The predominant environmental factors in the causation of cancer include chemicals, ionizing and ultraviolet radiation, as well as specific infectious agents, predominantly viruses. Although the majority of these agents may have as a principal component of their etiological mechanism some interaction with and/or alteration of the cellular genome, neoplastic disease resulting from the action of such agents is not generally thought of as hereditary or genetic disease. The term hereditary or genetic disease usually connotes an abnormality transmitted through the germline from parent to offspring. In this sense it is reasonable to state that, in considering all cases of human neoplasia, most cancers are not the direct result of heredity but are acquired through an interaction of the host with the environment. However, the interaction of the environment with the genetic composition of the host, either directly or indirectly through the regulation of the expression of the host genome, is important in the development of all human and animal neo- plasms. Therefore, although relatively few human neoplasms exhibit a clearly defined Mende- lian pattern of heredity, polygenic and multifactorial inheritance may play a significant role in increasing the risk of cancer for a large number of humans. This discussion centers largely on hereditary factors in human cancer, because there is a larger body of knowledge on this subject in this species; however, germline genetic factors in the development of cancer in lower animals are also considered.
DOMINANT AND RECESSIVE DISORDERS ASSOCIATED WITH A HIGH INCIDENCE OF HUMAN CANCER
Although the total number of cases of human cancer with a distinct Mendelian genetic mode of inheritance is small relative to the incidence of neoplasia in general, a variety of autosomal and sex-linked disorders, both dominant and recessive, are associated with or clearly causative of specific neoplasms both in humans and in animals. For obvious reasons, the largest number of examples of such conditions have been described and studied in humans. Some of these are listed in Table 5.1, with the associated neoplasm(s) and the mode of inheritance of the specific condition.
In the majority of autosomal recessive disorders, the principal biochemical defect con- cerns some aspects of DNA metabolism or chromosomal structure, especially DNA repair. The lack of capacity of cells from patients with xeroderma pigmentosum to repair ultraviolet damage to their DNA is well known (cf. Cleaver, 1990). Studies of mutations in this disease have led to the finding and characterization of 14 or more genes (Hoeijmakers, 1994) involved in nucleotide
excision repair (Chapter 3). Other autosomal recessive diseases with associated increased inci- dences of neoplasia may exhibit genetic abnormalities related to defects in the maintenance or repair of the structure of the genome. These include Bloom syndrome, Fanconi anemia, and ataxia telangiectasia (cf. Hanawalt and Sarasin, 1986). Several diseases in this category, such as Bloom syndrome, although manifest in all tissues, do not result in cancer of a wide variety of tissues, but the malignant lesions in such diseases are limited to specific and often uncommon organ sites (German, 1993). Individuals heterozygous for these diseases show little if any clini- cal abnormalities (Heim et al., 1992) with the exception of patients heterozygous for the gene of ataxia telangiectasia. A number of sites for cancer development have been reported in such heterozygous individuals (Swift et al., 1990), but a significant excess cancer risk occurs only for the breast in female relatives of ataxia telangiectasia patients (Easton, 1994). From an estimate of 1.4% incidence of ataxia telangiectasia heterozygotes in the U.S. population, Swift et al. (1990) have suggested that 9% to 18% of all cases of breast cancer in this country may occur in women heterozygous for mutation(s) in the ataxia telangiectasia gene, which has recently been cloned (Savitsky et al., 1995).
In addition to the specific disease entities mentioned above and listed in the table, it is now apparent that some individuals exhibit higher spontaneous mutation rates, as monitored by chro- mosome breakage rates, than other individuals (see below). Furthermore, it has been reported (Pero et al., 1989) that individuals with a family history of cancer exhibit a significant reduction in unscheduled DNA synthesis resulting from DNA repair, as evidenced in mononuclear leuko- cytes, compared with individuals with no family history of any major cancer. These factors, to- gether with the evidence that certain nonneoplastic diseases that may be associated with an increased incidence of malignancy can also exhibit chromosomal instability—e.g., sarcoidosis (Okabe et al., 1986), Down’s syndrome (Countryman et al., 1977), celiac disease (Fundia et al.,
1994), and ulcerative colitis (Emerit et al., 1972)—suggest that a significant segment of the population may be at increased genetic risk for the development of neoplasia because of abnor- malities in chromosomal stability. Several aspects of this phenomenon are considered later in this chapter.
