Genes Flashcards
RET
RET proto-oncogene encodes a receptor tyrosine kinase that binds glial-derived neurotrophic factor (GDNF) and other ligands in the GDNF family and transmits growth and differentiation signals (Chapter 7). Loss-of-function mutations in RET result in intestinal aganglionosis and Hirschsprung disease (Chapter 17). In contrast, in MEN-2A (as well as in MEN-2B), germline mutations constitutively activate the RET receptor, resulting in gain of function
VHL
3p25-p26
- tumor suppressor gene
- encodes a ubiquitously expressed 4.7-kilobase (kb) messenger ribonucleic acid (mRNA) that encodes 3 alternately spliced exons. The resultant 2 von Hippel-Lindau proteins (pVHL) shuttle between the nucleus and the cytoplasm, where they form a complex with several proteins. At present, this gene is the only gene known to cause von Hippel-Lindau disease.
- polyubiquination
- regulation of HIF1a and HIF2a & other hypoxia inducible genes
- cell cycle control
Rb
Retinoblastoma
13q14
tumor suppressor gene
blocks exit from G1 in cell cycle
p53
G1 arrest apoptosis
17p13.1
guardian of the genome
Li-Fraumeni syndrome
most commonly mutated gene in human cancer!
In a normal cell p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stresses, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will induce a cell cycle arrest (at the G1/S regulation point) to allow either repair and survival of the cell or apoptosis to discard the damaged cell. How p53 makes this choice is currently unknown.
APC
adenomatous polyposis coli
aka “deleted in polyposis 2.5 (DP2.5)”
5q21
The APC protein helps control how often a cell divides, how it attaches to other cells within a tissue, or whether a cell moves within or away from a tissue. This protein also helps ensure that the chromosome number in cells produced through cell division is correct. The APC protein accomplishes these tasks mainly through association with other proteins, especially those that are involved in cell attachment and signaling. The activity of one protein in particular, beta-catenin, is controlled by the APC protein (see: Wnt signaling pathway). Regulation of beta-catenin prevents genes that stimulate cell division from being turned on too often and prevents cell overgrowth.
The most common mutation in colon cancer is inactivation of APC. When APC does not have an inactivating mutation, beta catenin does. These mutations can be inherited, or arise sporadically, often as the result of mutations in other genes that produce chromosomal instability. A mutation on APC or β-catenin must be followed by other mutations to become cancerous; however, in carriers of an APC inactivating mutations, the risk of colorectal cancer by age 40 is almost 100%.[2]
Familial adenomatous polyposis (FAP) is caused by mutations in the APC gene.
NF-1
neurofibromin
17q11
prevents cell overgrowth by turning off another protein (called ras) that stimulates cell growth and division
In rare cases, inactivation of one copy of the NF1 gene in each cell increases the risk of developing juvenile myelomonocytic leukemia (JMML).
NF-2
neurofibromin 2 (aka merlin or schwannomin)
22q12
mainly made in Schwann cells
Merlin is believed to play a role in controlling cell shape, cell movement, and communication between cells. To carry out these tasks, merlin associates with the internal framework that supports the cell (the cytoskeleton). Merlin also functions as a tumor suppressor protein, which prevents cells from growing and dividing too fast or in an uncontrolled way.
type 2 neurofibromatosis
sporadic mutations - schwannomatosis (like NF2 but no vestibular schwannomas), meningioma, mesothelioma
DCC
deleted in colorectal carcinoma/cancer
18q21
DCC in a receptor for netrin-1 and is currently believed by some to be a conditional tumour suppressor gene, meaning that it normally prevents cell growth when in the absence of netrin-1. DCC in a receptor for netrin-1 and is currently believed by some to be a conditional tumour suppressor gene, meaning that it normally prevents cell growth when in the absence of netrin-1.
To put this into a biological systems context, some physiology is required. In the gastrointestinal tract, epithelial cells proliferate and die rapidly. The division of these cells occurs at the base of villi, and cells are pushed upwards by subsequent divisions to the tip where they enter apoptosis and shed off into the lumen. Netrin-1 is produced in the base of the villi, so a gradient of netrin is present that is weakest at the tip. In normal physiology, the presence of netrin-1 inhibits DCC-mediated cell death until the epithelial cell reaches the tip of the villus, where the now unbound DCC causes the cell to enter apoptosis. In a cancer state, the absence of DCC prevents the gradient from having an effect on the cell, making it more likely to continue to survive.
also involved in axon and neural crest cell migration in developing fetus
WT-1
Wilms tumor
11p13
encodes a transcription factor that contains four zinc finger motifs at the C-terminus and a proline / glutamine-rich DNA-binding domain at the N-terminus. It has an essential role in the normal development of the urogenital system, and it is mutated in a subset of patients with Wilms’ tumor, (sporadic and hereditary) the gene’s namesake.
Desnys-Drash syndrome (gonadal dysgenesis and nephropathy)
beta myosin heavy chain
chromosome 14
defect in hypertrophic cardiomyopathy (50%)
PiSZ
Alpha-1 antitrypsin
Others: PiSS, PiMZ
Chromosome 14
“Mmm Mmmm Good” (2 M alleles = good prognosis)
“PiZZ poor” (2 Z alleles = bad prognosis)
Activated protein C resistance mutations
- Factor V Leiden: arginine –> glutamine at position 506
- Factor V Cambridge: arginine –> threonine at position 306
Prothrombin G20210A Mutation
Guanidine to adenine substitution in the 3’
untranslated portion of prothrombin gene on Chr 11
EWS gene
aka EWSR1 (Ewing sarcoma breakpoint region 1)
22q12.2
ubiquitely expressed & required for cell survival in the central nervous system
Implicated in ES/PNET, DSRCT, myxoid/round cell liposarcoma, clear cell sarcoma of soft parts, angiomatoid fibrous histiocytoma, extraskeletal myxoid chondrosarcoma, rhabdomyosarcoma, giant cell tumor of bone, others
Neuroblastoma
N-myc = worse prognosis
follow VMA, HVA
