by Christian A Scerri MD PhD(Molecular Genetics)
Clinical and Molecular Geneticist
Clinical and Molecular Genetics Clinic
Speciality Clinics, Mater Dei Hospital 

Breast cancer is one of the most common cancers in the world. The incidence in Malta is around 94 per 100,000 population.1 Breast cancer is a complex and heterogeneous disease caused by the interaction of various genetic and environmental factors. The identification of breast cancer causative genes has been an ongoing process both because of the magnitude of the problem and as an opportunity to reduce the public health impact of the disease, as well as the utilisation of breast cancer as a model to study the molecular basis of cancer.

Though breast cancer that clusters in families is not infrequent, hereditary causes are only responsible for 15-20% of these cases.2 Other factors that can be correlated with familial clusters include localised environmental factors (carcinogens), culturally motivated behaviour that can alter risk factors such as age of first born and socioeconomic influences that could for example influence dietary habits.

Contrary to non-hereditary breast cancer that clusters in family, inheritable breast cancer has several distinctive clinical features, such as a lower age of onset, higher prevalence of bilateral disease and the presence of associated tumours in affected individuals such as ovarian, prostate, endometrial, colon and sarcomas.3,4

Genes that have been implicated with an increased risk of breast cancer include:

•         The BRCA1 or BRCA2 mutation syndromes

•         Ataxia telangiectasia (AT) gene

•         Li-Fraumeni syndrome due to TP53 mutation

•         Mutations in CHEK2

•         Cowden syndrome due to PTEN mutations

•         Peutz-Jeghers syndrome.

Mutations in each of these genes produce different clinical phenotypes of characteristic malignancies and in some instances, associated nonmalignant abnormalities. All of these mutations, except the ATM gene, are inherited in an autosomal dominant manner.

BRCA1 and BRCA2 genes

The BRCA1 gene is located on the long arm of chromosome 17 whilst BRCA2 is located in the long arm of chromosome 13. Both these genes are tumour suppressor genes. Tumour suppressor genes control the cell cycle by either regulating the cell cycle or else promote apoptosis (programmed cell death). Loss of both functional copies of a tumour suppressor gene causes a malignant change in the involved cells.

The BRCA1 gene is around 100Kbp long and composed of 24 exons. On the other hand the BRCA2 gene is around 70Kbp in length and composed of 26 exons. The relatively large size and the large number of known pathological mutations in both genes (over 800 in each gene), creates a problem in the identification of mutations in populations where no knowledge of the prevalent mutations exist, such as Malta.


Ataxia-telangiectasia is a rare inherited disorder of childhood affecting the nervous system, immune system and other body systems. It is characterised by progressive ataxia from early childhood together with telangiectasia occurring in the eyes and on the surface of the skin. Due to weakening of the immune systems, chronic lung infections, leukemias and lymphomas are common.

Ataxia-telangiectasia is due to mutations in the ATM gene, situated on the long arm of chromosome 11 and is around 150Kbp in length. The disorder is inherited in an autosomal recessive pattern, with carriers of the condition having an increased risk of breast cancer.  Ataxia-telangiectasia occurs in 1 in 40,000 to 100,000 people worldwide with a carrier rate of 0.6 to 1%.


Li-Fraumeni syndrome

The Li-Fraumeni syndrome (LFS) is a syndrome associated with soft-tissue sarcoma, breast cancer, leukaemia, osteosarcoma, melanoma, and cancer of the colon, pancreas, adrenal cortex and brain. The syndrome is caused by mutations in the transcription factor p53 coded by the tumour protein 53 gene, located on the short arm of chromosome 17 and around 20Kbp in length. p53 reacts to various cellular stresses in order to regulate target genes that induce cell cycle arrest, apoptosis, DNA repair and changes in metabolism. Loss of p53 function increases the risk of multiple primary cancers. Though p53 loss in somatic tumours is very common, the hereditary form i.e. LFS, is very rare, with around 400 families registered worldwide and around 392 different germline mutations identified.

