1. HEREDITARY CANCER
SYNDROMES
• DEFINITION: Change or mutation in a specific
gene which may have been inherited and
predispose a person to a particular type of cancer.
• Cancer due to an inherited trait results from a
change in at least one gene that occurred before
conception, and at least one additional change in a
gene occurring after conception
• Cancer linked to an inherited trait can be passed on
to a person’s family members
• Gene mutation increases the chance to develop one
or more cancers
2. MODES OF PRESENTATION
MENDELIAN CANCER SYNDROMES:
1)Autosomal dominant
2)Autosomal recessive
DEFECTIVE DNA REPAIR:
1) Autosomal recessive
2) Autosomal dominant
FAMILIAL CANCERS:
1)DEFINITION
2)Transmission pattern is not clear
3)Relative risk
4)Genetic testing
3. DOMINANTLY INHERITED CANCER
SYNDROMES
Inheritance of single mutant gene
Usually a point mutation of tumor suppressor gene
A) Retinoblastoma: 1. Mutation of RB tumor suppressor gene
2.Bilateral
3.Increased risk of developing second cancer
B) Familial Adenomatous Polyposis:
1.Mutation of APC Tumor suppressor gene
2.Polypoidal adenomas
3.Prognosis
C) Li-Fraumeni syndrome: Germ line mutation of p53 gene
It increases the chances of Breast, Sarcomas, Brain tumors
& childhood adrenocortical carcinomas & Acute
Leukemias
4. D) MEN1 & 2 :
MEN1:Increased risk for developing parathyroid
tumors, pancreatic tumors and/or pituitary tumors.
MEN2 :Mutation of RET proto-oncogene. Increased risk to
develop medullary thyroid cancers
Also have increased risk to develop pheochromocytoma,
parathyroid tumors, and/or mucosal neuromas on the lips
and tongue.
The diagnosis and classification of MEN depends on
family and medical history, clinical examination and
genetic testing
E) Hereditary nonpolyposis Colorectal cancer:
Increased risk of cancers of colon, ovary, endometrium,
stomach, small intestine & bile duct
5. F) Von Hippel- Lindau Disease:
1.Characterized by abnormal growth of blood vessels in
certain parts of the body
2.Increased risk to develop growths in blood capillaries
called angiomas or hemangioblastomas.
3.These growths may develop in the retinas, certain areas of
brain, spinal cord, adrenal glands and other parts of body
Retinal detachment & blindness
4.Angiomas in brain or spinal cord.
Cause symptoms e.g. headaches, problems with balance in
walking, or weakness of arms and legs.Development of cysts and tumors in kidney, pancreas, liver
or adrenal glands or in some cases RCC
6. G) NEUROFIBROMATOSIS TYPE 1:
Principally affects Schwann cells
Neurofibromas in nerve sheaths, tumors of CNS,
autonomous nervous system, meninges & eyes, skeletal
developmental defects
Also tumors like Lipomas, rhabdomyosarcomas, sebaceous
adenomas & chromaffinomas
Increased incidence of meningiomas & gliomas
H) PEUTZ-JEGHERS SYNDROME:
Multiple polyps throughout GIT
Cutaneous pigmentation around lips, oral mucosa, face,
genitalia
7. I) Cowden syndrome:
Increased risk of breast & thyroid cancers
J) Familial melanomas:
The genes involved are CMM1, CMM2, (CDKN2), CDK4
Approximately 5 to 7% patients are from genetically high
risk families
Characterized by invasive melanoma in at least two first
degree relatives. Some have 10 to 100 moles on upper trunk
and limbs.
.
8. CANCERS DUE TO DEFECTIVE DNA
REPAIR
Defective DNA repair results in DNA instability
Autosomal recessive
A) Xeroderma Pigmentosum: Defect in excision stage of
repair. Damage induced by UV radiations
B) Bloom’s Syndrome: Defect in the repair enzymes DNA
ligase 1. Increased risk of all forms of cancers
C) Ataxia telangiectasia: Defect in repair of gamma
radiation damage to nucleotide bases.
1. Reduced CMI
2. Cerebellar ataxia, telangiectasia in conjunctiva, sclera,
3.Predisposition to cancers like malignant lymphomas,
ovarian dysgerminomas & tumors of brain
9. FAMILIAL CANCERS
Increased risk to first degree relatives
The interplay hereditary & environmental factors is
documented e.g. Lung cancer
A) Breast cancer: Women at risk are-
Mutation of BRCA1 &2
Mutation of BRCA1 have 80-90% lifetime risk
B) Ovarian cancer: Closely related with breast cancers
Both occur in many dominant family & and often
in same individual
C) Colorectal carcinomas
10. SCREENING FOR COMMON INHERITED
CANCERS
Familial cancers should be suspected if-
Clustering of cancer in one family
Onset of adult type of carcinoma at early ages
Multiple independent carcinomas arising in individual
Bilateral cancer in paired organs
Presence of a rare cancer
Presence of the same or associated cancers that comprise a
syndrome
11. Breast cancer: Mammography
Breast self examination
Regular clinical examination
Ovarian cancers:
Colorectal carcinomas
Familial melanomas: Monthly skin exams,
twice yearly dermatologic evaluation and
early excision of suspicious lesions
12. GENETIC TESTING
Indications:
When an individual has a reasonable likelihood of
carrying a cancer predisposing gene change.
When a genetic test is available that can be
adequately interpreted
When results of testing will influence medical
management
When the information revealed from testing will be
meaningful and empowering to the person.
13. GENETIC TESTING
STEPS:
Selection of patient
Pretest counselling
Review of Family history
Informed consent
Testing of patient
Disease causing mutation is identified:
1.Screening of asymptomatic family members
A) Negative test
B) Positive test
Failure to identify disease causing mutation-
Noninformative
