Structural fetal anomalies complicate up to 5% of pregnancies and an underlying chromosomal or genetic etiology underlies up to half of cases. Understanding the fetal genome is increasingly key in attempting to make a prenatal diagnosis and in delineating a prognosis for the baby. Over the past decades, the field of prenatal genomics has advanced exponentially, beginning with the conventional ‘full’ karyotype available in the 1960s and going up to the present day and beyond with the application of next-generation sequencing (NGS) (Figure 4.1). Current and potential future advances in prenatal diagnostics will allow couples to make more informed decisions prospectively about their pregnancies in addition to aiding decisions on and the development of fetal therapies [1]. In the wake of advancing technologies and large prospective studies such as the United Kingdom’s ‘proof of principle’ 100 000 Genomes Project [2] and the Prenatal Assessment of Genomes and Exomes (PAGE) study [3], the degree of information obtained and turnaround time of results with the development of more sophisticated bioinformatic analytical pathways is likely to improve rapidly. Fetal medicine subspecialists, obstetricians, pediatricians, geneticists, genomic scientists and genetic counselors have a responsibility to stay up to date with this wealth of advances so that couples can be informed accordingly.

Head and neck cancer

General

Squamous carcinomas of the head and neck (a grouping which includes tongue and mouth, nasopharynx and larynx) are associated with cigarette smoking and alcohol ingestion (although the risk factors for different sites may differ). In addition, specific head and neck cancers may be associated with familial cancer syndromes such as hereditary non-polyposis colon cancer syndrome and Li–Fraumeni syndrome (larynx) and Fanconi anaemia (oral cancer). Foulkes et al. (1996) reported a relative risk of 3.7 for developing head and neck cancer in first-degree relatives of an affected case, but the relative risk was almost 8 if the index case had multiple primaries. Spitz et al. (1994) reported an association between mutagen susceptibility (bleomycin-induced chromosome breakage) and multiple primary head and neck cancers, and while new data from the Spitz group (Wu et al., 2002) and others (Cloos et al., 2000) have confirmed or extended these findings, some researchers have questioned the significance of these observations (Szekely et al., 2003), and the bleomycin sensitivity assay is not used clinically. Interestingly, IGF-1 levels also predict the risk of second primary head and neck cancers, and such an assay could be clinically useful (Wu et al., 2004).

Specific sites

Nasopharynx

Cancers of the nasopharynx account for 0.1 per cent of all cancers, and differ from tumours in other parts of the pharynx by not being associated with tobacco or alcohol.

Renal neoplasms

Cancers of the kidney account for approximately 1.5 per cent of all cancers and cancer deaths (with an incidence of 5-8 per 100 000 population in the UK, and commoner in males). Three main types of renal cancer are distinguished: (1) Wilms tumour, (2) renal cell carcinoma (RCC) (adenocarcinoma) and (3) medullary and transitional cell cancers of the renal pelvis.

Wilms tumour

Wilms tumour is one of the most common solid tumours in children, with an incidence of approximately 10 per 100 000 live births, and accounting for 8 per cent of all childhood cancers. Both sporadic and familial forms occur, although the latter is uncommon and only 1 per cent of Wilms tumour patients have a positive family history (Breslow et al., 1996). Median age at diagnosis of Wilms tumour is 3-4 years and 80 per cent of patients present by the age of 5 years. Approximately 5 per cent of cases have bilateral tumours, and this subgroup has an earlier age at diagnosis (mean 30 months), and an increased incidence of renal blastemal rests and congenital abnormalities (Breslow and Beckwith, 1982). In contrast to retinoblastoma, the age at onset and proportion of bilateral tumours are not significantly different in familial and sporadic cases. There are important associations between Wilms tumour and sporadic aniridia, Beckwith–Wiedemann syndrome, hemihypertrophy, genitourinary abnormalities, Drash syndrome and Perlman syndrome, Frasier syndrome and Simpson–Golabi syndrome (see part three). In addition, Wilms tumour has been associated occasionally with neurofibromatosis type 1, BRCA1 mutations and Bloom syndrome (Rahman et al., 1996).

The ocular tumours discussed in this section include retinoblastoma, haemangioblastoma, optic nerve glioma, meningioma and melanoma. Ocular rhabdomyosarcoma is discussed with rhabdomyosarcoma of other sites on pages 136 and 137. Genetic disorders associated with significant ocular manifestations (neoplastic and non-neoplastic) include neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), von Hippel–Lindau (VHL) disease, tuberose sclerosis and familial adenomatous polyposis (see Part Three).

