Week 13 Part 2 - Molecular Pathology Flashcards
Molecular Dx in Thyroid Tumours
Common thyroid tumours originate from follicular cell
Molecular alterations seen include:
- BRAF p.V600E
- RAS - point mutations
- fusion oncogenes (RET-PTC)
A small % of thyroid tumours arise from parafollicular C cells and are classified medullary thyroid carcinomas
Environmental Factors that Aid in Thyroid Tumours
Iodine in diet
Ionising radiation
Chemical carcinogenesis of dietary intake of nitrates and nitrites assoc with both PTC and FTC
Molecular Dx in Lung Cancers - Adenocarcinomas
High rate of somatic mutations
With 18 statistically significant genetic mutations
- TP53 (46%)
- KRAS (33%)
- STK11
- EGFR
- NFL
- BRAF
- others
Molecular Dx in Lung Cancers - Squamous Cell Carcinomas
Gene mutations:
- TP53 (90%)
- CDKN2A - inactivation (72%)
- PTEN
- AKT (47%)
- KEAP1 - related to oxidative damage
Molecular Dx in Lung Cancers - EGFR
One of the most common driver mutations in lung adeno ca
EGFR mutated adeno ca is characterized by East-Asian ethnicity, female, and non/light smoking history
Pathologically EFGR mutated lung Adeno show nuclear TTF-1 +ve with a mcropapillary growth pattern
Molecular Dx in Lung Cancer - PD-L1
PD-L1 is programmed cell death ligand, mediated between T cells and APC
Binding of PD-1 ligand to its receptors PD-L1 or programmed death ligand 2 (PD-L2) can prevent innate cytotoxic T cell response against tumour by inhibiting kinases involved in T cell activation
Immunotherapy with PD-L1 unleashes the innate immune system to react to tumour growth
Molecular Dx in Brain Tumours
Glioblastoma multiforme (GBM) is a highly aggressive malignancy demonstrating somatic mutations in the cytosolic isocitrate dehydrogenase 1 (IDH1)
Point mutations affect the conserved arginine residue at codon 132 in IDH1 gene and rarely the homologous arginine residue at codon 172 in IDH2 gene
IDH1 mutations are detected in >70% of low grade gliomas and >80% of secondary GBMs
When are Mutations in IDH1/IDH2 Genes not Detected?
Patients with other brain tumours with the exception of primitive neuroectodermal tumours (PNET) and atypical meningiomas
Molecular Dx in Head and Neck
Pathology
Microbiology PCR:
- HPV + Oropharyngeal SCC
- other infections EG; TB, Bartonella
Mutation testing Eg: BRAF V600E in PTC
Genetic translocations
Chromosomal gains/losses
Gene rearrangement studies/clonality
Secretory Carcinoma
Originally called Mammory analogue secretory carcinoma
Wide age range 10-85 yrs, M=F
t(12;15)(p13;q25) resulting in ETV6-NTRK3
Minor subset ETV6-RET
PAS+D globular mucin (vs granular in acinic)
IHC: S100+, mammaglobin+, SOX10+, DOG1-
Mucoepidermoid Carcinoma
Wide age range, peak incid 2nd decade
May develop post radiation
Majority harbour t(15;19)(q21;q26) resulting in CRTC1-MAML2
IHC: p63+, CK5/6+, SOX10-
Cystic and oncocytic lesions are challenging
Adenoid Cystic Carcinoma
Slow growing, relentless tumour
Wide age range, peak in 5th/6th decades
Poor long-term outcomes
50% harbour t(6;9)(q22-23;p23-24) resulting in MYB-NFIB
Smaller proportion MYBL1-NFIB
IHC: p63+, CD43+ (basal), CD117+ (luminal), MYB+, SOX10+
Molecular Dx in Ovarian Cancer
Susceptibility genes include BRCA1 and BRCA2
High gd serous carcinoma shows germline mutations within BRCA1/2 in 70% of cases
BRCA mutations lead to a homologous recombination deficiency (HRD) whereby cells reduce the ability to repair DNA double stranded breaks
BRCA mutations in ovarian ca are highly sensitive to platinum based chemotherapy and PARP inhibitors
Molecular Dx in Colon Cancer
EGFR is a therapeutic option
Patients with cancers bearing no mutation in the RAS
gene benefit from EGFR targeting antibodies
Mutations result in activation of the EGFR pathway
Molecular Pathology of Pancreatic Cyst Fluid Analysis
Diagnose using cytology, imaging, biochemistry, molecular techniques
Endoscopic ultrasound - guided FNA or fluid.
Pancreatic cysts may be benign or malignant, the fluid mucinous or serous
Small number of cells makes malignant diagnosis difficult
High CEA levels and KRAS mutations indicate malignancy