Almost all of the neoplasms resulting from the diseases listed in Table 5.1 show the fol- lowing characteristics: (1) a relatively early age of the clinical onset of the neoplasm, the same histogenetic type of neoplasm often occurring 20 or more years earlier than its occurrence in the general population in the absence of a specific genetic background; (2) an unusual excess of neoplasms occurring bilaterally in paired organs such as breast, adrenal, thyroid, kidney, acous- tic nerve; (3) the appearance of multiple primary or multicentric cancers in nonpaired organs at a much higher frequency than seen in comparable histogenetic neoplasms not having a genetic basis; and (4) a predominance of autosomal dominant inheritance (Lynch et al., 1979).
Autosomal dominant disorders associated with an increased incidence of neoplasia usu- ally exhibit an increase in one or a few specific types of neoplasms. One such disorder is familial polyposis of the colon, which is primarily associated with numerous polyps and ultimately carci- nomas of the large bowel. A related and probably identical condition is Gardner syndrome, which was originally felt to involve primarily adenomas of the small bowel as well as other neo- plasms, including those of the thyroid gland and the ampulla of Vater. However, recent investiga- tions (Iida et al., 1989) strongly argue that these two conditions are the same disease, because both exhibit tumors in the tissues mentioned above as well as osteomas, benign tumors of soft tissue (desmoids), medulloblastomas of the cerebellum (Jagelman, 1991), and hepatoblastomas (cf. Bülow, 1989). Chromosomes of cells, both intestinal and others, have been found by a num- ber of investigators to exhibit both numerical and structural aberrations (Gardner et al., 1982; Takai et al., 1986), and the morphology of skin fibroblasts grown in cell culture from patients with familial polyposis/Gardner syndrome exhibits changes indicating that such cells are abnor-
the development of neoplasms in a variety of tissues as well as the cellular changes noted above.
Clinically, a closely related disease is hereditary nonpolyposis colorectal cancer (HNPCC), which was initially described by Warthin but studied most extensively by Lynch and his associates (1995). This disease differs from hereditary polyposis, discussed above, in that very few adenomas or polyps are present in affected individuals, their incidence not being in- creased relative to the general population (cf. Smyrk, 1994). The adenomas that are present are more often villous than polypoid, with a flat, spreading pattern that has a much greater tendency to progress to malignancy. As in familial polyposis, patients develop colon cancer at a young age and exhibit multiple cancers of the colon, with almost three-fourths occurring proximal to the splenic flexure (cf. Smyrk, 1994). Originally this disease was termed the “cancer family syn- drome,” because several other sites where neoplasia commonly developed in these patients had been noted. These included the endometrium, small intestine, stomach, ovary, and genitourinary tract (Watson and Lynch, 1993). HNPCC is decidedly more prevalent than familial polyposis, its occurrence being estimated at from 2% to 6% of all colorectal cancers (Kee and Collins, 1991; Lynch et al., 1991). If one considers individuals less than 35 years of age, the percentage exhib- iting this genetic abnormality increases dramatically (Liu et al., 1995).
