Introduction

The last two decades have seen rapid expansion in our understanding of the genetic origins of cancers. Between 5–10% of cancers are due to inheritance of alterations in genes that confer a high life-time risk of certain malignancies, such as breast, colorectal cancer (see Table 5.1), and very rare tumours.

Table 5.1 The risk of common cancers associated with inherited cancer syndromes

Most of these so-called ‘hereditary cancer predisposition syndromes’ are due to mutations within a single allele (copy) of a tumour suppressor gene inherited in an autosomal dominant fashion.

Mechanisms of inherited cancer

Tumorigenesis involves contributions from two classes of genes. Oncogenes control cell growth and proliferation under normal circumstances, but once inappropriately activated or overexpressed can promote rapid clonal expansion. Tumour suppressor genes normally inhibit abnormal cell proliferation; reduced expression of these genes can result in uncontrolled cell division. Almost all hereditary cancer predisposition syndromes are due to the inheritance of a germline mutation in a tumour suppressor gene. The inherited mutation inactivates one copy of the gene and the subsequent development of a mutation in the remaining ‘normal’ copy of the gene results in failure of a cell to produce the tumour suppressor protein (Knudson ‘two-hit’ hypothesis – see Figure 5.1).

Figure 5.1 Comparison of tumourigenesis pathways in carriers and non-carriers of a mutation in a tumour suppressor gene – the Knudson ‘two hit theory’.

The concept of heritable cancer predisposition was originally developed from observations of an earlier age of onset of retinoblastoma in patients with a positive family history.

Inheritance of two alleles each carrying a mutation within the same tumour suppression gene is extremely rare and can result in a different and more severe phenotype than monoallelic mutation inheritance. For example, inheritance of one BRCA2 mutation from a single parent is associated with breast/ovarian cancer whilst biallelic BRCA2 mutations are a cause of Fanconi’s anaemia.

Diagnosis

A hereditary predisposition towards developing malignancy is characterized by young age at presentation, an increased incidence of bilateral tumours, more than one primary tumour site and a family history of specific cancers. The first step requires a detailed family history containing all maternal and paternal cases of malignant disease, with particular emphasis on age of onset and the site of the primary tumour. Wherever possible, verification of these diagnoses should be gained from pathology records.

Analysis of DNA for mutations in known cancer predisposition genes is performed in a limited number of specialist molecular genetics laboratories using DNA derived from a peripheral blood sample. The gold standard is direct sequencing of the whole gene but this is generally not commercially viable for very large genes such as BRCA1/2. Screening for pathogenic mutations is therefore often limited to analysis of coding regions only, or regions of the genes which carry the greatest density of reported mutations. Additional tests are required to detect gene deletions. A full screen for unknown mutations will take several weeks to process. ‘Predictive testing’, in which genetic testing is directed at establishing whether or not an individual has a specific mutation carried by another family member, is faster.

Genetic counselling

It is essential that any individual considering undergoing genetic screening for an inherited cancer predisposition syndrome receives expert counselling prior to testing and on receiving their result. Patients must be advised that failure to detect a mutation does not always mean that no mutation is present and that further results may become available in the future when genetic testing may become more sophisticated. The roles of genetic counselling are summarized in Box 5.1.

The remainder of this chapter will look in more detail at inherited breast and colorectal cancer, and the most common cancer predisposition syndromes.

Inherited breast cancer

Studies indicate that 20–30% of breast cancer patients report a positive family history of this condition (Box 5.2). Approximately 5% of all breast cancer cases are thought to be due to highly penetrant autosomal dominant cancer predisposition syndromes (Figure 5.2). The two most frequent highly penetrant breast cancer susceptibility genes are BRCA1 and BRCA2 where in some families lifetime penetrance for breast cancer can reach 80% but penetrance is clearly modified by other genetic and environmental factors. Much rarer syndromes including Li–Fraumeni, Cowden, Peutz–Jeghers and hereditary diffuse gastric cancer (HDGC) syndromes can be recognized either by other clinical manifestations or by the pattern of cancers in the family (Table 5.2). Lifetime breast cancer risk for carriers of these mutations is in the order of 20–100%. It is likely that most familial clusters of breast cancer are the consequence of multiple low penetrance cancer susceptibility genes acting in conjunction with environmental factors. Within the last few years a number of large case-control studies have identified variants in DNA repair genes (e.g. CHEK2, ATM, BRIP1 and PALB2), which double the risk of breast cancer. The population prevalence of these variants seems to be in the order of 1–5%.

Figure 5.2 The importance of inherited factors in the aetiology of breast cancer.

Genetics and pathology

BRCA1 and BRCA2 act as classical tumour suppressor genes; inheritance of mutations occurs in an autosomal dominant fashion and loss of the unmutated allele is found in tumour specimens. The precise functions of the BRCA1 and BRCA2 gene products remain unclear but evidence indicates that these proteins are involved in DNA repair and transcription regulation, with additional roles in cell cycle checkpoint control and cytokinesis. Sporadic breast cancers do not contain BRCA1 mutations and very rarely demonstrate BRCA2.

Diagnosis

A number of scoring systems exist to estimate the likelihood of a family carrying BRCA1 or BRCA2 mutations, e.g. the Gail model. Most cancer genetic units recommend screening for BRCA 1/2 mutations if the chance of carrying a mutation is estimated at more than 20%. Oncologists should consider the possibility of an underlying BRCA1/2 mutation in breast cancer patients with the clinical features listed in Box 5.3.

