Chronic Infection to Cancer

How does chronic HBV cause HCC

Hbx change gene expression and signal = genomic instability + (possible) cirrhosis from cell damage

How does chronic alcoholism cause HCC

ROS and Acetaldehyde cause DNA damage + cirrhosis

How does alcohol (high consumption) cause cirrhosis

High consumption metabolize by CYP2E1 → Release ROS

Alcohol increase gut permeability → LPS translocation → Kupffer activate by TLR4 → Cytokine release → Injury

What are the actions of Hbx that lead to carcinogenesis

Activate proliferative signal, interfere with p53, oxidative stress, alter transcription

What is the action of CYP2E1 and ROS production

CYP2E1 only used in high alcohol consumption → unstable and make ROS

ROS effect on DNA

Oxidize base → Promote single strand break → Damage replication fork → Promote double strand break

What are the action of stellate cells in HCC

Store Vit A → Diff in myofibroblast that make collagen and ECM → Deposit into liver → Distortion of architecture and formation of regenerative nodules

What alterations occur by Hbx and what are its effects

TERT promoter → Cell immortality

TP53 interference → Damaged cells survive

Wnt/beta-catenin pathway → Loss of APC/AXIn1 → Proliferation and survival

What are the histological characteristic of HCC

Trabeculae is >3 cells thick, pseudoacini, cytoplasm shrink (higher nuclei to cytoplasmic ratio), hyperchromasia

Why does HCC have higher arterial enhancement compared to portovenous phase on CT imaging

Tumor cell act on VEGF to promote angiogenesis of artery → Increased arterial supply → Arterial enhancement

How does H.pylori cause MALT formation

Secrete virulence factor to protect itself → Sensed by TLR → NF-kb activation → Release IL-8 → Innate immune → T and B cell recruitment → Ag stimulation → T cell activation → B cell proliferation → Lymphoid aggregates → MALT

What is Ag dependent proliferation in MALT lymphoma

H pylori stimulate T cell → B cell stimulated → B cell proliferation → Malignant B cells need H. pylori signal to proliferate

What is the effect of API2/BIRC-MALT1 fusion

Activate NF-kB pathway → Increased transcription of proliferation and survival genes for B cell

What are the canonical and non canonical NF-kB pathways

Canonical → IKK complex → IkB phosphorylation → Release NF-kB

Non canonical → NIK cleavage → persistent NIK activity → IKKa activation → Release NF-kB

What is the importance of t(11;18) translocation in determining treatment options

Translocation = B cell proliferation from NF-kB activation → Does NOT relate to H pylori → Require rituximab (CD20 on B cell specific) and BTK (NF-kb inhibit)

Without translocation = B cell proliferation depends on H.pylori signal → Abx can cure

What tumor suppressors are lost in MALT lymphoma

TP53 → Abnormal cells survive

CDKN2A/p16 inactivation → Abnormal cells can pass from G1 to S phase

Where can H.pylori and lymphocytes be found on gastric histology

H pylori is located in mucosa, lymphocytes in lamina propria

What is the action of polycyclic aromatic hydrocarbon in mutagenesis

PAH enter body → p450 activate itno diol-epoxide → Adduct to DNA → Copying error → Mutation

How does PM act as inflammatory drivers that lead to mutagenesis

Enter alveoli → Cytokine release → Inflammation state → cells need to rebuild → Higher multiplication → Mutations

How does PM trigger EGFR mutated AT2 cells

Inflammation state → Immune cell migration → MC release IL1b → Bind to receptor on mutated AT2 cells → Mutated cells proliferate

What is the action of Exon 19 deletion in oncogenesis

Gain of function → EGFR activation WITHOUT ligand → Constant TK pathway activation → Increased cell proliferation, division and survival

What are the characteristic of lepidic, acinar and papillary growth patterns

Lepidic → Growth in alveolar wall

Acinar → Growth in gland → true gland formation

Papillary → Form finger like projections in fibrovascular cores

What is the big difference between the 3 lung adenocarcinoma growth patterns and lung SCC

Lung SCC can see keratinization, intercellular bridges and squamous cells

Why is EGFR mutation essential for management

EGFR mediated = use TKI to treat → Good response to TKI drug like erlotinib and osimertinib