Another autosomal dominant condition in which neoplasms, primarily of mesenchymal origin, have been reported is that of von Recklinghausen neurofibromatosis. This condition is a relatively common trait, with a frequency of about 1 in 3000. Although the heterogeneous nature of the disease was recognized by von Recklinghausen himself, only recently has the disease been separated into at least two distinct clinical pictures, termed neurofibromatosis 1 and 2. The latter has also been termed bilateral acoustic neurofibromatosis (Martuza and Eldridge, 1988). Neurofibromatosis 1 affects approximately 100,000 people in the United States and is character- ized by multiple brown skin macules (café au lait spots), intertriginous freckling, iris hamarto- mas (Lisch nodules), and multiple skin neurofibromas. Other benign mesenchymal tumors, neurological impairment, and bone abnormalities may also be seen. The hallmark of neurofibro- matosis 2 is bilateral acoustic neuromas. Patients with mutations in the neurofibromatosis 2 gene are usually severely affected, and offspring show that the gene is almost completely penetrant. As with adenomas in familial polyposis, the neurofibromas may degenerate into neurofibro- sarcomas and malignant schwannomas. In addition, other neoplasms—such as rhabdomyosar- coma, leukemia, pheochromocytoma, and Wilms tumor—may also be found in these patients (Riccardi, 1981). Another autosomal dominant disease affecting the skin is the dysplastic nevus syndrome, which is associated with a marked increase in atypical (dysplastic) nevi of the skin, which exhibit a propensity to develop into malignant melanomas, especially in younger affected individuals (Greene, 1984; Goldstein et al., 1994). Although there have been examples of the dysplastic nevus syndrome in patients with neurofibromatosis (Stokkel et al., 1993), a more ex- tensive study revealed no significant excess of cancers other than malignant melanoma in pa- tients with the dysplastic nevus syndrome (Tucker et al., 1993). Interestingly, at least two studies (Lynch et al., 1993; Caporaso et al., 1987) reported that nonneoplastic cells of patients with the dysplastic nevus syndrome exhibited significant chromosomal instability.
In various tissues with symmetrical distribution within the human body—including the retina, kidney, breast, and thyroid—the bilateral occurrence of neoplasia at a relatively early age usually indicates an autosomal dominant form of disease. Perhaps best known of these condi- tions is bilateral retinoblastoma, which is also clinically inherited as an autosomal dominant condition. The hereditary form of the disease represents about 40% of all cases of retinoblas- toma; of these, 15% are unilateral and 25% bilateral. The remaining 60% are nonhereditary and unilateral (cf. Newsham et al., 1995). With respect to the hereditary form, there is nearly a 50% risk that a child of an affected parent will receive the gene for the retinoblastoma, with a 90% chance (penetrance) of manifesting the neoplasm. Complete penetrance (50% incidence) re- sulted in offspring from parents with bilateral hereditary retinoblastoma, while only 42% of off- spring of parents with hereditary unilateral retinoblastoma exhibited the disease (cf. Newsham et al., 1995). The vast majority of cases becine manifest during the first few years of life, and many patients may be treated successfully for this disease. However, such individuals have a drama- tically increased risk of developing other neoplasms later in life, especially sarcomas of bone and connective tissue, malignant melanoma, neoplasms of the brain, and a variety of other can- cers (Eng et al., 1993). Mortality from a second neoplasm is dramatically greater in patients with bilateral retinoblastoma than in those with unilateral disease. In addition, while somewhat con- troversial in the past, the study by Eng and his associates clearly indicates that patients with bilateral hereditary retinoblastoma receiving radiotherapy have a significantly greater risk of de- veloping second primary neoplasms. This finding conforms to the results of a number of other studies indicating that cells of patients with hereditary retinoblastoma exhibit a hypersensitivity to DNA-damaging agents, including ionizing radiation (Heras and Larripa, 1988).