Both BRCA1 and BRCA2 are extremely large genes but screening of all coding regions of the BRCA1 and BRCA2 genes for nonsense mutations can be done within 8 weeks, whilst predictive testing for known mutations can be accomplished within a week. Pre-natal and pre-implantation genetic diagnosis is now available. Over 20% of BRCA1 and BRCA2 screens identify missense mutations.

Primary prevention

For individuals with known BRCA1 or BRCA2 mutations, prophylactic double mastectomy is the most effective preventative measure, reducing the risk of breast cancer by up to 90%. More acceptable to many women is prophylactic oophorectomy which reduces breast cancer rates by 60% and ovarian cancer rates by 95%. The use of chemoprevention with tamoxifen remains controversial.

Secondary prevention

Regular breast screening by mammography, together with clinical breast examinations, has been recommended for all patients with known BRCA1 or BRCA2 mutations for some years. The 2006 National Institute for Health and Clinical Excellence (NICE) guidelines for the management of familial breast cancer include a recommendation for annual MRI surveillance of all BRCA1/2 mutation carriers aged 30–49 as this method of screening has proved more sensitive then mammography. Screening for ovarian cancer remains under investigation.

Treatment of BRCA associated breast cancer

The management of potential BRCA1/2 mutation carriers is summarised in Figure 5.3 and discussed in Chapter 10 on breast cancer.

Figure 5.3 Algorithm for management of potential BRCA1/2 mutation carrier.

Inherited colorectal cancer

Approximately 5% of cases of colorectal cancer are due to an underlying hereditary cancer syndrome, with an increased representation amongst young colorectal cancer patients. Any features listed in Box 5.4 should raise the suspicion of a familial colorectal cancer syndrome.

Most familial cases are due to either hereditary non-polyposis colon cancer (HNPCC), also known as Lynch syndrome, which accounts for an estimated 2–3% of all colorectal cancers or familial adenomatous polyposis coli (FAP), which accounts for less than 1% of all colorectal cancers. The key features of these two syndromes are summarized in Table 5.4.

Table 5.4 Clinical features of FAP and Lynch syndrome

In addition, an increased risk of gastrointestinal cancer is also observed in Peutz–Jeghers syndrome, caused by the inheritance of mutations in STK11.

Li–Fraumeni syndrome

First described in 1969, classic Li–Fraumeni syndrome (LFS), is a rare cancer susceptibility syndrome characterized by an autosomal dominant pattern of diverse neoplasms in children and young adults with a predominance of soft tissue sarcomas, osteosarcoma, and breast cancer and an excess of brain tumours, leukaemia, and adrenocortical carcinomas (see Box 5.6 for definition of classic LFS). Many additional tumours have also been reported in LFS families (see Table 5.6).

Table 5.6 Component tumours of classic Li–Fraumeni syndrome and other tumours associated with LFS

Cowden syndrome

Cowden syndrome is an autosomally dominant inherited cancer predisposition syndrome characterized by multiple hamartomas and a high risk of thyroid and breast cancers, with other tumours also at increased frequency.

A clinical diagnosis of Cowden syndrome is currently made according to the International Cowden Consortium operational criteria (see Table 5.7).

Table 5.7 Criteria for clinical diagnosis of Cowden syndrome

Retinoblastoma

Retinoblastoma is a rare primary malignant tumour of the retina. Unilateral tumours usually present before the age of 4 years (median age 18 months) whilst bilateral tumours present even earlier (median age 13 months). Only 5–10% of patients have a positive family history. Second primary tumours are seen in a quarter of surviving patients with hereditary retinoblastoma, occurring up to 40 years after the initial event. These include sarcomas, melanoma, brain tumours, breast cancers and leukaemia.

Von Hippel–Lindau syndrome

Von Hippel–Lindau (VHL) is a rare hereditary cancer syndrome consisting of haemangioblastomas of the retina and central nervous system (particularly cerebellar, medullary and spinal sites), associated with phaeochromocytomas and clear cell renal carcinomas. It is inherited in an autosomal dominant fashion. Hereditary phaeochromocytomas present earlier and are more frequently multiple than sporadic phaeochromocytomas but are less likely to undergo malignant transformation. Renal tumours occur in 25% of VHL families, presenting at a median age of 45 years. They are also more likely to be bilateral than sporadic renal carcinomas.

Multiple neuroendocrine neoplasia syndromes

The multiple endocrine neoplasia (MEN) syndromes are autosomal dominant disorders characterized by the development of multiple benign and malignant tumours of endocrine glands. The key clinical features of MEN1, MEN2A and MEN2B are summarized in Table 5.9.

Summary

In any oncology clinic, a patient with an inherited cancer syndrome will be a rarity. However, identification of the correct underlying high risk genetic mutation can have significant consequences for both the patient and their family by ensuring that the appropriate clinical interventions are adopted to minimize their morbidity from malignant disease. It is therefore essential to document a full family history for all patients presenting with cancer and to refer all patients that do have clinical features suspicious of a hereditary cancer predisposition syndrome for expert assessment and advice.

Acknowledgement

With thanks to Professor Diana Eccles for her helpful comments.