Page 146 - Concise Pathology for Exam Preparation ( PDFDrive )

6 Neoplasia 131

(b) Familial polyposis coli (FAP):
- Presents with polypoid adenomas at birth and shows 100% conversion to
familial polyposis coli by age of 50 years.
- The genetic defect in FAP is a germline mutation in the adenomatous polypo-
sis coli (APC) gene. Syndromes once thought to be distinct from FAP are now
recognized to be a part of the phenotypic spectrum of FAP.
- Syndromes with a germline mutation in the APC gene include FAP, Gardner
syndrome, some families with Turcot syndrome and attenuated adenomatous
polyposis coli (AAPC).
- Gardner syndrome is characterized by colonic polyposis typical of FAP, along
with osteomas (skull and mandible), dental abnormalities and soft tissue tu-
mours. Turcot syndrome is characterized by colonic polyposis typical of FAP,
along with CNS tumours (medulloblastoma). AAPC is characterized by fewer
colonic polyps as compared to classic FAP, which tend to develop late (average
age 36 years), and involve proximal colonic area.
(c) Multiple endocrine neoplasia (MEN) syndromes:
- The term MEN encompasses several distinct autosomal dominant syndromes
featuring both benign and malignant tumours derived from endocrine and
nonendocrine tissue.
- There are two major forms of MEN—type 1 and type 2—which are distin-
guished based on the genes involved and hormones secreted (MEN 1—
adenomas of pituitary, parathyroid and pancreas; MEN 2—medullary
carcinoma thyroid, pheochromocytoma and parathyroid tumours).
- Other component neoplasms include adrenocortical tumours; visceral and
cutaneous lipomas; meningiomas; facial angiofibromas and thymic, gastric
and bronchial carcinoids.
- MEN 1 follows Knudson’s ‘two-hit’ model for tumour suppressor gene carci-
nogenesis. First hit is a heterozygous MEN 1 germline mutation, inherited
from one parent (familial cases) or developed in an early embryonic stage
(sporadic cases) and present in all cells at birth. Second hit is a MEN 1 somatic
mutation, usually a large deletion, which occurs in predisposed endocrine
cells. MEN 2 is caused by a mutation of RET proto-oncogene.
(d) Neurofibromatosis (NF) or von Recklinghausen disease:
- NF is an autosomal dominant disorder that affects bones, nervous system, soft
tissue and skin.
- At least eight different clinical phenotypes of NF have been identified, and they
are linked to at least two genetic disorders. Commonly abbreviated NF1 (neu-
rofibromatosis type 1), the first is also known as von Recklinghausen disease.
It occurs following mutation of neurofibromin 1 on chromosome 17q11.2.
- Neurofibromin is a tumour suppressor gene whose function is to inhibit p21
RAS oncoprotein. In absence of the inhibitory control of RAS oncoprotein by
this gene, there is uncontrolled cellular proliferation and manifestation mainly
as neurofibromas and Café au lait spots.
- Neurofibromatosis type 2 (also called ‘central neurofibromatosis’) is a re-
sult of mutation of protein merlin (also known as ‘Neurofibromin 2’ or
‘schwannomin’) on chromosome 22q12. It accounts for only 10% of all cases
of NF. Normal function of merlin is not well understood.
(e) Li-Fraumeni syndrome: Results from germline mutation of P53 (see P53).
2. Defective DNA repair syndromes
Human syndromes with DNA repair deficiencies cause genomic instability which is the
driving force behind cancer development. There are four categories of DNA repair genes:
(a) Mismatch repair genes
(b) Base excision repair genes
(c) Nucleotide excision repair genes
(d) Double strand break repair genes
Mostly autosomal recessive in inheritance, common examples of DNA repair
defects include xeroderma pigmentosa, ataxia telangiectasia and Bloom
syndrome. Xeroderma pigmentosa manifests with extreme sensitivity to UV

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