Topic 9a: test to treatment decision Flashcards
what are some indications or hints that there is a genetic component to a cancer?
familial cancer and young age of onset
what is SCCOHT?
Small cell carcinoma of ovary, hypercalsemic type
what is the age of diagnosis of SCCOHT?
23.9 yrs old
what is knudson’s 2-hit model in carcinogenisis?
where cancers require the knockdown or mutation in the two alleles of the genes in order to actually get to cancer (and a person that is born or acquires the “1st” hit early on has more chance to acquire the 2nd hit)
what cancer is the SMARCA4 gene associated with?
SCCOHT
Small cell carcinoma of ovary, hypercalsemic type
what is the most common type of kidney cancer?
renal cell carcinoma (RCC)
what is special about RCC (renal cell carcinoma)?
why woudl we want to study it?
resistant to conventional chemotherapy, diverse set of outcomes with patients with same tumour type
what is the germline susceptibility to RCC?
5-8% syndromic (i.e inhertited mutations) the rest is sporadic
what was the most common mutated genes in ccRCC and non-ccRCC?
cc = clear cell
in japaneuse and european populations
in japanese populations: TP53 in ccRCC and BAP1/FH in non-ccRCC
in european: CHECK2 folllowed by MITF and ATM
in a canadian cohort, what was found to be the most commonly mutated genes in RCC?
CHECK2 deletion variant and MITF mutation
what are some specific genetic signatures seen in ccRCC, pRCC, chRCC, tRCC, ccpRCC?
- ccRCC: SNV in VHL
- pRCC: CNV gain in ch. 17+7
- chRCC: SNV in TP53
- tRCC: fusion
- ccpRCC: VHL methylation
what are some truncal vs branch mutations in RCC?
truncal: VHL
branch: SMARCA4, PTEN
can VHL be used as a prognostic marker?
no because it is present in all tumors independently of severity
Risk of disease recurrence increases with number of what?
number of mutated RCC genes (e.g. VHL + 0 has better disease-free survival than VHL +1, +2, +3, …)
this was also independent of age
how can classification of high risk (eligible for ajuvant therapy) vs low risk for RCC be improved?
is currently done by looking at histological gradig system, but when look at number of mutations alongside VHL, we can divide them into VHL+0 & VHL+1, who may not need ajuvant therapy, and VHL+2, VHL+>3 which are pripoitized for ajuvant therapy.
what type of mutations are the additional mutations measured in VHL+0,1,2,3 tumors?
driver mutations because it is indepndent from tumor mutational burden
how doess VHL work and what happens when there is a loss of function?
normal: when in normoxia, VHL will bind hydroxylated HIF-a, leading to its degradation, but when in hypoxia, HIF-a will not be hydroxylated so it will bind HIF-b, leading to formation of dimer TF and transcription of many genes leading to cell proliferation, metabolic shift toward glycolysis and angiogenesis
inactivation: in normoxia, the HIF-a will still be hydroxylated but since there not VHL, they will not be degraded, meaning that it will be able to bind to HIF-b, leading to tranxcription of those same genes, elading to more angiogenesis specifically which is important for tumor growth.
what was a target for RCC tumors that people tried to do as a targeted therapy?
VEGF inhibition which leads to angiogenesis that is being overexpressed because of lack of VHL
but only works for ccRCC because not present in others
what is common to both MSS (stable) vs MSI (instable) colorectal cancer genetic evolution?
the loss of genes in the Ras/bRaf signaling axis
what are some availbel targeted therpaies against the ras/raf pathway (what are the different targets)? which ones would actually work?
- EGFR-specific antibodies
- EGFR tyrosine kinase inhibitors
- braf inhibitors
- mek inhibitors
only the bottom two would work since the ras/raf are activatig mutations so would not make sense to target upsteam of them
wnat to inhibit before it gets to the nucleus
why is it that we saw lots of resistance to cetuximab in colorectal cancers?
because upstream of general driver mutations, so doesn’t actually prevent oevractivation
this drug prevents activation of EGFR from the outside of the cell
what is a liquid biopsy?
analysis of a liquid form the body and testing it for the presence of tumor DNA
blood, urine, breastmilk
what are advantages of a liquid biopsy vs tumor biopsy?
- non-invasive as compared to tissue
- easily accessible where it is not possible for sme tumors, especially metastatic lesions
- smaple volume is not limited (tumor biopsies often small)
- can be repeated to monitor course of disease
- capture genetic heterogeneity of tumors
what are advantages of analyzing ctDNA in liquid biopsies as compared to other measures of cancer?
- enables direct measurment of tumors through tumor-specific mutations
- can be detected in early stages of cancer
in ccRCC, how does the classification of VHL+>2 (high risk) vs VHL+<2 (low risk) affect therapy or testing?
high risk: more frequent follow-up imaging/biopsies, and early introduction to adjuvant therapu
low risk: redice unnecessary tests/ disease-associated travels/ anxiety related to medical visits
