Cancer Genetics

Familial Cancer Syndromes

Most sporadic cancers have associated familial cancer syndromes, although these are rare and usually make up less than 5% of cases of a particular cancer. Familial cancers are typically early onset, occur in over two first degree relatives of the index case, and may present with multiple tumours simultaneously.

Familial Breast Cancer

Germline mutation of the BRCA1 or BRCA2 genes leads to a much higher increase in the risk of developing breast cancer. Both BRCA1 and BRCA2 are DNA repair genes involved in homologous recombination. Penetrance is between 30 – 90% depending on the type of mutation. BRCA1 and 2 also increase the risk of developing ovarian cancer (20 – 40% lifetime risk).
Mutations of BRCA1 and 2 only account for 25% of familial breast cancers. Another single responsible gene may not be found, as it is likely that the remaining cases are due to the combination of multiple low-penetrance genes.

Familial Colon Cancer

Two common familial colon cancer syndromes are known.
Familial adenomatous polyposis is most commonly due to a defect in the adenomatous polyposis coli gene (APC). Transmission is autosomal dominant, as APC is an oncogene. FAP is associated with a 100% incidence of colon cancer, often before the age of 30.
Hereditary non-polyposis colon cancer is due to defects in mismatch repair genes. It predisposes to increased rates of colon cancer as well as other solid tumours. Colon cancers typically develop in the right side of the large bowel. If a single mutated mismatch repair gene is inherited, the other may be lost over time through epigenetic silencing or further mutation. This leads to microsatellite instability, and promotes the development of further mutations.

Li-Fraumeni Syndrome

Li-Fraumeni syndrome is an autosomal domination condition where a mutant copy of the TP53 gene is inherited. Loss of the second TP53 copy may occur sporadically and this leads to a 25-fold increase in the rate of tumours (typically sarcoma, brain tumours and leukaemia).

Molecular Basis of Multistep Carcinogenesis

Activation of a single oncogene is not sufficient to cause cancer, as is loss of a single allele for a tumour suppressor gene. It is thought that tumour development is the combination of numerous small steps, which must occur in some order, before a cancer can emerge. This is supported by numerous studies, knowledge of the function of oncogenes and tumour suppressor genes, as well as the genes and proteins involved in immortality, evasion of apoptosis, angiogenesis and metastasis.

The Vogelstein Model of Multistep Carcniogenesis

The first published model of a multistep carcinogenesis based on molecular changes was published in the 1980s by Vogelstein (although I have heard debate about who actually postulated this first). In this model, colon cancer develops along a series of steps, from normal epithelium, hyperplasia, adenoma and eventually carcinoma. Each step is associated with the mutation of additional genes.


Radiosensitivity Syndromes

Radiosensitivity syndromes frequently also predispose to malignancy due to the increased susceptibility to ionising radiation. The involved genes tend to be sensors of DNA damage (ATM, MRE11A or NBN) or repair pathways (FA).


This autosomal recessive condition is caused by loss of both alleles of the ataxia-telangiectasia mutated (ATM) gene. ATM is involved in the early (perhaps initial) response to double strand DNA breaks caused by ionising radiation. In the absence of this pathway, some DNA lesions are unable to be repaired.
Clinical features include early onset of ataxia leading to wheelchair confinement by the teenage years. Telangiectasia occurs over the body, including the conjunctiva.

Ataxia-Telangiectasia-Like Disorder

A protein also involved in double strand break sensing, MRE11A, is mutated in a similar autosomoal recessive disease. However, double strand breaks are repaired similar to wild-type cells leading to speculation as to how the radiosensitivity in this situation occurs.

Nimegen Breakage Syndrome

NBN is another protein which forms the MRN complex. It interacts closely with ATM and the exact function is not known – it seems that NBN is required for ATM activation and vice versa.

Fanconi Anaemia

There are eight proteins (FANC family) that form a complex which is important in homologous recombination, response to double strand breaks as well as chemically induced DNA damage. FA leads to chromosomal instability, susceptibility to interstrand crosslinks of DNA (cisplatin functions in this way) and occasionally sensitivity to ionising radiation. The mechanisms by which sensitivity to ionising radiation occurs is not fully understood.