Retinoblastoma

Retinoblastoma is the commonest malignant ocular tumour of childhood and affects 1 per 20 000 children. The tumour is derived from primitive retinal cells (retinoblasts) and usually presents in early childhood (90 per cent before the age of 5 years). Less than 10 per cent of children with retinoblastoma have a positive family history (where inheritance is autosomal dominant), but new mutations are frequent and approximately 40 per cent of retinoblastoma patients have a genetic predisposition. Retinoblastoma holds a unique place in human cancer genetics as the paradigm of the tumour suppressor gene.

Retinoblastoma typically presents as leukocoria (white eye, cat's eye reflex) or strabismus. It is bilateral in about 30 per cent of cases, and these children have a younger age at diagnosis (mean 8 months) than those with unilateral tumour (mean 25 months). Bilateral or multifocal tumours occur in patients with germline mutations of the retinoblastoma (RB1) gene, but about 15 per cent of children with a single tumour will have a germline mutation.

Bone tumours

In general, sarcomas of bone, muscle or connective tissue are rare, especially in children. Bone tumours comprise about 5 per cent of childhood cancers (3 per cent osteosarcomas and 2 per cent Ewing sarcoma) and their incidence overall is about 10 per million persons in the UK. The age-standardised rate of malignant bone tumours for white children (0–14 years of age) in the SEER Registry, 1983–1992 was 6.4 per million. Soft tissue sarcomas are slightly more common (10 per million). The rates are similar for black children in the same registry, except for Ewing sarcoma, which is nine times less common in black children (Parkin et al., 1993).

Osteosarcoma

Osteogenic sarcoma is commoner in males than in females, and shows two age peaks, one at adolescence and a second, which parallels that of chondrosarcoma, in the sixth and seventh decades. The tumour has a predilection for rapidly growing bone and is commoner in Paget disease. One family with three siblings with Paget disease has been reported. Two developed fatal osteosarcoma (Wu et al., 1991). Children with osteosarcoma are significantly taller at time of diagnosis than are unaffected controls (Gelberg et al., 1997). A similar, but not significant difference is seen for children with Ewing sarcoma. Interestingly, large dogs, such as Great Danes are at higher risk for osteosarcoma than are smaller breeds (Owen, 1967).

Tumours of the gastrointestinal system are among the most common tumours in humans, and although environmental influences have been clearly implicated, heredity is recognised as being of major importance in their aetiology.

Oesophageal tumours

The incidence of squamous cell carcinoma of the oesophagus shows marked geographical variation, with a high frequency in the Caspian littoral of Iran, certain parts of the interior of China and the Transkei region of South Africa, and a low incidence in European and North American whites. Oropharyngeal tumours are also commoner in areas with a high incidence of oesophageal cancer. These findings are thought to be the result of differences in exposure to ingested carcinogens rather than of major genetic factors, although the at-risk individuals who develop this cancer in these high-risk areas are predominantly of Mongol or Turkic origin. The incidence of oesophageal cancer in the UK is 6 per 100 000, and it is commoner in males. Almost all (98 per cent) of oesophageal cancers are squamous carcinomas.

Early studies suggested that genetic factors do not play a major role in most cases of oesophageal cancer as there did not appear to be an increased risk to relatives of index cases (Mosbech and Videbaek, 1955), and recent studies in the United States have been in agreement (Dhillon et al., 2001).

Demand for cancer risk assessment based upon the estimation of the genetic component of cancer risk to a given individual is increasing rapidly. This is both because of increased public awareness of the genetic aspects of cancer susceptibility and as a result of requests from clinicians for evaluation of their patients so that appropriate surveillance protocols can be developed. Risk prediction in common cancers is based upon careful assessment of family history of cancer and cancerrelated syndromes, and a personal history and examination (where appropriate). The genetic risk assessment requires confirmation of the diagnosis in affected relatives whenever possible. Close links with oncologists and clinicians involved in organising surveillance are essential. Joint or multidisciplinary clinics may be appropriate in this context and, ideally, a cancer family clinic network should be developed throughout each region, province or state. Education for primary care physicians should be provided, with guidelines for appropriate referrals.

