Page 430 - Concise Pathology for Exam Preparation ( PDFDrive )

14 The Oral Cavity and Gastrointestinal Tract 415

• APC is the chief negative regulator of b-catenin, which in turn forms a part of the
Wnt signalling pathway.
• APC protein binds to and degrades b-catenin.
• The latter accumulates if there is loss of APC and moves to the nucleus where it com-
plexes with the DNA-binding factor TCF to induce transcription of genes like MYC
and Cyclin D1, which promote cellular proliferation.

Normal mucosal
epithelium

Germline (inherited) or somatic (acquired) mutation of cancer suppressor
‘gatekeeper’ APC (adenomatous polyposis coli) gene located at 5q21 (first hit)

Hyperproliferative
epithelium

Methylation abnormalities or inactivation of normal alleles of APC,
β-catenin, and MutS Homolog 2 or MSH2 (second hit)

Early adenoma

Mutation in proto-oncogene (K-RAS at 12p12)

Intermediate adenoma

Homozygous loss of additional cancer suppressor genes LOH at 18q21
(Mothers against decapentaplegic homolog 2 or SMAD2 and 4, which affect TGF-β signalling)

Late adenoma

• Homozygous loss of additional cancer suppressor gene p53 at 17p13.
• Additional mutations and gross chromosomal alteration of many genes

Carcinoma
FLOWCHART 14.2. Adenoma–carcinoma sequence (APC b-catenin pathway).

2. Microsatellite instability pathway (defective DNA repair):
(a) Microsatellites are repeated sequences of 1–6 nucleotides in the genome. They may
undergo insertion or deletion of bases during normal cellular replication and these
are corrected by DNA mismatch repair (MMR) genes.
(b) Deficiency in cellular MMR leads to widespread mutagenesis and neoplastic devel-
opment.
(c) An important diagnostic feature of MMR-deficient tumours is the high rate of mu-
tations that accumulate in repetitive nucleotide regions and these mutations are
known as microsatellite instability (MSI).
(d) A standard panel of markers to test for MSI in tumours has been recommended and
efficiently separates tumours into those with high, low or no microsatellite instability
(MSI-H, MSI-L or MSS).

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