Page 154 - Concise Pathology for Exam Preparation ( PDFDrive )

6 Neoplasia 139

Mutated form of p53 behaves like an oncogene to induce carcinomas of lung, head,
neck, colon and breast. It also contributes to sequential development of carcinoma
in situ in invasive carcinoma. Cancers of multiple organs (breast, bone and brain
sarcomas) are caused by damage to both alleles of p53 (Li-Fraumeni syndrome).
p53 family has other members like p63 and p73 which show relative tissue
specificity unlike p53 which is ubiquitously present.
3. Transforming growth factor (TGF-b): Inhibitor of cell proliferation, TGF-b acts on G 1
phase. Its mutant form has impaired-growth-inhibiting effect, leading to uncontrolled
cell proliferation and cancer as in carcinoma of pancreas, colon and stomach.
4. Adenomatous polyposis gene (APC):
• APC is a component of WNT-signalling pathways which controls cell adhesion and
polarity during embryogenesis. An important function of the APC protein is to
downregulate b-catenin.
• In the absence of WNT-signalling, APC causes proteasomal degradation of
b-catenin by forming a ‘destruction complex’, thus preventing its accumulation in
the cytoplasm. In the event of APC gene inactivation, there is disruption of this
complex, thereby increasing cellular levels of b-catenin, which, in turn, translocates
to the nucleus.
• In the nucleus, b-catenin forms a complex with TCF-a transcription factor which
upregulates cellular proliferation by promoting the transcription of c-MYC, CYCLIN
Dl and other genes.
• APC is mutated in familial adenomatous polyposis and sporadic colonic carcino-
mas. Also, colonic tumours in some cases have normal APC genes but mutated
b-catenin, which is not inhibited by APC.
• Dysregulation of the APC–b-catenin pathway is also present in more than 50% of
hepatoblastomas and in approximately 20% of hepatocellular carcinomas.
5. Wilms tumour (WT)-1 gene: The WT-1 gene, located on chromosome l 1p13, is associated
with the development of Wilms tumour. It is a transcriptional activator of genes involved
in renal and gonadal differentiation. Both inherited and sporadic forms of Wilms tumour
occur, and mutational inactivation of the WT- I locus have been seen in both forms.
6. Neurofibroma (NF) gene: Prevents proliferation of Schwann cells and is involved in
neurofibromatosis-1 and -2.
7. Breast cancer susceptibility genes (BRCA) 1 and 2:
• BRCA1 gene is located on the long arm of chromosome 17, and its protein product
is involved in DNA damage repair and transcriptional regulation. Variations in the
gene have been implicated in a number of hereditary cancers, namely breast, ovary
and prostate.
• BRCA2 gene is located on the long arm of chromosome 13 and is essential for
repairing damaged DNA; the BRCA2 protein binds to and regulates the protein
produced by the RAD51 gene to fix breaks in DNA. Abnormalities of the BRCA2
gene may cause an increased risk of breast cancer along with cancer of the ovaries,
prostate and pancreas, as well as malignant melanoma.
8. von Hippel–Lindau (VHL) gene: Germline mutation of VHL gene on chromosome
3p is associated with hereditary renal cell carcinoma, pheochromocytoma, haeman-
gioblastoma of the central nervous system, retinal angiomas and renal cysts. Mutations
in VHL gene are sometimes also noted in sporadic renal cell cancers.
9. Phosphatase and tensin homologue (PTEN) gene: This is located on chromosome 10 and
is frequently deleted in endometrial cancer and glioblastoma. PTEN activity causes cell
cycle arrest and apoptosis as well as inhibition of cell motility. It has been proposed
that PTEN blocks the cell cycle by increasing the transcription of the
p27 Cip/Kip cell-cycle inhibitor and stabilizing the protein. With loss of PTEN, the
cells continuously replicate.
10. Cadherins:
• Cadherins are a family of transmembrane proteins that play an important role
in cell adhesion. They are dependent on calcium ions to function, hence their
name. Loss of Cadherins induces loss of cohesion of cells, which then invade locally
as well as metastasize.

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