Genetic counsellors and trained genetic nurses may be increasingly employed in specialised familial cancer clinics in cancer units and primary care, with the remit of assessing empiric cancer risks on the basis of personal and family histories, and to arrange surveillance protocols (audited centrally, if possible) for individuals at moderately increased risk, reassure those at low risk, and refer those at high risk of a genetic cancer susceptibility to the Regional Genetics Centre for further evaluation, advice and management.

Genetic predisposition to skin cancer may involve a variety of mechanisms. Firstly, there is a group of genetic disorders associated with a predisposition to specific skin cancers, and in which the premalignant lesions are primarily confined to the skin (see Table 11.1). These disorders are discussed below under the specific skin cancer involved. A second group comprises hereditary skin disorders which (possibly by virtue of chronic inflammation) predispose to skin cancers (see Table 11.1). These are described after the specific skin cancers (p. 139). The final group includes genetic disorders which (i) predispose to both skin and systemic neoplasms, or (ii) predispose to systemic neoplasia but are associated with cutaneous stigmata. These conditions are discussed in part three and include the chromosome breakage disorders (Bloom syndrome (p. 174), Fanconi anaemia (p. 193), ataxia telangiectasia (p. 167), xeroderma pigmentosum (p. 259), Cowden syndrome (p. 179), dermatitis herpetiformis/coeliac disease (p. 178), Di George syndrome, familial hyperglucagonaemia, Gardner syndrome (p. 184), Gorlin syndrome (p. 196), haemochromatosis, multiple endocrine neoplasia type 2 (MEN2B, p. 224), neurofibromatosis type 1 (NF1, p. 230), porphyria (p. 243), tuberose sclerosis (p. 246) and tylosis (p. 252).

Specific skin cancers

With Julia A Newton-Bishop

Melanoma is a relatively uncommon cancer, with an incidence in most of Northern Europe of around 10 per 100 000 per annum (Parkin et al., 1997). In many countries, and particularly in the UK, it is more common in women.

Thyroid tumours

The incidence of primary epithelial cancer of the thyroid is 0.7 per 100 000 in males and 1.9 per 100 000 in females in the UK. Overall, the annual incidence of thyroid cancer is between 0.9 and 5.2 per 100 000 people, with a ratio of women to men of 2–3:1. Thyroid cancer is the most rapidly rising incident cancer in women and the second most rapidly rising incident cancer in men in the USA. Whether the papillary or follicular histology is favoured is dependent on the amount of dietary iodine in a particular region. Papillary carcinoma (PTC) accounts for more than 50 per cent of cases in the UK and USA, the next most common type of thyroid cancer being follicular carcinoma (FTC). Less frequent types are medullary (MTC), anaplastic (undifferentiated), Hurthle cell and squamous cell carcinomas. Other non-epithelial malignancies that may be observed in the thyroid include lymphomas and sarcomas, but these are rare.

PTC of the thyroid

Genetic susceptibility to PTC can be seen in familial adenomatous polyposis syndrome (FAP), Cowden syndrome (CS), possibly Carney complex (CNC) and in a familial site-specific syndrome. These syndromes are described in detail in the next section. Thyroid cancers can be detected in 5–25 per cent of FAP patients. It should be noted that there is preliminary evidence that what is commonly referred to as “PTC” in FAP is not identical to classic PTC.

Breast cancer

Background: epidemiology and family history

Breast cancer is the most common cancer in women, accounting for 20 per cent of all new cases of cancer. The lifetime risk of breast cancer in the UK is one in nine females, with an incidence of <10 per 100,000 women aged <30 years, rising to 300 per 100 000 in women aged over 85 years. Similar, but slightly higher rates are seen in North America. It is rare in men (<1 per 100 000). Breast cancer incidence shows marked geographical variation: it is much less common in Asian than in Caucasian women, and less frequent in South America and Spain than in Northern Europe, North America and Australia. In India, the prevalence is lower (although rising) except amongst Parsee women. In North America, the incidence of breast cancer appears to have increased in recent years; some of this increase is due to mammographic detection of ductal carcinoma in situ leading to early diagnosis of minimally-invasive ductal carcinoma.

In 1948, Penrose and colleagues observed that breast cancer may have a hereditary basis in some families (Penrose et al., 1948). A genetic influence on breast cancer susceptibility is suggested by twin studies, as the concordance for breast cancer in identical twins (0.28) is more than twice that in dizygotic twins (0.12) (Petrakis, 1977; Bishop and Gardner, 1980).