CHEK2 Mutations

The CHK2 checkpoint homolog (CHEK2) gene is located on the long arm of chromosome 22 and is about 22Kbp in length. Checkpoint kinase 2 is a tumour suppressor gene that regulates cell growth. It is activated when the DNA becomes damaged by agents such as toxic chemicals, radiation or ultraviolet rays. In response to DNA damage, the CHK2 protein interacts with several other proteins, including tumor protein 53, to halt cell growth and determine whether the DNA damage can be repaired, otherwise apoptosis sets in. Germ line mutations in the CHEK2 gene have been associated with some cases of breast cancer, in particular, a single mutation (1100delC) is associated with a moderately increased risk of breast cancer in European populations.

Cowden Syndrome

Cowden syndrome is a relatively rare disorder, mainly characterised by noncancerous, tumour-like growths called hamartomas (typically occurring during the late 20’s), but with an increase risk of certain cancers such as breast, thyroid and endometrial carcinoma. In addition, there is a higher than normal risk of macrocephaly, mental retardation and non-cancerous brain tumours.

The majority of the Cowden Syndrome cases are associated with mutations in the Phosphatase and TENsin homolog (PTEN gene), situated in the long arm of chromosome 10 and about 100Kbp in length. Similarly to the BRCA and TP53, PTEN is also a tumour suppressor gene and thus has similar functions in that it stops cell growth and induces apoptosis. It is estimated that the worldwide incidence of Cowden Syndrome is of 1 in 200,000.

Peutz-Jeghers syndrome

Peutz-Jeghers syndrome is a rare disorder characterised by hamartomatous polyposis of the entire digestive tract, an increased risk for tumors of the ovary, cervix and pancreas, and a higher risk for cancer of the breast and of the thyroid. It is a rare condition with a prevalence of under 1 in 50,000 and is inherited in an autosomal dominant pattern. In 70% of families, the syndrome is due to mutations in the STK11 gene on chromosome 19.

Diagnostic Criteria for Hereditary Breast Cancer

In addition to the breast cancer cases that show a clear pattern of inheritance, another 25% of breast cancer cases have some family history. It is thus clear that genetic testing for all breast cancer cases would produce a large number of negative tests. It is therefore imperative that one sets defined criteria so as to select the cases that warrant genetic testing as well as to formulate proper risk assessment.

Hereditary breast cancer is highly suspected when:

1.      Present in more than two generations

2.      Early age of onset (<40years)

3.      Present in a male relative or if a male relative has early onset prostatic carcinoma

4.      Patient or relatives suffered from other types of cancer, congenital malformations or genetic syndromes.                                     


Is there a need for Predictive Genetic Testing in Hereditary Breast Cancer Cases?

Predictive genetic testing for hereditary breast cancer has a number of positive effects that include:

·         Clarification of the actual risk evaluation

·         Target prevention efforts to the identified carriers (intensified screening procedures, prophylactic hormonal therapy and prophylactic mastectomy with reconstruction)

·         Exclude the non-carriers and thus reduce the psychological stress

·         Knowledge that there is no risk for the children of proven non-carriers.

Though the advances in molecular biology techniques have increased the ability to be able to identify mutations within specific genes and thus identify individuals at risk, the results obtained can sometimes be ambiguous. This may happen because of two circumstances i.e. when no mutation is identified in a family where no known mutation is present and in those cases where a new polymorphism is identified but its pathological status is not clear. These cases present a dilemma for the counselor and the surgeon since although a family history is obviously present, no definite molecular defect is identified.


1. Ferlay J,  Autier P,  Boniol M et al. Estimates of the cancer incidence and mortality in Europe in 2006. Annals of Oncology 2007; 18:581–92.

2. Slattery ML, Kerber RA. A comprehensive evaluation of family history and breast cancer risk. The Utah Population Database. JAMA 1993; 270:1563-8.

3. Anderson DE, Badzioch MD. Familial breast cancer risks. Effects of prostate and other cancers. Cancer 1993; 72:114-9.

4. Nelson, C. L., Sellers, T. A., Rich, S. S., Potter, J. D., McGovern, P. G., & Kushi, L. H. (1993). Familial clustering of colon, breast, uterine, and ovarian cancers as assessed by family history. Genet Epidemiol, 10, 235-244.