Solid Tumour Flashcards
Where does cholangiocarcinoma occur and what are the sub-types?
Cholangiocarcinoma are rare cancers which can occur anywhere in the biliary tract or within the liver.
These cancers are heterogenous and are best classified according to the primary anatomic subtype; intrahepatic CCA (iCCA) and extrahepatic CCA (perihilar CCA (pCCA) or distal CCA (dCCA))
What is the targetable genetic alteration found in cholangiocarcinoma and in which subtype is it found?
FGFR2 fusions - almost exclusively identified in intrahepatic cholangiocarcinoma
What is the pathogenesis of FGFR family genes, as found in cholangiocarcinoma?
FGFR family of tyrosine kinase receptors. The family consists of 4 genes that encode single-pass transmembrane receptions that bind to FGF on the extracellular domain. Ligand binding triggers a cascade that may exercise several cellular functions, including cell survival.
Chromosomal rearrangements cause intragenic translocations that encode functional proteins derived from each of the original proteins. Normally, FGF-FGFR signalling is triggered by the ligand dependant dimerization. The activation of the receptor leads to intracellular phosphorylation of receptor dependant kinase domains resulting in a cascade of intracellular signalling and gene transcription. FGFR2 kinase activity is linked to oncogene addictive pathways including RAS-MAPK, JAK-STAT and PIK3-AKT-mTOR, promising progressive growth, invasiveness, epithelial mesenchymal transition and neo angiogenesis.
What does a typical FGFR2 rearrangement as seen in cholangiocarcinoma look like and what is its biological impact?
FGFR2 fusions typically result from chromosomal events that lead to an in frame fusion between the 5’ portion of FGFR2 and a partner gene. FGFR2 is located on chromosome 10, and around 50% of FGFR fusions arise from intrachromosomal events. On a structural level FGFR2 portion of the fusion retains the extracellular domain as well as the kinase domain. The fusion partner contributes a dimerization signal, leading to pathway activation. A diagnostic advantage is that the location of the breakpoint in the FGFR2 gene appears to be nearly universal within intron 17 or exon 18. However, with respect to potential partner genes, more than 150 fusion partners have been described until now, albeit with variable frequency.
What test is recommended for detection of FGFR or NTRK fusions and why?
Next generation sequencing - there are many fusion partners so becomes difficult to create probes (FISH or RQ-PCR) for the many combinations and would risk missing a novel fusion.
IHC can also be used, however, specificity, reproducibility and comparability of results between labs is difficult and the fusion partner may impact result quality
What is the name of the FGFR inhibitor approved by NICE for FGFR2 fusion positive cholangiocarcinoma?
Pemigatinib
In what proportion of colorectal cancer cases has a germline cause been found?
5%
What are the two forms of phenotypical evolution in colorectal cancer?
APC;TP53;KRAS and serrated neoplasia
Describe the evolution of colorectal cancer in the APC;TP53;KRAS phenotype
o Adenoma occurs with the occurrence with an inactivating mutation in APC, adenocarcinoma occurs with the occurrence of inactivating mutations in TP53, telomere dysfunction and double stranded DS breakage and invasive/metastatic disease often shows activating KRAS mutations
Describe the types of variants most often seen in the serrated neoplasm colorectal cancer type
o Serrated neoplasms exhibit a higher frequency of inactivating mutations in BRAF and KRAS, hypermutation rates and rarely APC mutations.
Whats is the clinical significance of KRAS and NRAS variants in colorectal cancer, in which exons are they found and in what proportion of cases?
CRC with an NRAS or KRAS variant do not respond to the EGFR inhibitors cetuximab and panitumumab. The variants occur in exons 2, 3 and 4 of each gene. KRAS - 40%, NRAS - 3-5%
Why do patients with KRAS or NRAS variants not respond to EGFR inhibitors?
KRAS and NRAS is downstream of EGFR in the RAS/RAF/MEK/ERK pathway and so escape being influenced by EGFR inhibition.
What is the clinical significance of BRAF V600E variants in colorectal cancer?
Approximately 5-9% of CRCs have a BRAF V600E variant
-poor prognosis
The mutated BRAF protein is believed to be constitutively
active and occurs downstream in the pathway, thereby bypassing inhibition of EGFR by cetuximab or pantitumumab.
BRAF V600E makes response to cetuximab or panitumumab highly unlikely unless given with a BRAF inhibitor.
What is the clinical significance of oncogenic non-V600E BRAF variants in colorectal cancer?
In contrast to the V600E variants, some of these may lead to inactivation of the kinase, co-occur with RAS mutations and are not enriched in MSI-H CRCs
What biomarkers can be used to predict response to immune checkpoint inhibitors in CRC and which of these is approved by NICE for treatment with pembrolizumab?
MSI High - Approved by NICE
Tumour Mutational Burden
POLE and POLD1 mutations
What are the two testing methodologies which can be used as the initial test in the Lynch screening pathway?
Immunohistochemistry and MSI
What inherited cancer syndromes are associated with colorectal cancer?
Lynch syndrome and familial adenomatous polyposis (FAP)
Describe the lynch testing pathway for colorectal cancer
IHC for lynch genes
- If IHC MLH1 abnormal proceed to BRAF V600E
- If MSH2, MSH6 or PMS2 immunohistochemistry results are abnormal, confirm Lynch syndrome
- If all proficient, no further testing
MSI
- If MSI-H proceed to BRAF analysis
- If MSI-L - likely sporadic
Both
BRAF V600E analysis
- If not variant detected proceed to MLH1 promoter hypermethylation analysis
- If positive - likely sporadic
MLH1 promoter hypermethylation analysis
- If negative proceed to germline testing
- If positive - likely sporadic (consider germline MLH1 methylation)
What are the most frequently mutated genes in uveal melanoma and at what frequency are the identified?
GNAQ and GNA11. Mutations are generally mutually exclusive and found in 90% of cases
What are the biomarkers for a higher risk of metastasis in uveal melanoma?
Monosomy of chromosome 3 (50% of cases)
Gains of chromosome 8p (coexistence with monosomy 3 = higher risk)
Bi-allelic inactivation of BAP1
What genetic abnormality offers protection from metastasis in uveal melanoma in the context of monosomy 3 and gain of 8q.
Gain of 6p
What are the hotspots of GNAQ and GNA11 in uveal melanoma?
Exons 4 & 5
Codons Q209 and R183
What are the different subtypes of cutaneous melanoma?
Non chronic sun damage (non-CSD)
Melanomas on skin without sun damage (CSD)
Acral melanoma on the soles and palms
In what proportion of cutaneous melanoma patients is a BRAF mutation found and what subtype is it associated with?
BRAF mutations occur in around 50% of cases and are associated with the non chronic sun damage (CSD) sub type
What are the treatment implications for metastatic melanoma patients with a BRAF V600 mutation?
BRAF V600 mutations are associated with response to BRAF inhibitors and MEK inhibitors. Trials have shown that a combination of BRAF and MEK inhibitors are superior to either agent alone
What are the treatment implications for non-V600 BRAF mutations including fusions in metastatic melanoma?
o Mutations near V600 in exon 15 have shown response to BRAF and MEK inhibitors
o Fusions of BRAF have also shown responses to MEK inhibitors and non specific RAF inhibitors
o Mutations in other codons in exon 11 or 15 have not demonstrated response to BRAF or MEK inhibition
In what proportion of melanoma cases are KIT mutations detected and with which subtype(s) is it associated?
KIT mutations are found in 2-8% of melanoma cases and are associated with chronic sun damage acral and mucosal melanomas
