes are what?

mutations are gain of function

• provide a persistent proliferative signal

mutations that affect tumor suppressor genes are what?

mutations are loss of function

what are oncomirs?

oncogene microRNAs

most oncogenes are dominant which means what?

only one allele has to be affected to cause an abnormality

most oncogenic activators occur through mutations involved in what?

growth factor signaling:

• growth factors

• receptors for growth factors

• intracellular signaling pathway components

• transcription factors

other type of oncogene activation mutations involve what?

• telomerase

• anti-apoptotic proteins

point mutations within ERBB2/HER2 create what?

constitutively active protein

HER2/ERBB2 are members of what?

epidermal growth factor receptor (EGFR) family

Brca1/2 mutations are associated with what?

hereditary breast cancer and ovarian cancer

ERBB2 (HER2) mutations are associated with what?

sporadic (non-inherited) breast cancer

what describes myc oncoprotein family (c-myc, N-myc, L-myc)?

transcription factors with roles in controlling cell cycle progression, apoptosis, and transformation

c-myc are expressed where?

in most rapidly proliferating cells

N-myc are expressed where?

in pre-B cells, kidney, brain, and intestine

L-myc are expressed where?

during embryogenesis in the kidney and lung

myc oncoprotein family upregulates what?

cyclins

myc oncoprotein family downregulates what?

• p21

• Bcl-2

what describes Burkitt’s lymphoma?

characterized by chromosomal translocations resulting in the fusion of the heavy chain immunoglobulin gene (IgH) with oncogene myc

with burkitt’s lymphoma, since in B lymphocytes there is a high expression of IgH, the translocation results in what?

over expression of myc, causing proliferation of the B cells, leading to lymphoma

BRC-ABL is what?

a fusion of BCR (breakpoint cluster region) with Abl kinase on chromosome that leads to production of an activated oncogene

presence of BRC-ABL is a hallmark fo what?

chronic myelogenous leukemia (CML) 

loss of miRNAs that function as tumor suppressors can allow for what?

overexpression of oncogenes

overexpression of miRNAS that inhibit tumor suppressors can promote what?

tumor progression

sporadic cancers are what?

• not due to inherited mutation

• majority (80%) of cancer cases

what describes familial cancers?

arise due a combination of risk factors that included inherited susceptibility and environmental factors (15-20% of cases)

what describes inherited cancers?

cancer that results from genetic mutations that are passed on from one generation to the next (5-10% of cases)

what are features that suggest hereditary cancer?

• unusually early age of cancer onset

• cancers occurring in multiple generations of a family

• unusual presentation of cancer

• rare cancers associated with birth defects

what describes multiple endocrine neoplasia (MEN)?

autosomal dominant mode of inheritance

when MEN1 gene is mutated what happens?

tumor supressor gene is mutated and results in loss of function

when RET gene is mutated, what happens?

a mutation occurs in the receptor tyrosine kinase, resulting in an oncogene and a gain of function mutation 

what are the two types of multiple endocrine neoplasia?

• type 1: MEN1 is mutated

• type 2: RET is mutated

what describes Li-Fraumeni Syndrome?

an extremely rare inherited cancer syndrome that is associated with a variety of cancers including breast, brain, leukemia, sarcomas, and adrenal carcinomas

Li-Fraumeni Syndrome is associated with mutation in what?

TP53, a tumor suppressor

Retinoblastoma is associated with mutations in what?

RB1, tumor suppressor gene

Von Hippel-Lindau Syndrome predisposes individual to a variety of tumors of what?

eye, brain, spinal cord, kidney, pancreas, and adrenal glands

Von Hippel-Lindau Syndrome is associated with mutations in what?

tumor suppressor gene VHL

under normal conditions, VHL is involved in the degradation of hypoxia inducible factor (HIF1), which means it does what?

inhibits formation of blood vessels

mutations involved VHL give rise to what?

highly vascularized tumors

Hereditary Breast-Ovarian Cancer Syndrome is associated with mutations in what?

BRCA1/BRCA2, tumor suppressor genes

Hereditary Nonpolyposis Colon Cancer (Lynch Syndrome) is associated with mutations in what?

MLH1 or MSH2

under normal conditions, MLH1 or MSH2 do what?

encodes proteins involved with mismatch repair

inactivation of MLH1 or MSH2 leads to what?

increase in point mutations and genetic instability in microsatellite regions or tandem repeats known as Replicative Error positive (RER+) phenotype

gel electrophoresis can be used to identify what?

the RER+ phenotype in DNA extracted from tumor samples

mutations in MLH1 or MSH2 will result in either what?

increase or decrease in the size of specific microsatellite regions in the DNA

Familial Adenomatous Polyposis (FAP) is associated with mutations in what?

APC

what is the risk of Familial Adenomatous Polyposis (FAP) if the mutation is inherited?

100%

what describes neurofibromatosis?

individuals develop tumors of the nervous system, these are usually benign

Neurofibromatosis Type 1 is associated with mutations in what?

NF1, which is a negative regulator of the Ras signaling pathway (normally a tumor suppressor)

most tumor suppressors are inherited in what fashion?

autosomal dominant fashion, meaning an individual only needs to inherit one abnormal copy of the gene to get the disease

in order for cancer to form, what must happen to tumor suppressor genes?

both alleles of a tumor suppressor must be inactivated

what describes autosomal dominant?

inheriting an abnormal copy of a particular gene from one parent is sufficient for disease

although an individual inherits only one mutated allele of a tumor suppressor, the chance that the other allele will undergo mutation in that individual’s lifetime is what?

very high