Cancer Biology Flashcards
1p19q codeletion
Present in up to 70-85% of oligodendrogliomas and 50% of oligoastrocytomas
Since the updated 4th edition of the WHO classification of CNS tumors (2016), the 1p19q codeletion and IDH mutation status are essential features for diagnosis/classification of WHO grade II gliomas:
WHO grade II gliomas are divided into three classes: IDH-wildtype, IDH-mutant and no 1p/19q codeletion (astrocytoma), and IDH-mutant and 1p/19q-codeleted (oligodendroglioma, better prognosis)
Oncogenes on chromosome 7
EGFR
MET
BRAF
CDK6
Tumor suppressors on chromosome 17
TP53
BRCA1
NF1
TOP2A (topoisomerase IIa)
EGFRvIII
In-frame deletion of exons 2-7, including the entire L1 and CR1 domains.
This results in deficient ligand binding and constitutive signaling.
Overwhelmingly found in gliomas, approximately 40% of GBMs, only rarely in other tumor types (case report rare).
Biology of IDH1/2 mutated neoplasms
IDH1 and IDH2 are enzymes of the TCA cycle. The oncogenic mutations we see result in production of 2-hydroxygluratate rather than alpha-ketoglutarate, which downstream alters DNA methylation and blocks cell differentiation.
Enasidenib
Mutant IDH2 inhibitor
Approved for mutations in IDH2 codons 140 and 172
Ivosidenib
Mutant IDH1 inhibitor
Approved for mutations in IDH1 codon 132
Vyxeos
Liposomal 5:1 cytarabine:daunarubicin.
For secondary AML or AML with myelodysplasia-related changes (About 25% of AML cases, usually poor prognosis)
Offers superior survival compared to 7+3 with this protocol
TP53 mutated AML/MDS has a worse overall prognosis, but responds better to. . .
Cytarabine
Pathogenesis of FOS dysregulation
FOS is a leucine zipper transcription factor with a transactivation domain spanning positions 60-84. It makes up one of the components of the AP-1 heterodimer (Fos, Jun, ATF, JDP).
When the C-terminal domain is lost, as in v-Fos or by a translocation in exon 4 of c-Fos producing an early stop codon, an isoform of Fos which is resistant to degradation and thereby to downregulation is generated, effectively procuding a constitutively active Fos.
Specifically, truncation results in loss of the C-terminal ψKXE motif for SUMOylation at K265 in the C-terminal aspect of exon 4 as well as a structured domain at the very end of the C-terminal domain (last four residues of the protein).
CREB pathway
CREB = cAMP response element binding protein
FOS is an imporant target of CREB-mediated transcription.
CREB S133
Key serine residue which is a target of phosphorylation during CREB activation.
CREB S133 phosphorylation enables CREB to bind to CBP and act as a transciption factor.
Human CREB-family transcription factors
KID = kinase inducible domain, contains several imporant serine residues which are phosphorylated in CREB activation, including Ser133 in CREB.
Oncogenic MET mutations
Common variants interfere with the exon 14 splice donor site (c.3028+1, c.3028+2) leading to exon 14 skipping.
Mutations at D1028 (the final residue of exon 14) also frequently result in mis-splicing and yield exon 14 skipping. These are most commonly seen in lung NSCLCs.