Another example of a bilateral neoplasm exhibiting an autosomal dominant mode of in- heritance is Wilms tumor of the kidney. The incidence of synchronous bilateral Wilms tumor varies between 4.4% and 9% of all cases (Mesrobian, 1988); Knudson and Strong (1972) have presented evidence that all bilateral cases and a substantial number of unilateral cases of Wilms tumor are the result of a germinal mutation. On this basis, although the exact incidence of the hereditary form of Wilms tumor is not as clear as that of retinoblastoma, more than 10% of all cases of Wilms tumor exhibit a Mendelian type of inheritance. Furthermore, most cases of the hereditary form arise in multiple sites in both kidneys, at times producing a condition known as nephroblastomatosis, a phenomenon related to the normal method of growth of the renal blast- ema (Mesrobian, 1988). Of patients with bilateral Wilms tumor, 60% also exhibit various con- genital abnormalities, the most common of which is aniridia. In this latter instance, the combination of Wilms tumor with aniridia (lack of ocular irises), genitourinary malformations, and mental retardation forms a syndrome known as the WAGR syndrome. Two other syndromes in which Wilms tumor occurs are the Denys-Drash syndrome, in which many patients exhibit intersexual disorders along with the Wilms tumor, and the Beckwith-Wiedemann syndrome, in which patients sometimes exhibit Wilms tumor in association with enlargement of a number of organs. Genes for each of these conditions occur near that for Wilms tumor on the short arm of chromosome 11 (cf. Coppes et al., 1994). Patients with hereditary Wilms tumor show little if any evidence of an increased risk for the development of other neoplasms; however, another autoso- mal dominant condition, von Hippel-Lindau disease (vHL), is manifest by the development of renal adenocarcinoma and, in addition, exhibits complex manifestations in multiple organ sys- tems with tumors, both benign and malignant, in the brain, pancreas, and adrenals (Lamiell et al., 1989). Renal malignancy is seen in about 25% of vHL patients, and about 60% of these exhibit bilateral incidence of neoplasms. Evidence of neoplasia in vHL patients occurs prior to age 40; by careful screening, the diagnosis may be made much earlier. Unlike the histology of Wilms tumor, which exhibits an embryonic pattern, tumors in vHL are renal cell (clear cell) carcinomas or hypernephromas (Linenan et al., 1995). In addition, at least two other forms of hereditary renal cell cancer, one exhibiting a pattern similar to that of vHL and the other exhibit- ing a papillary pattern, have been described (Maher and Yates, 1991; Linenan et al., 1995). Inter- estingly, several investigators (Foster et al., 1994; Shuin et al., 1994; Whaley et al., 1994) have reported that from one-third to more than one-half of sporadic renal cell carcinomas exhibit mu- tations in the vHL gene.
The endocrine system is another organ system exhibiting bilaterality of hereditary neopla- sia. As noted in Table 5.1, there are two general types of multiple endocrine neoplasia (MEN)—types I and II. Type II is separated into A and B subtypes, since the clinical picture in these cases differs somewhat, resulting from different mutations within the affected gene. The bilateral neo- plasms seen in MEN I are those of the parathyroids, small glands associated with the lateral aspects of the thyroid gland, usually occurring in pairs on each side of the neck. Patients exhibit abnormalities in calcium metabolism resulting from the hyperfunctioning of both hyperplasias and neoplasms of the parathyroid. In addition, neoplasms of the pancreatic islet cells as well as the pituitary are found (Bone, 1990). The age of onset of this disease is variable but is rare in childhood and uncommonly seen after age 60. Years may elapse between the discovery of one neoplasm and the appearance of the next (Schimke, 1984). In MEN II, the predominant neo- plasms seen in both the A and B subtypes are medullary thyroid carcinoma and pheochromocy- toma. The A form of this condition also exhibits parathyroid neoplasia, whereas the B form does not. Conversely, the B form exhibits striking facial features, such as enlargement of the lips, and abnormalities of the peripheral nervous system, including neuromatous nodules in and around the mouth, as well as mucosal neuromas in the gastrointestinal tract and other abnormalities of the nerves in the digestive tract, especially the colon. In the A form, the parafollicular C cell of the thyroid becomes focally hyperplastic at an early age; from it, multifocal, bilateral medullary thyroid cancers may develop (Schimke, 1984; Gagel, 1994). Medullary thyroid cancers in the B form develop at an even earlier age and are usually more malignant than those in the A form (Schimke, 1984).
