D: Familial Cancer

There are a number of familial cancer syndromes, the most important of which are discussed here.

Genetic Testing

Genetic testing is indicated when there is sufficient clinical concern that a patient may be at risk of a familial cancer syndrome, either due to their own cancer or due to cancer in family members. Examples include:

  • A 30 year old woman with breast cancer
  • A 50 year old woman with breast cancer whose mother and sister also were diagnosed with breast cancer


Genetic testing may be carried through a number of means:

  • PCR - The gene in question can be targeted by heating a DNA molecule so it divides into separate strands. A promotor which allows DNA polymerase to attach is targetted to the section of the genome of interest. The DNA polymerase then duplicates the section in question. The newly formed DNA is then reheated to form four strands; this process is repeated several times so that the DNA sequence of interest is copied hundreds of times, allowing it to be detected.
  • In Situ Hybridisation - An antibody that binds to the DNA sequence in question is designed and attached to a molecule that can be detected through fluorescence (FISH) or other methods (silver ISH or SISH). This allows detection of particular genes.

Benefits and Risks of Testing

The benefits of genetic testing are:

  • If positive, identification of a familial cancer syndrome in:
    • The patient, allowing them to make decisions on further treatment and surveillance for other cancers, thereby potentially extending their life
    • The relatives of the patient, allowing them to make decisions on screening or prophylactic surgery
  • If negative, reassurance of the patient and family that their cancer was likely sporadic

The risks of genetic testing are numerous:

  • The potential for genetic discrimination of the patient or relatives (eg. life insurance)
  • The potential to discover non-relatedness of family members
  • False positive results (ie. patient has no syndrome but is told they are, thereby causing them to have unnecessary procedures)
  • False negative results (ie. patient falsely re-assured, does not undergo proper screening in future)
  • Psychosocial impact on the family and relatives regardless of result

Informed Consent

Informed consent is a crucial part of performing genetics testing. The informed consent of the patient relies on the patient understanding the benefits and risks of genetic testing as it applies to them. These include:

Test characteristics
  • What the test is for (eg. specific mutation, any mutation)
  • The accuracy of the test
What happens after the test
  • What the test will mean if it is positive or negative (eg. likelihood of further cancers in each setting)
  • The possibility of an unknown result (eg. mutation that has not been seen before or which does not have prognostic significance yet)
  • The probability of cancer without the genetic test (eg. based on family history alone)
  • The potential to transmit the gene to children and implications for children if they are carriers (eg. surveillance for BRCA1 mutation carriers)
  • The need to notify relatives of the test result (the patient has the right to refuse)
  • The screening process if the test is positive or negative (ie. more intensive vs standard)
  • The potential psychosocial implications on the family
  • The risk of genetic discrimination
  • Discovering non-relatedness of family members
  • The cost of the test

Specific Familial Cancer Syndromes

Familial cancer syndromes are typically due to germline loss of a single tumour suppressor gene whose normal counterpart is lost during the patient's life (Knudson's Two-Hit Hypothesis). A smaller number are due to recessive diseases (eg. Ataxia-Telangiectasia) where both copies of the gene must be lost from both parents to cause a noticable syndrome.

BRCA 1 & 2

Mutations in BRCA1 and BRCA2 are responsible for 50% and 30% of familial breast cancers respectively. There is a 50% lifetime risk of breast cancer with mutation (slightly higher for BRCA1 than BRCA2). Both are associated with a high risk of contralateral breast recurrence, at least 25-50%, and prophylactic contralateral mastectomy is considered standard by some groups. BRCA1 is strongly associated with ovarian cancer (50% lifetime risk) whereas the association is weaker for BRCA2 (10%); prophylactic oophrectomy is often recommended.

MEN 1 & 2

MEN1 is due to mutation of the MEN1 gene and loss of function of menin. Patients develop typically benign tumours that begin with 'P': Parathyroid adenoma, pituitary adenoma and
MEN2 is due to inactivating mutation of RET (not MEN2). Patients with MEN2A (most cases) develop medullary thyroid cancer at a young age (sometimes in childhood), primary hyperparathyroidism and phaeochromocytoma. Patients should undergo thyroidectomy at a young age (based on the site of the RET mutation) but no later than 10; screening of urine for catecholamines is recommended but has low specificity. MEN2B is a less common form arising from a specific RET mutation; these patients do not develop hyperparathyroidism but do develop multifocal medullary thyroid cancers.

Familial Adenomatous Polyposis

Germline inactivating mutation of APC leads to accumulation of beta-catenin and avoidance of apoptosis and terminal differentiation. This leads to increased cell proliferation and adenoma formation, often in the hundreds or thousands. FAP is associated with upper GI polyps that can become malignant (particularly in the duodenum) and desmoid tumours. Treatment is with colectomy once the polyps have started to form.

Lynch Syndrome

Microsatellite instability arising from germline mutation of a number of mismatch repair genes is the cause of Lynch syndrome. Although colon cancer is the most common malignancy arising in this condition, other cancers (particularly endometrial, but also stomach, pancreatic, small bowel, urothelial and brain) are also more common. Management is through regular surveillance of high risk sites and early intervention once malignancy has developed.

Li Fraumeni Syndrome

Germline mutation of TP53 leads to heightened risk of multiple tumours. The most commonly seen are breast cancer (in women), soft tissue sarcoma, adrenocortical carcinoma and gliomas. The syndrome is very rare but is diagnosed when patients have a sarcoma before the age of 45, a family history of sarcomas (in two or more first degree relatives) or with a combination of sarcoma and other suggestive tumour (eg breast, adrenocortical).

Gorlin Syndrome

Mutation in PTCH1 leads to unrestricted activity of SMO; this promotes malignant transformation. Patients develop hundreds of BCCs from a young age (usually 20-30) which are problematic due to the numbers of treatments required. Patients also have an elevated risk of medulloblastoma. Radiotherapy should be avoided.

Tuberous Sclerosis

Mutations of TSC1 (hamartin protein) or TSC2 (tuberin protein) lead to increased activity of mTOR and ras proteins. The most common findings are angiofibromas of the skin and a number of patients develop hamartomas of the brain and subependymal tumours. Radiotherapy should be avoided as it may induce future malignancies. Everolimus, which inhibits mTOR, may provide significant reduction in tumour size for these patients.

Neurofibromatosis 1 & 2

Mutations in NF1 and N

Peutz-Jeghers Syndrome

Mutation of LKB1 leads to loss of cell polarity and is likely a tumour suppressor gene. Patients develop polyps throughout the gastrointestinal tract which can develop into malignancy, often in the colon but also stomach and small bowel. Regular endoscopy from age of 8 if polyps are detected, and 3 yearly from age of 18 is recommended. Surveillance for breast, cervical and testicular cancers is also done from an early age (25, 18 and 5 respectively).

Cowden Syndrome

A very rare (1/200,000) familial cancer syndrome due to mutation of PTEN, a tumour suppressor gene that inhibits the function of AKT and mTOR. Patients develop skin lesions, and are at elevated risk for breast (50%), endometrial (25%), thyroid (70 fold increase), brain (20%), renal (10%) and colorectal cancers (20%). Treatment is with increased screening for these malignancies.

Xeroderma Pigmentosum

Familial Cutaneous Melanoma