One of the more obvious bilateral organs exhibiting a high incidence of neoplasia is the female breast. The environmental risks associated with the development of breast cancer are the subject of a later chapter (Chapter 10). The genetic risks to relatives of patients with breast can- cer have been a topic of considerable study for the past several decades. In general, the risk of developing breast cancer in immediate relatives of cases diagnosed prior to age 40 is fivefold greater than that in individuals with no family history and twofold greater for relatives of cases diagnosed over age 50 (cf. Easton et al., 1993). The risk of breast cancer is much greater in women with two or more affected first-degree relatives than in women with only one affected relative. The risk of developing breast cancer is also significantly greater in the relatives of metachronous bilateral cases of breast cancer than in those relatives of patients with unilateral breast cancer (Bernstein et al., 1992). These findings, which have developed during the past de- cade, led to the suggestion that a small proportion of breast cancer cases are likely due to the inheritance of a highly penetrant gene, the proportion of genetic cases being highest at younger ages, especially in those under age 30 (Easton et al., 1993). In the last few years, several candi- date genes for dominant breast cancer susceptibility have been discovered and/or proposed (Eeles et al., 1994). In a recent estimation, Friedman et al. (1994) suggested that as many as 1 in
200 women will develop breast cancer over the normal life span as a result of a germline inher- ited susceptibility in the United States. It is likely that more than a single gene is involved in this inherited susceptibility, and breast cancer is still one of the most common genetic diseases in the world. To date the most frequent single gene associated with hereditary breast cancer is the BRCA1 gene, first localized by Hall et al. (1990b) through linkage studies and recently isolated and characterized by Miki and his colleagues (1994). The frequency of significant mutations in the BRCA1 gene contributing to breast and also ovarian cancer has been estimated to be 7 in
10,000 individuals or roughly 0.1% of the population (Easton et al., 1993). For patients bearing a mutated copy of the BRCA1 gene, the cumulative risk of developing breast and ovarian cancer is seen in Figure 5.1. The data in this figure, developed from a study of human patients, are drawn for two different susceptibility alleles or mutations conferring high or moderate risk of ovarian cancer, whereas the same two alleles show little difference in the risk of breast cancer. In contrast, if one considers the proportion of breast cancer cases that result from dominant gene mutations as a function of age at diagnosis, the curves are the reverse of that seen in Figure 5.1
Figure 5.1 Cumulative risks of breast cancer (continuous lines) and ovarian cancer (dashed lines) in car- riers of the BRCA1 mutation. These risk estimates assume allelic heterogeneity in which there are two sus- ceptibility alleles, one of which is associated with a high ovarian cancer risk (1) and the other with moderate to low ovarian cancer risk (2). (Reproduced from Easton et al., 1993, with permission of authors and publisher.)
(Figure 5.2). Interestingly, Tulinius et al. (1994) have presented evidence that the risk of cancer at all sites in relatives of breast cancer patients is increased over that of the general, unrelated population. While this latter study was carried out in Iceland, it still further emphasizes that the genetics of breast cancer development is complex and in many instances, where there is some genetic predisposition, is likely to be multifactorial.
The onset of breast cancer at a relatively early age is also a characteristic of the Li- Fraumeni syndrome, which is a clinically dominant disease in which gene carriers exhibit a high risk of childhood sarcomas, early onset of breast cancer, brain tumors, leukemia, and adrenocor- tical carcinoma (Li et al., 1988; Malkin, 1994). However, this is a relatively rare disease and is causative in far less than 1% of all breast cancers (Eeles et al., 1994). In cultured fibroblasts from these patients, spontaneous aneuploidy and relative resistance to the killing effect of ioniz- ing radiation are noted (Bischoff et al., 1990; Chang et al., 1987). The gene whose mutations are the basis for most patients with the Li-Fraumeni syndrome, the p53 gene, has been well charac- terized and is discussed later.
Although Mendelian inheritance suggests that the genetic constitution of the host is the prime causative factor in the development of benign and malignant neoplasms listed in Table 5.1, it should be obvious that the environment also plays a significant role. This becomes even more important in consideration of the multigenic inheritance of a predisposition to cancer.
Figure 5.2 The proportion of breast cancer cases resulting from dominant mutations in autosomal genes as a function of the age of the patient. (Reproduced from Eeles et al., 1994, with permission of authors and publisher.)